|
1
|
Kallinikas G, Haronis G, Kallinika E, Kozyrakis D, Rodinos E, Filios A, Filios P, Mityliniou D, Safioleas K, Zarkadas A, Bozios D, Karmogiannis A, Konstantinopoulos V, Konomi AM, Ektesabi AM, Tsoporis JN. A Brief Overview of Cholinergic and Phosphodiesterase-5 Inhibitors in Diabetic Bladder Dysfunction. Int J Mol Sci 2024; 25:10704. [PMID: 39409033 PMCID: PMC11476953 DOI: 10.3390/ijms251910704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 09/25/2024] [Accepted: 10/01/2024] [Indexed: 10/20/2024] Open
Abstract
Diabetic bladder dysfunction (DBD) comprises a wide spectrum of lower urinary tract symptoms that impact diabetic patients' lives, including urinary frequency, urgency, incontinence, and incomplete bladder emptying. To relieve symptoms, anticholinergics have been widely prescribed and are considered an effective treatment. There is increasing evidence that diabetic patients may benefit from the use of phosphodiesterase 5 (PDE5) inhibitors. This narrative review aims to provide a brief overview of the pathophysiology of DBD along with a focus on cholinergic and phosphodiesterase inhibitors as therapies that benefit DBD. An examination of the literature suggests compelling avenues of research and underscores critical gaps in understanding the mechanisms underlying DBD. New tools and models, especially rodent models, are required to further elucidate the mechanisms of action of current therapies in the treatment of DBS.
Collapse
Affiliation(s)
- Georgios Kallinikas
- Department of Urology, Konstantopouleion–Patision Hospital, N. Ionia, 14233 Attika, Greece; (G.K.); (G.H.); (D.K.); (E.R.); (A.F.); (P.F.); (D.M.); (K.S.); (A.Z.); (D.B.); (A.K.); (V.K.); (A.M.K.)
| | - Georgios Haronis
- Department of Urology, Konstantopouleion–Patision Hospital, N. Ionia, 14233 Attika, Greece; (G.K.); (G.H.); (D.K.); (E.R.); (A.F.); (P.F.); (D.M.); (K.S.); (A.Z.); (D.B.); (A.K.); (V.K.); (A.M.K.)
| | - Eirini Kallinika
- Department of Molecular Biology and Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| | - Diomidis Kozyrakis
- Department of Urology, Konstantopouleion–Patision Hospital, N. Ionia, 14233 Attika, Greece; (G.K.); (G.H.); (D.K.); (E.R.); (A.F.); (P.F.); (D.M.); (K.S.); (A.Z.); (D.B.); (A.K.); (V.K.); (A.M.K.)
| | - Evangelos Rodinos
- Department of Urology, Konstantopouleion–Patision Hospital, N. Ionia, 14233 Attika, Greece; (G.K.); (G.H.); (D.K.); (E.R.); (A.F.); (P.F.); (D.M.); (K.S.); (A.Z.); (D.B.); (A.K.); (V.K.); (A.M.K.)
| | - Athanasios Filios
- Department of Urology, Konstantopouleion–Patision Hospital, N. Ionia, 14233 Attika, Greece; (G.K.); (G.H.); (D.K.); (E.R.); (A.F.); (P.F.); (D.M.); (K.S.); (A.Z.); (D.B.); (A.K.); (V.K.); (A.M.K.)
| | - Panagiotis Filios
- Department of Urology, Konstantopouleion–Patision Hospital, N. Ionia, 14233 Attika, Greece; (G.K.); (G.H.); (D.K.); (E.R.); (A.F.); (P.F.); (D.M.); (K.S.); (A.Z.); (D.B.); (A.K.); (V.K.); (A.M.K.)
| | - Despoina Mityliniou
- Department of Urology, Konstantopouleion–Patision Hospital, N. Ionia, 14233 Attika, Greece; (G.K.); (G.H.); (D.K.); (E.R.); (A.F.); (P.F.); (D.M.); (K.S.); (A.Z.); (D.B.); (A.K.); (V.K.); (A.M.K.)
| | - Konstantinos Safioleas
- Department of Urology, Konstantopouleion–Patision Hospital, N. Ionia, 14233 Attika, Greece; (G.K.); (G.H.); (D.K.); (E.R.); (A.F.); (P.F.); (D.M.); (K.S.); (A.Z.); (D.B.); (A.K.); (V.K.); (A.M.K.)
| | - Anastasios Zarkadas
- Department of Urology, Konstantopouleion–Patision Hospital, N. Ionia, 14233 Attika, Greece; (G.K.); (G.H.); (D.K.); (E.R.); (A.F.); (P.F.); (D.M.); (K.S.); (A.Z.); (D.B.); (A.K.); (V.K.); (A.M.K.)
| | - Dimitrios Bozios
- Department of Urology, Konstantopouleion–Patision Hospital, N. Ionia, 14233 Attika, Greece; (G.K.); (G.H.); (D.K.); (E.R.); (A.F.); (P.F.); (D.M.); (K.S.); (A.Z.); (D.B.); (A.K.); (V.K.); (A.M.K.)
| | - Athanasios Karmogiannis
- Department of Urology, Konstantopouleion–Patision Hospital, N. Ionia, 14233 Attika, Greece; (G.K.); (G.H.); (D.K.); (E.R.); (A.F.); (P.F.); (D.M.); (K.S.); (A.Z.); (D.B.); (A.K.); (V.K.); (A.M.K.)
| | - Vasileios Konstantinopoulos
- Department of Urology, Konstantopouleion–Patision Hospital, N. Ionia, 14233 Attika, Greece; (G.K.); (G.H.); (D.K.); (E.R.); (A.F.); (P.F.); (D.M.); (K.S.); (A.Z.); (D.B.); (A.K.); (V.K.); (A.M.K.)
| | - Anna Maria Konomi
- Department of Urology, Konstantopouleion–Patision Hospital, N. Ionia, 14233 Attika, Greece; (G.K.); (G.H.); (D.K.); (E.R.); (A.F.); (P.F.); (D.M.); (K.S.); (A.Z.); (D.B.); (A.K.); (V.K.); (A.M.K.)
| | - Amin M. Ektesabi
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON M5B 1W8, Canada
| | - James N. Tsoporis
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON M5B 1W8, Canada
| |
Collapse
|
|
2
|
Muñoz JP, Calaf GM. Acetylcholine, Another Factor in Breast Cancer. BIOLOGY 2023; 12:1418. [PMID: 37998017 PMCID: PMC10669196 DOI: 10.3390/biology12111418] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 11/08/2023] [Accepted: 11/09/2023] [Indexed: 11/25/2023]
Abstract
Acetylcholine (ACh) is a neurotransmitter that regulates multiple functions in the nervous system, and emerging evidence indicates that it could play a role in cancer progression. However, this function is controversial. Previously, we showed that organophosphorus pesticides decreased the levels of the enzyme acetylcholinesterase in vivo, increasing ACh serum levels and the formation of tumors in the mammary glands of rats. Furthermore, we showed that ACh exposure in breast cancer cell lines induced overexpression of estrogen receptor alpha (ERα), a key protein described as the master regulator in breast cancer. Therefore, here, we hypothesize that ACh alters the ERα activity through a ligand-independent mechanism. The results here reveal that the physiological concentration of ACh leads to the release of Ca+2 and the activity of MAPK/ERK and PI3K/Akt pathways. These changes are associated with an induction of p-ERα and its recruitment to the nucleus. However, ACh fails to induce overexpression of estrogen-responsive genes, suggesting a different activation mechanism than that of 17ß-estradiol. Finally, ACh promotes the viability of breast cancer cell lines in an ERα-dependent manner and induces the overexpression of some EMT markers. In summary, our results show that ACh promotes breast cancer cell proliferation and ERα activity, possibly in a ligand-independent manner, suggesting its putative role in breast cancer progression.
Collapse
Affiliation(s)
- Juan P. Muñoz
- Laboratorio de Bioquímica, Departamento de Química, Facultad de Ciencias, Universidad de Tarapacá, Arica 1000007, Chile;
| | - Gloria M. Calaf
- Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile
| |
Collapse
|
|
3
|
Dalkir FT, Aydinoglu F, Ogulener N. The role of rhoA/rho-kinase and PKC in the inhibitory effect of L-cysteine/H 2S pathway on the carbachol-mediated contraction of mouse bladder smooth muscle. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:2023-2038. [PMID: 36894621 DOI: 10.1007/s00210-023-02440-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 02/20/2023] [Indexed: 03/11/2023]
Abstract
We investigated the role of RhoA/Rho-kinase (ROCK) and PKC in the inhibitory effect of L-cysteine/hydrogen sulfide (H2S) pathway on the carbachol-mediated contraction of mouse bladder smooth muscle. Carbachol (10-8-10-4 M) induced a concentration-dependent contraction in bladder tissues. L-cysteine (H2S precursor; 10-2 M) and exogenous H2S (NaHS; 10-3 M) reduced the contractions evoked by carbachol by ~ 49 and ~ 53%, respectively, relative to control. The inhibitory effect of L-cysteine on contractions to carbachol was reversed by 10-2 M PAG (~ 40%) and 10-3 M AOAA (~ 55%), cystathionine-gamma-lyase (CSE) and cystathionine-β-synthase (CBS) inhibitor, respectively. Y-27632 (10-6 M) and GF 109203X (10-6 M), a specific ROCK and PKC inhibitor, respectively, reduced contractions evoked by carbachol (~ 18 and ~ 24% respectively), and the inhibitory effect of Y-27632 and GF 109203X on contractions was reversed by PAG (~ 29 and ~ 19%, respectively) but not by AOAA. Also, Y-27632 and GF 109203X reduced the inhibitory responses of L-cysteine on the carbachol-induced contractions (~ 38 and ~ 52% respectively), and PAG abolished the inhibitory effect of L-cysteine on the contractions in the presence of Y-27632 (~ 38%). Also, the protein expressions of CSE, CBS, and 3-MST enzymes responsible for endogenous H2S synthesis were detected by Western blot method. H2S level was increased by L-cysteine, Y-27632, and GF 109203X (from 0.12 ± 0.02 to 0.47 ± 0.13, 0.26 ± 0.03, and 0.23 ± 0.06 nmol/mg respectively), and this augmentation in H2S level decreased with PAG (0.17 ± 0.02, 0.15 ± 0.03, and 0.07 ± 0.04 nmol/mg respectively). Furthermore, L-cysteine and NaHS reduced carbachol-induced ROCK-1, pMYPT1, and pMLC20 levels. Inhibitory effects of L-cysteine on ROCK-1, pMYPT1, and pMLC20 levels, but not of NaHS, were reversed by PAG. These results suggest that there is an interaction between L-cysteine/H2S and RhoA/ROCK pathway via inhibition of ROCK-1, pMYPT1, and pMLC20, and the inhibition of RhoA/ROCK and/or PKC signal pathway may be mediated by the CSE-generated H2S in mouse bladder.
Collapse
Affiliation(s)
- Fatma Tugce Dalkir
- Department of Pharmacology, Medical Faculty, Cukurova University, Adana, Turkey
| | - Fatma Aydinoglu
- Department of Pharmacology, Pharmacy Faculty, Cukurova University, Adana, Turkey
| | - Nuran Ogulener
- Department of Pharmacology, Medical Faculty, Cukurova University, Adana, Turkey.
| |
Collapse
|
|
4
|
Marghich M, Amrani O, Karim A, Harit T, Beyi L, Mekhfi H, Bnouham M, Aziz M. Myorelaxant and antispasmodic effects of the essential oil of Artemisia campestris L., and the molecular docking of its major constituents with the muscarinic receptor and the L-type voltage-gated Ca 2+channel. JOURNAL OF ETHNOPHARMACOLOGY 2023; 311:116456. [PMID: 37019158 DOI: 10.1016/j.jep.2023.116456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 03/26/2023] [Accepted: 04/01/2023] [Indexed: 06/19/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Gastrointestinal disorders are among the most common diseases that cause discomfort to people who are affected. In Morocco, aromatic and medicinal plants are widely used to calm these pains and eliminate their symptoms. Among these plants, Artemisia campestris L. which is used in eastern Morocco to treat digestive system problems. AIM OF THE STUDY Our study aimed to experimentally verify the traditional use of this plant by evaluating the myorelaxant and antispasmodic effects of the essential oil of Artemisia campestris L. (EOAc). MATERIALS AND METHODS Gas Chromatography-Mass Spectrometry analysis (GC-MS) was performed to identify the compounds present in the EOAc. Then, these molecules were subjected to the in silico study for molecular docking. The myorelaxant and antispasmodic evaluation of the EOAc were tested in vitro on an isolated rabbit and rat jejunum mounted on an organ bath. Then, an isotonic transducer connected to an amplifier recorded the graph related to intestinal contractility. RESULTS GC-MS analysis of the essential oil of Artemisia campestris L. showed the presence of m-Cymene (17.308%), Spathulenol (16.785%), β Pinene (15.623%), α Pinene (11.352%), α.-Campholenal (8.848%) as main constituents. The EOAc gave a dose-dependent and reversible myorelaxant effect on the spontaneous contractions of jejunum isolated from rabbits, with an IC50 equal to 72.16 ± 15.93 μg/mL. This effect did not occur through adrenergic receptors. The EOAc has an antispasmodic effect on the contractions of rat jejunal induced by a medium with low (25 mM) or high concentration (75 mM) of KCl, and carbachol 10-6 M. The obtained inhibitory effects are comparable to those of a non-competitive antagonist of cholinergic receptors. The major compounds of EOAc allowed the establishment of a relationship between these phytoconstituents and the antispasmodic effect found by the EOAc. The obtained results are also supported by a docking study. CONCLUSION The obtained results confirm favorably the use of Artemisia campestris L. in traditional Moroccan medicine for the treatment of digestive tract illness, which gives us a new route to valorize the effects obtained by a phytomedicine specific for the digestive tract.
Collapse
Affiliation(s)
- Mohamed Marghich
- Laboratory of Bioresources, Biotechnology, Ethnopharmacology and Health, Department of Biology, Faculty of Sciences, Mohammed First University, 60000 Oujda, Morocco.
| | - Ouafa Amrani
- Laboratory of Bioresources, Biotechnology, Ethnopharmacology and Health, Department of Biology, Faculty of Sciences, Mohammed First University, 60000 Oujda, Morocco
| | - Ahmed Karim
- Laboratory of Bioresources, Biotechnology, Ethnopharmacology and Health, Department of Biology, Faculty of Sciences, Mohammed First University, 60000 Oujda, Morocco
| | - Tarik Harit
- Laboratory of Applied Chemistry and Environment, Faculty of Sciences, Mohammed First University, 60000 Oujda, Morocco
| | - Leila Beyi
- Laboratory of Bioresources, Biotechnology, Ethnopharmacology and Health, Department of Biology, Faculty of Sciences, Mohammed First University, 60000 Oujda, Morocco; Regional Center for Professions of Education and Training, Oriental Region, 60000 Oujda, Morocco
| | - Hassane Mekhfi
- Laboratory of Bioresources, Biotechnology, Ethnopharmacology and Health, Department of Biology, Faculty of Sciences, Mohammed First University, 60000 Oujda, Morocco
| | - Mohamed Bnouham
- Laboratory of Bioresources, Biotechnology, Ethnopharmacology and Health, Department of Biology, Faculty of Sciences, Mohammed First University, 60000 Oujda, Morocco
| | - Mohammed Aziz
- Laboratory of Bioresources, Biotechnology, Ethnopharmacology and Health, Department of Biology, Faculty of Sciences, Mohammed First University, 60000 Oujda, Morocco
| |
Collapse
|
|
5
|
Corsetti M, Forestier S, Jiménez M. Hyoscine butylbromide mode of action on bowel motility: From pharmacology to clinical practice. Neurogastroenterol Motil 2023; 35:e14451. [PMID: 35972266 DOI: 10.1111/nmo.14451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 06/25/2022] [Accepted: 08/01/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND Hyoscine butylbromide (HBB) has been available for use as an antispasmodic since 1951 and is indicated for the treatment of abdominal pain associated with cramps. A previous review in 2007 summarized the evidence on the mode of action of HBB in vitro and in vivo in both animal and human studies. However, since then, novel publications have appeared within the literature and also our knowledge of what represents normal motility in humans has evolved. PURPOSE This review is the result of the collaboration between a basic scientist and clinicians with the aim of providing an updated overview of the mechanisms of action of HBB and its clinical efficacy to guide not only use in clinical practice, but also future research.
Collapse
Affiliation(s)
- Maura Corsetti
- NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham Digestive Diseases Biomedical Research Centre, Nottingham, UK
| | | | - Marcel Jiménez
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain
| |
Collapse
|
|
6
|
Zhong QM, Zheng YH, Wang JL. Seasonal flexibility of the gut structure and physiology in Eremias multiocellata. J Comp Physiol B 2023; 193:281-291. [PMID: 36995414 DOI: 10.1007/s00360-023-01485-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 03/09/2023] [Accepted: 03/21/2023] [Indexed: 03/31/2023]
Abstract
Although gut seasonal plasticity has been extensively reported, studies on physiological flexibility, such as water-salt transportation and motility in reptiles, are limited. Therefore, this study investigated the intestinal histology and gene expression involved in water-salt transport (AQP1, AQP3, NCC, and NKCC2) and motility regulation (nNOS, CHRM2, and ADRB2) in desert-dwelling Eremias multiocellata during winter (hibernating period) and summer (active period). The results showed that mucosal thickness, the villus width and height, the enterocyte height of the small intestine, and the mucosal and submucosal thicknesses of the large intestine were greater in winter than in summer. However, submucosal thickness of the small intestine and muscularis thickness of the large intestine were lower in winter than in summer. Furthermore, AQP1, AQP3, NCC, nNOS, CHRM2, and ADRB2 expressions in the small intestine were higher in winter than in summer; AQP1, AQP3, and nNOS expressions in the large intestine were lower in winter than in summer, with the upregulation of NCC and CHRM2 expressions; no significant seasonal differences were found in intestinal NKCC2 expression. These results suggest that (i) intestinal water-salt transport activity is flexible during seasonal changes where AQP1, AQP3 and NCC play a vital role, (ii) the intestinal motilities are attenuated through the concerted regulation of nNOS, CHRM2, and ADRB2, and (iii) the physiological flexibility of the small and large intestine may be discrepant due to their functional differences. This study reveals the intestinal regulation and adaptation mechanisms in E. multiocellata in response to the hibernation season.
Collapse
Affiliation(s)
- Qiu-Mei Zhong
- College of Biological Sciences and Engineering, North Minzu University, Yinchuan, 750021, China
- Key Laboratory of Ecological Protection of Agro-Pastoral Ecotones in the Yellow River Basin of National Ethnic Affairs Commission, Yinchuan, 750021, China
| | - Yang-Hui Zheng
- College of Biological Sciences and Engineering, North Minzu University, Yinchuan, 750021, China
- Key Laboratory of Ecological Protection of Agro-Pastoral Ecotones in the Yellow River Basin of National Ethnic Affairs Commission, Yinchuan, 750021, China
| | - Jian-Li Wang
- College of Biological Sciences and Engineering, North Minzu University, Yinchuan, 750021, China.
- Key Laboratory of Ecological Protection of Agro-Pastoral Ecotones in the Yellow River Basin of National Ethnic Affairs Commission, Yinchuan, 750021, China.
| |
Collapse
|
|
7
|
|
|
8
|
Suppression of Inflammatory and Fibrotic Signals by Cinnamon (Cinnamomum cassia) and Cinnamaldehyde in Cyclophosphamide-Induced Overactive Bladder in Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5205759. [PMID: 34976095 PMCID: PMC8716214 DOI: 10.1155/2021/5205759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 11/19/2021] [Accepted: 12/03/2021] [Indexed: 11/18/2022]
Abstract
Cinnamon (Cinnamomum cassia) is a well-known traditional Chinese medicine used to treat nocturia by tonifying and warming the kidney. Our recent clinical study found that overactive bladder (OAB) patients treated with cinnamon powder (CNP) patches exhibited significantly ameliorated OAB symptoms without significant side effects, but the mechanism of action is unclear. To explore the beneficial effects and action mechanisms of CNP and its major active component cinnamaldehyde (CNA) in an OAB-related murine model, cyclophosphamide- (CYP-) induced OAB injury was performed on male ICR mice in the presence or absence of CNP and CNA, as well as solifenacin, a clinical drug for OAB as a reference. Twenty-four-hour micturition patterns (frequency of urination and volume of urine per time), as well as histopathological examination, immunohistochemistry (IHC), and Western blotting of the bladder, were analyzed for mechanism elucidation. Administration of CYP (300 mg/kg, i.p.) induced typical OAB pathophysiological changes, including increased frequency of urination and reduced volume of urine. CYP-induced mice displayed strong edema of the bladder and hemorrhagic cystitis, accompanied by loss of normal corrugated folds and decreased muscarinic receptors (M2/M3) in the urothelium, and disordered/broken structures of the lamina propria and detrusor. These changes were correlated with increased leukocyte (CD11b) infiltration colocalized with inflammatory (pp65 NFκB, macrophage migration inhibitory factor (MIF)/Toll-like receptor 4 (TLR4)) and fibrotic (stem cell factor (SCF)/c-Kit, α-smooth muscle actin (α-SMA)/β-catenin) signals. Treatment with CNP (600 mg/kg, p.o.) and CNA (10–50 mg/kg, p.o.), but not solifenacin (50 mg/kg), 30 min after CYP induction significantly ameliorated CYP-induced dysfunction in micturition patterns and pathophysiological changes. CNP and CNA further suppressed MIF/TLR4-associated inflammatory and SCF/c-Kit-related fibrotic signaling pathways. Our findings indicate that suppression of inflammatory and fibrotic signals contributes to the crucial mechanism in the improvement of CYP-induced OAB by CNP and CNA.
Collapse
|
|
9
|
Gut bacteria-derived 5-hydroxyindole is a potent stimulant of intestinal motility via its action on L-type calcium channels. PLoS Biol 2021; 19:e3001070. [PMID: 33481771 PMCID: PMC7857600 DOI: 10.1371/journal.pbio.3001070] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 02/03/2021] [Accepted: 12/29/2020] [Indexed: 12/24/2022] Open
Abstract
Microbial conversion of dietary or drug substrates into small bioactive molecules represents a regulatory mechanism by which the gut microbiota alters intestinal physiology. Here, we show that a wide variety of gut bacteria can metabolize the dietary supplement and antidepressant 5-hydroxytryptophan (5-HTP) to 5-hydroxyindole (5-HI) via the tryptophanase (TnaA) enzyme. Oral administration of 5-HTP results in detection of 5-HI in fecal samples of healthy volunteers with interindividual variation. The production of 5-HI is inhibited upon pH reduction in in vitro studies. When administered orally in rats, 5-HI significantly accelerates the total gut transit time (TGTT). Deciphering the underlying mechanisms of action reveals that 5-HI accelerates gut contractility via activation of L-type calcium channels located on the colonic smooth muscle cells. Moreover, 5-HI stimulation of a cell line model of intestinal enterochromaffin cells results in significant increase in serotonin production. Together, our findings support a role for bacterial metabolism in altering gut motility and lay the foundation for microbiota-targeted interventions.
Collapse
|
|
10
|
Orjatsalo M, Partinen E, Wallukat G, Alakuijala A, Partinen M. Activating autoantibodies against G protein-coupled receptors in narcolepsy type 1. Sleep Med 2020; 77:82-87. [PMID: 33341642 DOI: 10.1016/j.sleep.2020.11.038] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 11/26/2020] [Accepted: 11/29/2020] [Indexed: 12/01/2022]
Abstract
STUDY OBJECTIVES Narcolepsy type 1 is a rare hypersomnia of central origin, which is caused by loss of hypothalamic neurons that produce the neuropeptides hypocretin-1 and -2. Hypocretin-containing nerve terminals are found in areas known to play a central role in autonomic control and in pain signaling. Cholinergic M2 receptors are found in brain areas involved with the occurrence of hallucinations and cataplexy. In addition to classical symptoms of narcolepsy, the patients suffer frequently from autonomic dysfunction, chronic pain, and hypnagogic/hypnopompic hallucinations. We aimed to test whether narcolepsy type 1 patients have autoantibodies against autonomic β2 adrenergic receptor, M2 muscarinic receptors, or nociception receptors. METHODS We tested the serum of ten narcolepsy type 1 patients (five female) for activating β2 adrenergic receptor autoantibodies, M2 muscarinic receptor autoantibodies, and nociception receptor autoantibodies. RESULTS Ten of ten patients were positive for muscarinic M2 receptor autoantibodies (P < 0.001), 9/10 were positive for autoantibodies against nociception receptors (P < 0.001), and 5/10 were positive for β2 adrenergic receptor autoantibodies (P < 0.001). CONCLUSIONS Narcolepsy type 1 patients harbored activating autoantibodies against M2 muscarinic receptors, nociception receptors, and β2 adrenergic receptors. M2 receptor autoantibodies may be related to the occurrence of cataplexy and, moreover, hallucinations in narcolepsy since they are found in the same brain areas that are involved with these symptoms. The occurrence of nociception receptor autoantibodies strengthens the association between narcolepsy type 1 and pain. The connection between narcolepsy type 1, autonomic complaints, and the presumed cardiovascular morbidity might be associated with the occurrence of β2 adrenergic receptor autoantibodies. On the other hand, the presence of the autoantibodies may be secondary to the destruction of the hypocretin pathways.
Collapse
Affiliation(s)
- Maija Orjatsalo
- Department of Clinical Neurophysiology, HUS Medical Imaging Center, Helsinki University Hospital, Finland; Department of Neurological Sciences, University of Helsinki, Helsinki, Finland.
| | - Eemil Partinen
- Department of Neurological Sciences, University of Helsinki, Helsinki, Finland; Vitalmed Research Center, Helsinki Sleep Clinic, Valimotie 21, 00380, Helsinki, Finland
| | | | - Anniina Alakuijala
- Department of Clinical Neurophysiology, HUS Medical Imaging Center, Helsinki University Hospital, Finland; Department of Neurological Sciences, University of Helsinki, Helsinki, Finland
| | - Markku Partinen
- Department of Neurological Sciences, University of Helsinki, Helsinki, Finland; Vitalmed Research Center, Helsinki Sleep Clinic, Valimotie 21, 00380, Helsinki, Finland
| |
Collapse
|
|
11
|
Pant J, Mohan L, S S. Avian gut experiments: an alternative approach for teaching the properties of intestinal smooth muscles. ADVANCES IN PHYSIOLOGY EDUCATION 2020; 44:295-304. [PMID: 32484404 DOI: 10.1152/advan.00195.2019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Experiments on isolated mammalian gut are essential components of the physiology curriculum worldwide. Over the years, these routine experiments have been largely replaced by simulation modules, to reduce the euthanization of animals for understanding established facts and mechanisms in gut physiology. However, a medical undergraduate needs hands-on training to handle a living tissue to have a better understanding of physiology. The present sourcebook update describes the use of avian gut, which is usually discarded in abattoirs, as an effective replacement of mammalian gut to understand basic gut smooth muscle physiology. The avian gut can be used to study the effect of various drugs and ions as used in mammalian gut experiments. The experiment protocol described in the update can be performed by students of basic sciences and medical students using minimal laboratory set up and at low cost, producing results comparable to mammalian gut experiments. Ethical permissions may not be necessary; however, the disposal of tissue waste has to follow proper guidelines.
Collapse
Affiliation(s)
- Jayanti Pant
- Department of Physiology, All India Institute of Medical Sciences, Rishikesh (Uttarakhand), India
| | - Latika Mohan
- Department of Physiology, All India Institute of Medical Sciences, Rishikesh (Uttarakhand), India
| | - Srikant S
- Department of Physiology, All India Institute of Medical Sciences, Rishikesh (Uttarakhand), India
| |
Collapse
|
|
12
|
Bhargava T, Srivastava D, Kumar A, Singh TK, Sahu S. Intravesical dexmedetomidine in renal transplant recipients: A potential step to reduce postoperative catheter-related discomfort. J Clin Anesth 2020; 67:110010. [PMID: 32862073 DOI: 10.1016/j.jclinane.2020.110010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/17/2020] [Accepted: 07/25/2020] [Indexed: 11/26/2022]
Affiliation(s)
- Tanvi Bhargava
- Anesthesia Department of Anesthesiology, Dr Ram Manohar Lohia Hospital and Postgraduate Institute of Medical Education and Research, New Delhi, India
| | - Divya Srivastava
- Anesthesia Department of Anesthesiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Abhishek Kumar
- Anesthesia Department of Oncoanesthesia and Palliative Medicine Brairch, Aiims, New Delhi, India.
| | - Tapas Kumar Singh
- Anesthesia Department of Anesthesiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Sandeep Sahu
- Anesthesia Department of Anesthesiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| |
Collapse
|
|
13
|
Yarullina DR, Shafigullin MU, Sakulin KA, Arzamastseva AA, Shaidullov IF, Markelova MI, Grigoryeva TV, Karpukhin OY, Sitdikova GF. Characterization of gut contractility and microbiota in patients with severe chronic constipation. PLoS One 2020; 15:e0235985. [PMID: 32678865 PMCID: PMC7367488 DOI: 10.1371/journal.pone.0235985] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 06/25/2020] [Indexed: 12/12/2022] Open
Abstract
Chronic constipation (CC) is one of the most common gastrointestinal disorders worldwide. Its pathogenesis, however, remains largely unclear. The purpose of the present work was to gain an insight into the role of contractility and microbiota in the etiology of CC. To this end, we studied spontaneous and evoked contractile activity of descending colon segments from patients that have undergone surgery for refractory forms of CC. The juxta-mucosal microbiota of these colon samples were characterized with culture-based and 16S rRNA sequencing techniques. In patients with CC the spontaneous colonic motility remained unchanged compared to the control group without dysfunction of intestinal motility. Moreover, contractions induced by potassium chloride and carbachol were increased in both circular and longitudinal colonic muscle strips, thus indicating preservation of contractile apparatus and increased sensitivity to cholinergic nerve stimulation in the constipated intestine. In the test group, the gut microbiota composition was assessed as being typically human, with four dominant bacterial phyla, namely Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria, as well as usual representation of the most prevalent gut bacterial genera. Yet, significant inter-individual differences were revealed. The phylogenetic diversity of gut microbiota was not affected by age, sex, or colonic anatomy (dolichocolon, megacolon). The abundance of butyrate-producing genera Roseburia, Coprococcus, and Faecalibacterium was low, whereas conventional probiotic genera Lactobacillus and Bifidobacteria were not decreased in the gut microbiomes of the constipated patients. As evidenced by our study, specific microbial biomarkers for constipation state are absent. The results point to a probable role played by the overall gut microbiota at the functional level. To our knowledge, this is the first comprehensive characterization of CC pathogenesis, finding lack of disruption of motor activity of colonic smooth muscle cells and insufficiency of particular members of gut microbiota usually implicated in CC.
Collapse
Affiliation(s)
- Dina R. Yarullina
- Department of Microbiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Republic of Tatarstan, Russian Federation
- * E-mail: ,
| | - Marat U. Shafigullin
- Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Republic of Tatarstan, Russian Federation
| | - Kirill A. Sakulin
- Department of Surgical Diseases, Kazan State Medical University, Kazan, Republic of Tatarstan, Russian Federation
| | - Anastasiia A. Arzamastseva
- Department of Microbiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Republic of Tatarstan, Russian Federation
| | - Ilnar F. Shaidullov
- Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Republic of Tatarstan, Russian Federation
| | - Maria I. Markelova
- "Omics Technologies" Laboratory, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Republic of Tatarstan, Russian Federation
| | - Tatiana V. Grigoryeva
- "Omics Technologies" Laboratory, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Republic of Tatarstan, Russian Federation
| | - Oleg Yu. Karpukhin
- Department of Surgical Diseases, Kazan State Medical University, Kazan, Republic of Tatarstan, Russian Federation
| | - Guzel F. Sitdikova
- Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Republic of Tatarstan, Russian Federation
| |
Collapse
|
|
14
|
Bassiouni W, Senbel A, Norel X, Daabees T. Sildenafil corrects the increased contractility of rat detrusor muscle induced by alprostadil in vitro. Pharmacol Rep 2019; 71:659-668. [PMID: 31195343 DOI: 10.1016/j.pharep.2019.03.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 02/09/2019] [Accepted: 03/11/2019] [Indexed: 01/09/2023]
Abstract
BACKGROUND Sildenafil (PDE5-inhibitor) and alprostadil (PGE1) are used in combination clinically for the management of some cases of erectile dysfunction. Despite the roles of prostaglandins (PG) and nitric oxide (NO) pathways in contractility of bladder smooth muscle are frequently studied, the effect of sildenafil/alprostadil combination and the crosstalk between NO/cGMP and PG pathways on bladder activity is not documented. METHODS Organ-bath experiments were performed using isolated rat detrusor muscle. Direct and neurogenic contractions were induced using ACh and electric stimulation (EFS, 4Hz, 80V, 1ms), respectively. The contractile responses in absence and presence of the tested drugs at different concentrations were compared. Results are expressed as mean ± SEM (n = 5-7). RESULTS Alprostadil (0.01-10 μM) concentration-dependently potentiated ACh (100μM)- and EFS (4 Hz)- induced contraction. Maximum potentiation of ACh-contraction in presence of alprostadil was 40 ± 5%. Sildenafil potentiated ACh-induced contraction at low concentrations (0.01-1 μM), but inhibited it at higher ones (10-100 μM). IBMX (non-selective PDE-inhibitor, 0.01-100μM) and SNP (NO-donor, 1nM-1 mM) produced the same biphasic pattern. The potentiatory phase of sildenafil was inhibited by atropine (0.1μM), L-NAME (non-selective NOS-inhibitor, 100μM), N-PLA (nNOS-inhibitor, 30μM) or MB (nonselective GC-inhibitor, 10μM). In presence of sildenafil (0.1μM), the concentration-response curve of alprostadil (0.01-10μM) on both ACh and EFS-induced contraction was clearly shifted downward. CONCLUSIONS A crosstalk between PGE1 and NO/cGMP pathways may exist. At low concentrations only, the effect of sildenafil on bladder contractility is dependent on NO/cGMP. cGMP intracellularly-elevated by sildenafil, may inhibit the activity of PLC and hence the cascade of EP1-receptors, thus masking the hyperactivity of bladder caused by alprostadil, which adds to the advantages of this combination.
Collapse
Affiliation(s)
- Wesam Bassiouni
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt
| | - Amira Senbel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt; Laboratory for Vascular Translational Sciences, INSERM U1148, X. Bichat Hospital, University Paris XIII, France.
| | - Xavier Norel
- Laboratory for Vascular Translational Sciences, INSERM U1148, X. Bichat Hospital, University Paris XIII, France
| | - Tahia Daabees
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt
| |
Collapse
|
|
15
|
Paily A, Preziosi G, Trivedi P, Emmanuel A. Anti-muscarinic drugs increase rectal compliance and exacerbate constipation in chronic spinal cord injury : Anti-muscarinic drug effect on neurogenic bowel. Spinal Cord 2019; 57:662-668. [PMID: 30804425 DOI: 10.1038/s41393-019-0263-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 02/12/2019] [Accepted: 02/13/2019] [Indexed: 12/15/2022]
Abstract
STUDY DESIGN Prospective cohort study OBJECTIVES: We hypothesized that anti-muscarinic agents alter rectal compliance in SCI patients and that altered rectal compliance relates to bowel symptomatology. Our primary aim was to compare rectal compliance before and after the institution of anti-muscarinics (solifenacin and tolterodine) and an adrenoceptor agonist (mirabegron) in these patients. Additionally, we wanted to evaluate if anorectal manometry differed before and after use of anti-muscarinic agents. SETTING Tertiary neurogastroenterology clinic, London METHODS: Thirty-five patients with supraconal spinal cord injury (SCI) underwent anal manometry, assessment of rectoanal inhibitory reflex (RAIR) and rectal compliance before and after anti-muscarinic treatment (for overactive bladder) was started (mean follow-up 12 weeks). Patients were assessed identically, pre-and post-treatment (solifenacin n = 17, tolterodine n = 10, mirabegron n = 8). Doses used were as for non-SCI patients. RESULTS Resting, squeeze and cough pressures were unchanged after anti-muscarinic treatment. Rectal compliance was significantly raised after anti-muscarinic treatment (p = 0.001). The percent amplitude of maximal sphincter relaxation of the RAIR was decreased (p < 0.001) and excitation latency was increased (p = 0.006). There was no significant change in the duration of recovery of the RAIR. There was a significant increase of the Wexner Constipation Score (p = 0.001) but no change in the Wexner Incontinence Score. There was a significant correlation between change in rectal compliance and change in Wexner Constipation Score (p = 0.001). Thus, increasing compliance of the rectum is associated with worsening of constipation after anti-muscarinic therapy. However, there were no changes in anorectal manometry or rectal compliance in those who received mirabegron. CONCLUSION Anti-muscarinic therapy for overactive bladder increases compliance of the neurogenic rectum and alters anorectal reflex activity, with worsening of constipation.
Collapse
Affiliation(s)
- Abhilash Paily
- Department of GI Physiology, University College London Hospital, 235 Euston Road, London, NW1 2BU, UK. .,Department of Gastroenterology, Spinal Injuries Unit, Royal National Orthopaedic Hospital, Brockley Hill, Stanmore, Middlesex, HA7 4LP, UK.
| | - Guiseppe Preziosi
- Department of GI Physiology, University College London Hospital, 235 Euston Road, London, NW1 2BU, UK
| | - Prateesh Trivedi
- Department of GI Physiology, University College London Hospital, 235 Euston Road, London, NW1 2BU, UK
| | - Anton Emmanuel
- Department of GI Physiology, University College London Hospital, 235 Euston Road, London, NW1 2BU, UK.,Department of Gastroenterology, Spinal Injuries Unit, Royal National Orthopaedic Hospital, Brockley Hill, Stanmore, Middlesex, HA7 4LP, UK
| |
Collapse
|
|
16
|
Hypoactivity of rat detrusor muscle in a model of cystitis: exacerbation by non-selective COX inhibitors and amelioration by a selective DP 1 receptor antagonist. Naunyn Schmiedebergs Arch Pharmacol 2018; 392:437-450. [PMID: 30552456 DOI: 10.1007/s00210-018-01599-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 11/27/2018] [Indexed: 01/25/2023]
Abstract
Various studies have confirmed that prostaglandins (PG) alter the bladder motor activity and micturition reflex in both human and animals. However, no sufficient data is reported about the effect of cyclooxygenase (COX) inhibitors neither in normal bladder physiology nor in pathological conditions. This study aims to compare the potential effects of some COX inhibitors with varying COX-1/COX-2 selectivities (indomethacin, ketoprofen, and diclofenac) with that of the selective COX-2 inhibitor (DFU) on bladder function. The role played by some PGs and their receptors in controlling detrusor muscle function in normal condition and in cystitis is also studied. Organ bath experiments were performed using isolated rat detrusor muscle. Direct and neurogenic contractions were induced using ACh and electric stimulation (EFS), respectively. A model of hemorrhagic cystitis was induced by single injection of cyclophosphamide (300 mg/kg) in rats, and confirmed by histophathological examination. Results are expressed as mean ± SEM of 5-9 rats. Alprostadil and iloprost (1 nM- 10 µM) concentration-dependently potentiated ACh (100 μM)- and EFS (4 Hz)-induced contraction, with maximum potentiation of 40.01 ± 5.29 and 27.59 ± 6.64%, respectively, in case of ACh contractions. In contrast, ONO-AE1-259 (selective EP2 agonist, 1 nM-10 μM) inhibited muscle contraction. SC51322 (EP1-antagonist, 10 μM) and RO1138452 (IP antagonist, 10 μM) inhibited both direct and neurogenic responses. Hemorrhagic cystitis reduced both ACh and EFS responses as well as the potentiatory effect of iloprost and the inhibitory effect of RO1138452 on ACh contractions. ONO-AE3-237 (DP1 antagonist, 1 μM) significantly potentiated contractions in cystitis but showed no effect in normal bladder. A significant inhibition of contractile response was observed in presence of indomethacin, ketoprofen, and diclofenac at all tested concentrations (20, 50, and 100 μM). Highest effect was induced by diclofenac. The effect of these COX inhibitors on EFS contractions was intensified in case of cystitis, indomethacin being the most potent. Atropine (1 nM) significantly reduced indomethacin effect on ACh contraction only in normal rats. On the other hand, DFU (10-6 M) significantly potentiated the contractile effect of ACh in case of cystitis although it showed no effect in normal rats. EP1 receptors seem to play an important role in rat bladder contractility. DP1 receptors as COX-2, on the other hand, gain an important role only in case of cystitis. The use of non-selective COX inhibitors in cystitis may be associated with bladder hypoactivity; selective COX-2 inhibitors may be a safer option.
Collapse
|
|
17
|
Frias B, Phillips AA, Squair JW, Lee AHX, Laher I, Krassioukov AV. Reduced colonic smooth muscle cholinergic responsiveness is associated with impaired bowel motility after chronic experimental high-level spinal cord injury. Auton Neurosci 2018; 216:33-38. [PMID: 30196037 DOI: 10.1016/j.autneu.2018.08.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Revised: 08/29/2018] [Accepted: 08/31/2018] [Indexed: 02/07/2023]
Abstract
The mechanisms underlying bowel dysfunction after high-level spinal cord injury (SCI) are poorly understood. However, impaired supraspinal sympathetic and parasympathetic control is likely a major contributing factor. Disruption of the descending autonomic pathways traversing the spinal cord was achieved by a T3 complete spinal cord transection, and colonic function was examined in vivo and ex vivo four weeks post-injury. Total gastrointestinal transit time (TGTT) was reduced and contractility of the proximal and distal colon was impaired due to reduced M3 receptor sensitivity. These data describe a clinically relevant model of bowel dysfunction after SCI.
Collapse
Affiliation(s)
- B Frias
- International Collaboration on Repair Discoveries, University of British Columbia, Canada.
| | - A A Phillips
- International Collaboration on Repair Discoveries, University of British Columbia, Canada; Experimental Medicine Program, University of British Columbia, Canada; Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Canada.
| | - J W Squair
- International Collaboration on Repair Discoveries, University of British Columbia, Canada
| | - A H X Lee
- International Collaboration on Repair Discoveries, University of British Columbia, Canada; Experimental Medicine Program, University of British Columbia, Canada.
| | - I Laher
- Department of Anaesthesiology, Pharmacology and Therapeutics, University of British Columbia, Canada.
| | - A V Krassioukov
- International Collaboration on Repair Discoveries, University of British Columbia, Canada; Experimental Medicine Program, University of British Columbia, Canada; Division of Physical Medicine and Rehabilitation, Department of Medicine, University of British Columbia, Canada; GF Strong Rehabilitation Center, Vancouver Coastal Health, Vancouver, BC, Canada.
| |
Collapse
|
|
18
|
Chatturong U, Kajsongkram T, Tunsophon S, Chanasong R, Chootip K. Ginger Extract and [6]-Gingerol Inhibit Contraction of Rat Entire Small Intestine. J Evid Based Integr Med 2018; 23:2515690X18774273. [PMID: 29756476 PMCID: PMC5954582 DOI: 10.1177/2515690x18774273] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
This study aims to investigate the effect of oral administration and the direct action of ginger extract or [6]-gingerol on small intestinal contractility. The direct effect of 10 minutes preincubation of ginger ethanolic extract (10, 100 and 300 μg/mL) or [6]-gingerol (1, 30, and 100 μM) on 0.01 to 30 μM ACh-induced contractions of all parts of the small intestine isolated from normal rats was investigated using the organ bath technique. For in vivo study, the rats were orally administered with extract (10, 20, and 100 mg/kg/d) or [6]-gingerol (2 mg/kg/d) for 7 days, followed by determining the contractile responses to ACh of rat isolated duodenum, jejunum, and ileum and their histology were assessed. Direct application of the extract or [6]-gingerol attenuated ACh-induced contractions in each small intestinal segment, Emax was reduced by 40% to 80%, while EC50 increased 3- to 8-fold from control. Similarly, in the in vivo study ACh-induced contractions were reduced in all parts of the small intestine isolated from rats orally treated with ginger extract (20 and 100 mg/kg/d) or [6]-gingerol (2 mg/kg/d). Emax decreased 15% to 30%, while EC50 increased 1- to 3-fold compared to control. No discernable changes in the histology of intestinal segments were detectable. Thus, the results support the clinical application of ginger for disorders of gastrointestinal motility.
Collapse
Affiliation(s)
| | - Tanwarat Kajsongkram
- 2 Thailand Institute of Scientific and Technological Research, Pathum Thani, Thailand
| | | | | | | |
Collapse
|
|
19
|
Nagano H, Sobue Y, Matsuyama H, Saito S, Sakai H, Alom F, Tanahashi Y, Ishii T, Unno T. Muscarinic M 2 receptor promotes vasopressin synthesis in mice supraoptic nuclei. J Endocrinol 2018; 237:207-216. [PMID: 29563233 DOI: 10.1530/joe-17-0630] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 03/21/2018] [Indexed: 11/08/2022]
Abstract
Muscarinic acetylcholine receptors have been suggested to be implicated in arginine-vasopressin secretion because intracerebroventricular muscarinic agonist administration induces arginine-vasopressin release into the circulation. Although which subtype is involved in the regulation of arginine-vasopressin secretion is unclear, M2 receptors have been reported to be highly expressed in the hypothalamus. In the present study, M2 receptor-knockout mice were used to elucidate whether M2 receptor regulates arginine-vasopressin synthesis in the paraventricular nuclei and supraoptic nuclei of the hypothalamus. The number of arginine-vasopressin-immunoreactive neurons in M2 receptor-knockout mice was significantly decreased in the supraoptic nuclei, but not in the paraventricular nuclei compared with wild-type mice. Plasma arginine-vasopressin level in M2 receptor-knockout mice was also significantly lower than in the wild-type mice. Urinary volume and frequency as well as water intake in M2 receptor-knockout mice were significantly higher than those in wild-type mice. The V2 vasopressin receptor expression in kidneys of M2 receptor-knockout mice was comparable with that of wild-type mice, and increased urination in M2 receptor-knockout mice was significantly decreased by administration of desmopressin, a specific V2 receptor agonist, suggesting that V2 receptors in the kidneys of M2 receptor-knockout mice are intact. These results suggest that M2 receptors promote arginine-vasopressin synthesis in the supraoptic nuclei and play a role in the regulation and maintenance of body fluid.
Collapse
Affiliation(s)
- Hiroshi Nagano
- Department of Pathogenetic Veterinary ScienceUnited Graduate School of Veterinary Science, Gifu University, Gifu, Japan
| | - Yuki Sobue
- Laboratory of Veterinary PharmacologyFaculty of Applied Biological Science, Gifu University, Gifu, Japan
| | - Hayato Matsuyama
- Laboratory of Veterinary PharmacologyFaculty of Applied Biological Science, Gifu University, Gifu, Japan
| | - Shoichiro Saito
- Laboratory of Veterinary AnatomyFaculty of Applied Biological Science, Gifu University, Gifu, Japan
| | - Hiroki Sakai
- Laboratory of Veterinary PathologyFaculty of Applied Biological Science, Gifu University, Gifu, Japan
| | - Firoj Alom
- Department of Pathogenetic Veterinary ScienceUnited Graduate School of Veterinary Science, Gifu University, Gifu, Japan
| | - Yasuyuki Tanahashi
- Department of Animal Medical SciencesFaculty of Life Science, Kyoto Sangyo University, Kyoto, Japan
| | - Toshiaki Ishii
- Department of Basic Veterinary MedicineObihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan
| | - Toshihiro Unno
- Laboratory of Veterinary PharmacologyFaculty of Applied Biological Science, Gifu University, Gifu, Japan
| |
Collapse
|
|
20
|
Berndt-Paetz M, Herbst L, Weimann A, Gonsior A, Stolzenburg JU, Neuhaus J. Highly specific detection of muscarinic M3 receptor, G protein interaction and intracellular trafficking in human detrusor using Proximity Ligation Assay (PLA). Acta Histochem 2018; 120:329-339. [PMID: 29551457 DOI: 10.1016/j.acthis.2018.03.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2017] [Revised: 02/08/2018] [Accepted: 03/09/2018] [Indexed: 01/06/2023]
Abstract
PURPOSE Muscarinic acetylcholine receptors (mAChRs) regulate a number of important physiological functions. Alteration of mAChR expression or function has been associated in the etiology of several pathologies including functional bladder disorders (e.g bladder pain syndrome/interstitial cystitis - BPS/IC). In a previous study we found specific mAChR expression patterns associated with BPS/IC, while correlation between protein and gene expression was lacking. Posttranslational regulatory mechanisms, e.g. altered intracellular receptor trafficking, could explain those differences. In addition, alternative G protein (GP) coupling could add to the pathophysiology via modulation of muscarinic signaling. In our proof-of-principle study, we addressed these questions in situ. We established PLA in combination with confocal laserscanning microscopy (CLSM) and 3D object reconstruction for highly specific detection and analysis of muscarinic 3 receptors (M3), G protein (GP) coupling and intracellular trafficking in human detrusor samples. MATERIAL AND METHODS Paraffin sections of formalin-fixed bladder tissue (FFPE) of BPS/IC patients receiving transurethral biopsy were examined by Cy3-PLA for M3 expression, coupling of M3 to GPs (Gαq/11, Gαs, Gαi) and interaction of M3 with endocytic regulator proteins. Membranes were labeled with wheat germ agglutinin-Alexa Fluor®488, nuclei were stained with DAPI. Object density and co-localization were analyzed in 3D-reconstruction of high resolution confocal z-stacks. RESULTS Confocal image stack processing resulted in well demarcated objects. Calculated receptor densities correlated significantly with existing confocal expression data, while significantly improved specificity of M3 detection by PLA was verified using bladder tissue samples from transgenic mice. 50-60% of the M3 receptor complexes were plasma membrane associated in human bladder detrusor. Application of PLA for M3 and GPs allowed visualization of M3-GP interactions and revealed individual GP-subtype coupling patterns. Detection of M3 interactions with endocytic trafficking proteins by PLA resulted in object sizes correlating with well-documented vesicle sizes of the endocytosis pathway. CONCLUSION PLA enabled highly specific detection of M3 receptor expression, demonstration of M3/GP differential coupling and intracellular M3 trafficking in human detrusor smooth muscle cells. This new approach minimized background fluorescence and antibody cross-reactions resulting from single antibody application, and enhanced specificity due to the use of two primary antibodies. Use of subcellular markers allowed visualization of subcellular receptor location. PLA/CLSM allows analyses of muscarinic "receptor - G protein - promiscuity" and intracellular trafficking even in bladder paraffin sections and may give new insights into the etiology and pathology of BPS/IC.
Collapse
|
|
21
|
Abstract
BACKGROUND The options for the treatment of diarrhea and constipation are evolving as emerging therapies target small bowel receptors. The goal of this review is to discuss small bowel receptors involved in intestinal absorption, secretion, and motility. The review highlights therapies already approved or currently being studied for the modulation of these receptors. METHODS The articles cited in this review focus on the molecular level of pathways involved in diarrhea and constipation, and highlight the respective pharmacotherapies. RESULTS The majority of the studies in the current literature investigate the effects of both the small and large intestine receptors on diarrhea and constipation. There are fewer studies that isolate the effects of these receptors solely on the small bowel, and focusing more on the receptors found distinctly in the small intestine may be an area of interest for future studies as this can inspire more targeted therapies.
Collapse
Affiliation(s)
- Elizabeth S John
- Department of Internal Medicine, Rutgers Robert Wood Johnson Medical School, 1 RWJ Place, New Brunswick, NJ, 08901, USA.
| | | |
Collapse
|
|
22
|
Franx BAA, Arnoldussen IAC, Kiliaan AJ, Gustafson DR. Weight Loss in Patients with Dementia: Considering the Potential Impact of Pharmacotherapy. Drugs Aging 2017; 34:425-436. [PMID: 28478593 DOI: 10.1007/s40266-017-0462-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Unintentional body weight loss is common in patients with dementia and is linked to cognitive impairment and poorer disease outcomes. It is proposed that some dementia medications with market approval, while aiming to improve cognitive and functional outcomes of a patient with dementia, are associated with reported body weight or body mass index loss. This review presents evidence in the published literature on body weight loss in dementia, describes selected theories behind body weight loss, evaluates the potential impact of approved dementia pharmacotherapies on body weight, considers the potential role for medical foods, understands the potential influence of treatments for neuropsychiatric symptoms and signs, and finally, summarizes this important area.
Collapse
Affiliation(s)
- Bart A A Franx
- Department of Anatomy, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ilse A C Arnoldussen
- Department of Anatomy, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Amanda J Kiliaan
- Department of Anatomy, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Deborah R Gustafson
- Department of Neurology, Section for NeuroEpidemiology, State University of New York, Downstate Medical Center, 450 Clarkson Avenue, Box 1213, Brooklyn, NY, 11203, USA. .,Neuropsychiatric Epidemiology Unit (EPINEP), Institute for Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. .,Department of Health and Education, University of Skövde, Skövde, Sweden.
| |
Collapse
|
|
23
|
Nakato J, Ho YY, Omae R, Mizushige T, Uchida K, Tominaga M, Kim M, Goto T, Takahashi N, Kawada T, Akiduki S, Kanamoto R, Ohinata K. l-Ornithine and l-lysine stimulate gastrointestinal motility via transient receptor potential vanilloid 1. Mol Nutr Food Res 2017; 61. [PMID: 28722259 DOI: 10.1002/mnfr.201700230] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 06/15/2017] [Accepted: 07/04/2017] [Indexed: 01/09/2023]
Abstract
SCOPE The gastrointestinal (GI) tract senses and responds to intraluminal nutrients and these interactions often affect GI functions. We found that, among basic amino acids, l-ornithine (Orn) and l-lysine (Lys) stimulated but l-arginine (Arg) suppressed GI motility after oral administration (24 mmol/kg) in mice (Orn and Lys, 14.3 and 26.4% promotion; Arg, 7.7% suppression). We investigated the mechanism of the action of Orn and Lys on GI motility. METHODS AND RESULTS Orn-induced promotion of small intestinal transit was significantly inhibited (p<0.05) by oral administration of capsazepine, a transient receptor potential vanilloid 1 (TRPV1) antagonist. Moreover, the stimulatory effect of Orn and Lys was abolished in TRPV1-knockout mice. In TRPV1-transfected HEK293 cells, Orn and Lys (10 mM) evoked Ca2+ influx, which was blocked by ruthenium red, a TRP channel antagonist. These results suggest that Orn and Lys promote GI motility via activation of TRPV1. The GI motility stimulation by Orn and Lys was also blocked by atropine, a muscarinic acetylcholine receptor (mAChR) antagonist, or NG -nitro-l-arginine methyl ester, a nitric oxide (NO) synthase inhibitor. CONCLUSION Orally administered Orn and Lys stimulate GI motility via TRPV1, mAChR and NO synthase in mice.
Collapse
Affiliation(s)
- Junya Nakato
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
| | - Yee Yin Ho
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
| | - Ryo Omae
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
| | - Takafumi Mizushige
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan.,Research Unit for Physiological Chemistry, C-PIER, Kyoto University, Kyoto, Japan
| | - Kunitoshi Uchida
- Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), Okazaki, Aichi, Japan.,Department of Physiological Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi, Japan
| | - Makoto Tominaga
- Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), Okazaki, Aichi, Japan.,Department of Physiological Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi, Japan
| | - Minji Kim
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
| | - Tsuyoshi Goto
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan.,Research Unit for Physiological Chemistry, C-PIER, Kyoto University, Kyoto, Japan
| | - Nobuyuki Takahashi
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan.,Research Unit for Physiological Chemistry, C-PIER, Kyoto University, Kyoto, Japan
| | - Teruo Kawada
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan.,Research Unit for Physiological Chemistry, C-PIER, Kyoto University, Kyoto, Japan
| | - Saori Akiduki
- Healthcare Products Development Center, KYOWA HAKKO BIO CO., LTD., Tsukuba, Ibaraki, Japan
| | - Ryuhei Kanamoto
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
| | - Kousaku Ohinata
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
| |
Collapse
|
|
24
|
Xu D, Anderson HD, Tao A, Hannah KL, Linnebur SA, Valuck RJ, Culbertson VL. Assessing and predicting drug-induced anticholinergic risks: an integrated computational approach. Ther Adv Drug Saf 2017; 8:361-370. [PMID: 29090085 PMCID: PMC5638173 DOI: 10.1177/2042098617725267] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 07/19/2017] [Indexed: 11/17/2022] Open
Abstract
Background: Anticholinergic (AC) adverse drug events (ADEs) are caused by inhibition of muscarinic receptors as a result of designated or off-target drug–receptor interactions. In practice, AC toxicity is assessed primarily based on clinician experience. The goal of this study was to evaluate a novel concept of integrating big pharmacological and healthcare data to assess clinical AC toxicity risks. Methods: AC toxicity scores (ATSs) were computed using drug–receptor inhibitions identified through pharmacological data screening. A longitudinal retrospective cohort study using medical claims data was performed to quantify AC clinical risks. ATS was compared with two previously reported toxicity measures. A quantitative structure–activity relationship (QSAR) model was established for rapid assessment and prediction of AC clinical risks. Results: A total of 25 common medications, and 575,228 exposed and unexposed patients were analyzed. Our data indicated that ATS is more consistent with the trend of AC outcomes than other toxicity methods. Incorporating drug pharmacokinetic parameters to ATS yielded a QSAR model with excellent correlation to AC incident rate (R2 = 0.83) and predictive performance (cross validation Q2 = 0.64). Good correlation and predictive performance (R2 = 0.68/Q2 = 0.29) were also obtained for an M2 receptor-specific QSAR model and tachycardia, an M2 receptor-specific ADE. Conclusions: Albeit using a small medication sample size, our pilot data demonstrated the potential and feasibility of a new computational AC toxicity scoring approach driven by underlying pharmacology and big data analytics. Follow-up work is under way to further develop the ATS scoring approach and clinical toxicity predictive model using a large number of medications and clinical parameters.
Collapse
Affiliation(s)
- Dong Xu
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Idaho State University, 1311 East Central Drive, Meridian, ID 83642, USA
| | - Heather D Anderson
- Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Aoxiang Tao
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Idaho State University, Meridian, ID, USA
| | - Katia L Hannah
- School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Sunny A Linnebur
- Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Robert J Valuck
- Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Vaughn L Culbertson
- Department of Pharmacy Practice and Administrative Sciences, College of Pharmacy, Idaho State University, 1311 East Central Drive, Meridian, ID 83642, USA
| |
Collapse
|
|
25
|
Batista-Lima FJ, Gadelha KKL, Oliveira DM, Vasconcelos TB, Brito TS, Magalhães PJC. A simple laboratory exercise with rat isolated esophagus and stomach fundus to reveal functional differences between striated and smooth muscle cells. ADVANCES IN PHYSIOLOGY EDUCATION 2017; 41:291-297. [PMID: 28526693 DOI: 10.1152/advan.00150.2016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 04/03/2017] [Accepted: 04/04/2017] [Indexed: 06/07/2023]
Abstract
This study describes an undergraduate student laboratory activity using isolated preparations from rat gastrointestinal tissues that possess contractile profiles typically exhibited by striated and smooth muscle cells. While students are introduced to an ex vivo methodology, they can compare differences in trace experiments, twitch aspects, phasic and tonic properties, force-frequency relationships, and pharmacological responsiveness of esophageal (striated) and fundic (smooth muscle) segments. Muscle strips were subjected to electrical field stimulation (EFS) applied by platinum electrodes immersed in the physiological solution. The contractile profile of EFS responses varied between these two types of gut preparations. Atropine and tubocurarine revealed differential inhibitory influences in esophagus or fundus tissues; caffeine and procaine produced similar effects, i.e., potentiation and blockade of the EFS-induced contractile response in these tissues, respectively. Experimental results obtained during the activity helped the improvement of student learning about basic concepts previously discussed in theoretical lectures. To measure student learning with this laboratory exercise, a questionnaire was applied before and after the activity, and the number of expected correct answers, concerning the mechanisms of contraction in striated and smooth muscle, could be clearly evidenced.
Collapse
Affiliation(s)
- Francisco José Batista-Lima
- Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Kalinne Kelly Lima Gadelha
- Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Daniel Maia Oliveira
- Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Thiago Brasileiro Vasconcelos
- Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Teresinha Silva Brito
- Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Pedro Jorge Caldas Magalhães
- Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| |
Collapse
|
|
26
|
Kim H, Kim HJ, Yang D, Jung MH, Kim BJ. Depolarizing Effects of Daikenchuto on Interstitial Cells of Cajal from Mouse Small Intestine. Pharmacogn Mag 2017; 13:141-147. [PMID: 28216898 PMCID: PMC5307899 DOI: 10.4103/0973-1296.196312] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 01/21/2016] [Accepted: 01/06/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Daikenchuto (DKT; TJ-100, TU-100), a traditional herbal medicineis used in modern medicine to treat gastrointestinal (GI) functional disorders. Interstitial cells of Cajal (ICCs) are the pacemaker cells of the GI tract and play important roles in the regulation of GI motility. OBJECTIVE The objective of this study was to investigate the effects of DKT on the pacemaker potentials (PPs) of cultured ICCs from murine small intestine. MATERIALS AND METHODS Enzymatic digestions were used to dissociate ICCs from mouse small intestine tissues. All experiments on ICCs were performed after 12 h of culture. The whole-cell patch-clamp configuration was used to record ICC PPs (current clamp mode). All experiments were performed at 30-32°C. RESULTS In current-clamp modeDKT depolarized and concentration-dependently decreased the amplitudes of PPs. Y25130 (a 5-HT3 receptor antagonist) or SB269970 (a 5-HT7 receptor antagonist) did not block DKT-induced PP depolarization, but RS39604 (a 5-HT4 receptor antagonist) did. Methoctramine (a muscarinic M2 receptor antagonist) failed to block DKT-induced PP depolarization, but pretreating 4-diphenylacetoxy-N-methylpiperidine methiodide (a muscarinic M3 receptor antagonist) facilitated blockade of DKT-induced PP depolarization. Pretreatment with an external Ca2+-free solution or thapsigargin abolished PPsand under these conditions, DKT did not induce PP depolarization. Furthermore Ginseng radix and Zingiberis rhizomes depolarized PPs, whereas Zanthoxyli fructus fruit (the third component of DKT) hyperpolarized PPs. CONCLUSION These results suggest that DKT depolarizes ICC PPs in an internal or external Ca2+-dependent manner by stimulating 5-HT4 and M3 receptors. Furthermore, the authors suspect that the component in DKT largely responsible for depolarization is probably also a component of Ginseng radix and Zingiberis rhizomes. SUMMARY Daikenchuto (DKT) depolarized and concentration-dependently decreased the amplitudes of pacemaker potentials (PPs)Y25130 (a 5-HT3 receptor antagonist) or SB269970 (a 5-HT7 receptor antagonist) did not block DKT-induced PP depolarization, but RS39604 (a 5-HT4 receptor antagonist) didMethoctramine (a muscarinic M2 receptor antagonist) failed to block DKT-induced PP depolarization, but pretreating 4-DAMP (a muscarinic M3 receptor antagonist) facilitated blockade of DKT-induced PP depolarizationGinseng radix and Zingiberis rhizomes depolarized PPswhereas Zanthoxyli fructus fruit (the third component of DKT) hyperpolarized PPs. Abbreviation used: DKT: Daikenchuto, GI: Gastrointestinal, ICCs: Interstitial cells of Cajal, PPs: Pacemaker Potentials.
Collapse
Affiliation(s)
- Hyungwoo Kim
- Division of Pharmacology, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Hyun Jung Kim
- Division of Longevity and Biofunctional Medicine and Healthy Aging Korean Medical Research Center, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Dongki Yang
- Department of Physiology, College of Medicine, Gachon University, Incheon, Republic of Korea
| | - Myeong Ho Jung
- Division of Longevity and Biofunctional Medicine and Healthy Aging Korean Medical Research Center, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Byung Joo Kim
- Division of Longevity and Biofunctional Medicine and Healthy Aging Korean Medical Research Center, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| |
Collapse
|
|
27
|
Moreno CA, Metze K, Lomazi EA, Bertola DR, Barbosa RHA, Cosentino V, Sobreira N, Cavalcanti DP. Visceral myopathy: Clinical and molecular survey of a cohort of seven new patients and state of the art of overlapping phenotypes. Am J Med Genet A 2016; 170:2965-2974. [PMID: 27481187 DOI: 10.1002/ajmg.a.37857] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 06/13/2016] [Indexed: 12/14/2022]
Abstract
Visceral motility dysfunction is a key feature of genetic disorders such as megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS, MIM moved from 249210 to 155310), chronic intestinal pseudo-obstruction (CIPO, MIM609629), and multisystemic smooth muscle dysfunction syndrome (MSMDS, MIM613834). The genetic bases of these conditions recently begun to be clarified with the identification of pathogenic variants in ACTG2, ACTA2, and MYH11 in individuals with visceral motility dysfunction. The MMIHS was associated with the heterozygous variant in ACTG2 and homozygous variant in MYH11, while the heterozygous variant in ACTA2 was observed in patients with MSMDS. In this study, we describe the clinical data as well as the molecular investigation of seven individuals with visceral myopathy phenotypes. Five patients presented with MMIHS, including two siblings from consanguineous parents, one had CIPO, and the other had MSMDS. In three individuals with MMIHS and in one with CIPO we identified heterozygous variant in ACTG2, one being a novel variant (c.584C>T-p.Thr195Ile). In the individual with MSMDS we identified a heterozygous variant in ACTA2. We performed the whole-exome sequencing in one sibling with MMIHS and her parents; however, the pathogenic variant responsible for her phenotype could not be identified. These results reinforce the clinical and genetic heterogeneity of the visceral myopathies. Although many cases of MMIHS are associated with ACTG2 variants, we suggest that other genes, besides MYH11, could cause the MMIHS with autosomal recessive pattern. © 2016 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Carolina Araujo Moreno
- Faculty of Medical Sciences, Departmentof Medical Genetics, State University of Campinas, Campinas, Brazil
| | - Konradin Metze
- Faculty of Medical Sciences, Department of Pathology, State University of Campinas, Campinas, Brazil
| | - Elizete Aparecida Lomazi
- Faculty of Medical Sciences, Department of Pediatrics, State University of Campinas, Campinas, Brazil
| | - Débora Romeo Bertola
- Genetic Unit, Faculty of Medicine, Children's Institute, University of São Paulo, São Paulo, Brazil
| | | | - Viviana Cosentino
- CEMIC (Center for Medical Education and Clinical Research), Buenos Aires, Argentina
| | - Nara Sobreira
- Department of Pediatrics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Denise Pontes Cavalcanti
- Faculty of Medical Sciences, Departmentof Medical Genetics, State University of Campinas, Campinas, Brazil.
| |
Collapse
|
|
28
|
Farro G, Gomez-Pinilla PJ, Di Giovangiulio M, Stakenborg N, Auteri M, Thijs T, Depoortere I, Matteoli G, Boeckxstaens GE. Smooth muscle and neural dysfunction contribute to different phases of murine postoperative ileus. Neurogastroenterol Motil 2016; 28:934-47. [PMID: 26891411 DOI: 10.1111/nmo.12796] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 01/15/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND Postoperative ileus (POI) is characterized by a transient inhibition of gastrointestinal (GI) motility after abdominal surgery mediated by the inflammation of the muscularis externa (ME). The aim of this study was to identify alterations in the enteric nervous system that may contribute to the pathogenesis of POI. METHODS Gastrointestinal transit, contractility of isolated smooth muscle strips and inflammatory parameters were evaluated at different time points (1.5 h to 10 days) after intestinal manipulation (IM) in mice. Immune-labeling was used to visualize changes in myenteric neurons. KEY RESULTS Intestinal manipulation resulted in an immediate inhibition of GI transit recovering between 24 h and 5 days. In vitro contractility to K(+) (60 mM) or carbachol (10(-9) to 10(-4) M) was biphasically suppressed over 24 h after IM (with transient recovery at 6 h). The first phase of impaired myogenic contractility was associated with increased expression of TNF-α, IL-6 and IL-1α. After 24 h, we identified a significant reduction in electrical field stimulation-evoked contractions and relaxations, lasting up to 10 days after IM. This was associated with a reduced expression of chat and nos1 genes. CONCLUSIONS & INFERENCES Intestinal manipulation induces two waves of smooth muscle inhibition, most likely mediated by inflammatory cytokines, lasting up to 3 days after IM. Further, we here identify a late third phase (>24 h) characterized by impaired cholinergic and nitrergic neurotransmission persisting after recovery of muscle contractility. These findings illustrate that POI results from inflammation-mediated impaired smooth muscle contraction, but also involves a long-lasting impact of IM on the enteric nervous system.
Collapse
Affiliation(s)
- G Farro
- Division of Gastroenterology, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - P J Gomez-Pinilla
- Division of Gastroenterology, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - M Di Giovangiulio
- Division of Gastroenterology, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - N Stakenborg
- Division of Gastroenterology, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - M Auteri
- Division of Physiology, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - T Thijs
- Division of Gastroenterology, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - I Depoortere
- Division of Gastroenterology, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - G Matteoli
- Division of Gastroenterology, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - G E Boeckxstaens
- Division of Gastroenterology, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| |
Collapse
|
|
29
|
Montgomery LEA, Tansey EA, Johnson CD, Roe SM, Quinn JG. Autonomic modification of intestinal smooth muscle contractility. ADVANCES IN PHYSIOLOGY EDUCATION 2016; 40:104-109. [PMID: 26873897 DOI: 10.1152/advan.00038.2015] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Intestinal smooth muscle contracts rhythmically in the absence of nerve and hormonal stimulation because of the activity of pacemaker cells between and within the muscle layers. This means that the autonomic nervous system modifies rather than initiates intestinal contractions. The practical described here gives students an opportunity to observe this spontaneous activity and its modification by agents associated with parasympathetic and sympathetic nerve activity. A section of the rabbit small intestine is suspended in an organ bath, and the use of a pressure transducer and data-acquisition software allows the measurement of tension generated by the smooth muscle of intestinal walls. The application of the parasympathetic neurotransmitter ACh at varying concentrations allows students to observe an increase in intestinal smooth muscle tone with increasing concentrations of this muscarinic receptor agonist. Construction of a concentration-effect curve allows students to calculate an EC50 value for ACh and consider some basic concepts surrounding receptor occupancy and activation. Application of the hormone epinephrine to the precontracted intestine allows students to observe the inhibitory effects associated with sympathetic nerve activation. Introduction of the drug atropine to the preparation before a maximal concentration of ACh is applied allows students to observe the inhibitory effect of a competitive antagonist on the physiological response to a receptor agonist. The final experiment involves the observation of the depolarizing effect of K(+) on smooth muscle. Students are also invited to consider why the drugs atropine, codeine, loperamide, and botulinum toxin have medicinal uses in the management of gastrointestinal problems.
Collapse
Affiliation(s)
- Laura E A Montgomery
- Centre for Biomedical Sciences Education, Queen's University Belfast, Belfast, United Kingdom
| | - Etain A Tansey
- Centre for Biomedical Sciences Education, Queen's University Belfast, Belfast, United Kingdom
| | - Chris D Johnson
- Centre for Biomedical Sciences Education, Queen's University Belfast, Belfast, United Kingdom
| | - Sean M Roe
- Centre for Biomedical Sciences Education, Queen's University Belfast, Belfast, United Kingdom
| | - Joe G Quinn
- Centre for Biomedical Sciences Education, Queen's University Belfast, Belfast, United Kingdom
| |
Collapse
|
|
30
|
Gao X, Qin Q, Yu X, Liu K, Li L, Qiao H, Zhu B. Acupuncture at heterotopic acupoints facilitates distal colonic motility via activating M3 receptors and somatic afferent C-fibers in normal, constipated, or diarrhoeic rats. Neurogastroenterol Motil 2015; 27:1817-30. [PMID: 26459908 DOI: 10.1111/nmo.12694] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 08/29/2015] [Indexed: 01/18/2023]
Abstract
BACKGROUND Previous studies have demonstrated the efficacy of somatic stimulation for patients with gastrointestinal motility disorders. However, little effort has been made to investigate the effects of acupuncture on colonic motility, particularly in pathological conditions. The precise mechanism employed in the regulation of acupuncture on colonic motility still remains unclear. METHODS We assessed the effect of acupuncture at heterotopic acupoints on distal colonic motility using a warm-water-filled manometric balloon inserted 5-6 cm into the rectum of anesthetized normal rats or rats with diarrhea or constipation. Choline chloride, 4-DAMP, cobra venom and capsaicin were separately applied to investigate the role of M3 receptors in the regulation of distal colonic motility by acupuncture at heterotopic acupoints, and whether Aδ- and/or C-fibers are required for triggering distal colonic motility by acupuncture. KEY RESULTS Acupuncture at heterotopic acupoints increased distal colonic motility not only in normal rats but also in rats with constipation or diarrhea. M3 receptors play an important role in the facilitation of distal colonic motility triggered by acupuncture at heterotopic acupoints. Afferent nerve Aδ- and C-fibers mediate the transduction of the acupuncture signal and C-fibers are essential for enhancing the effect of acupuncture at the heterotopic acupoint on distal colonic motility. CONCLUSIONS & INFERENCES Our results reveal that acupuncture at heterotopic acupoints increases distal colonic motility regardless of normal or pathological conditions via predominately activating C-fibers of somatic afferent nerve and M3 receptors.
Collapse
Affiliation(s)
- X Gao
- Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
| | - Q Qin
- Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
- Department of Acupuncture and Moxibustion, Henan Orthopedics Hospital, Luoyang, Henan Province, China
| | - X Yu
- Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
| | - K Liu
- Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
| | - L Li
- Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
| | - H Qiao
- Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
- Third Clinical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, USA
| | - B Zhu
- Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
| |
Collapse
|
|
31
|
Murine embryonic stem cell line CGR8 expresses all subtypes of muscarinic receptors and multiple nicotinic receptor subunits: Down-regulation of α4- and β4-subunits during early differentiation. Int Immunopharmacol 2015; 29:110-4. [DOI: 10.1016/j.intimp.2015.07.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 07/14/2015] [Accepted: 07/20/2015] [Indexed: 02/06/2023]
|
|
32
|
Sheffrin M, Miao Y, Boscardin WJ, Steinman MA. Weight Loss Associated with Cholinesterase Inhibitors in Individuals with Dementia in a National Healthcare System. J Am Geriatr Soc 2015; 63:1512-8. [PMID: 26234945 PMCID: PMC4737921 DOI: 10.1111/jgs.13511] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
OBJECTIVES To determine whether initiation of cholinesterase inhibitors is associated with significant weight loss in a real-word clinical setting. DESIGN Retrospective cohort study from 2007 to 2010 comparing weight loss in individuals with dementia newly prescribed cholinesterase inhibitors and those newly prescribed other chronic medications. SETTING National Veterans Affairs data. PARTICIPANTS Individuals aged 65 and older with a diagnosis of dementia who received a new prescription for a cholinesterase inhibitor or other new chronic medication. MEASUREMENTS The primary outcome was time to 10-pound weight loss over 12 months. Propensity score matching was used to control for the likelihood of receiving a cholinesterase inhibitor based on baseline characteristics. Data were analyzed in a priori defined subgroups according to age, comorbid burden, and initial weight. RESULTS Of 6,504 individuals that met study criteria, 1,188 started on cholinesterase inhibitors were matched to 2,189 started on other medications. The propensity-matched cohorts were well balanced on baseline covariates. Participants initiated on cholinesterase inhibitors had a higher risk of weight loss than matched controls at 12 months (hazard ratio = 1.23, 95% confidence interval (CI) = 1.07-1.41). At 12 months, 29.3% of participants taking cholinesterase inhibitors had experienced weight loss, compared with 22.8% of nonusers, corresponding to a number needed to harm of 21.2 (95% CI = 12.5-71.4) over 1 year. There were no significant differences in the risk of weight loss within subgroups. CONCLUSION These results are consistent with the available data from randomized controlled trials. Clinicians should consider the risk of weight loss when prescribing cholinesterase inhibitors.
Collapse
Affiliation(s)
- Meera Sheffrin
- Division of Geriatrics, University of California at San Francisco and the San Francisco VA Medical Center, San Francisco, California
| | - Yinghui Miao
- Division of Geriatrics, University of California at San Francisco and the San Francisco VA Medical Center, San Francisco, California
| | - W. John Boscardin
- Division of Geriatrics, University of California at San Francisco and the San Francisco VA Medical Center, San Francisco, California
- Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, California
| | - Michael A. Steinman
- Division of Geriatrics, University of California at San Francisco and the San Francisco VA Medical Center, San Francisco, California
| |
Collapse
|
|
33
|
Mitra R, Aronsson P, Winder M, Tobin G, Bergquist F, Carlsson T. Local Change in Urinary Bladder Contractility Following CNS Dopamine Denervation in the 6-OHDA Rat Model of Parkinson's Disease. JOURNAL OF PARKINSON'S DISEASE 2015; 5:301-11. [PMID: 25697958 PMCID: PMC4923752 DOI: 10.3233/jpd-140509] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND Urinary problems, including urinary frequency, urgency, and nocturia are some of the non-motor symptoms that correlate most with poor quality of life in Parkinson's disease. However, the mechanism behind these symptoms is poorly understood, in particular regarding peripheral bladder pathophysiology following dopamine degeneration. OBJECTIVE In this study, we compared the contractile responsiveness of urinary bladder from the 6-OHDA unilateral rat model of Parkinson's disease with that of normal untreated animals. METHODS The contractility of the urinary detrusor muscle was evaluated in bladder strip preparations using electrical field stimulation, and muscarinic and purinoceptor stimulations in an vitro organ bath setup. RESULTS Our data show that the overall contractile response following electrical field stimulation was significantly higher (43% at maximum contraction by 20-40 Hz stimulation) in the 6-OHDA-lesioned rats as compared to control animals. This increase was associated with a significant increase in the cholinergic contractile response, where the muscarinic agonist methacholine produced a 44% (at 10 -4 M concentration) higher response in the 6-OHDA-treated rats as compared to controls with a significant left-shift of the dose response. This indicates an altered sensitivity of the muscarinic receptor system following the specific central 6-OHDA-induced dopamine depletion. In addition a 36% larger contraction of strips from the 6-OHDA animals was also observed with purinoceptor activation using the agonist ATP (5×10 -3 M) during atropine treatment. CONCLUSIONS Our data shows that it is not only the central dopamine control of the micturition reflex that is altered in Parkinson's disease, but also the local contractile function of the urinary bladder. The current study draws attention to a mechanism of urinary dysfunction in Parkinson's disease that has previously not been described.
Collapse
Affiliation(s)
- Reinika Mitra
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Patrik Aronsson
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Michael Winder
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Gunnar Tobin
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Filip Bergquist
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Thomas Carlsson
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| |
Collapse
|
|
34
|
Qin QG, Gao XY, Liu K, Yu XC, Li L, Wang HP, Zhu B. Acupuncture at heterotopic acupoints enhances jejunal motility in constipated and diarrheic rats. World J Gastroenterol 2014; 20:18271-18283. [PMID: 25561794 PMCID: PMC4277964 DOI: 10.3748/wjg.v20.i48.18271] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Revised: 07/09/2014] [Accepted: 07/30/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect and mechanism of acupuncture at heterotopic acupoints on jejunal motility, particularly in pathological conditions.
METHODS: Jejunal motility was assessed using a manometric balloon placed in the jejunum approximately 18-20 cm downstream from the pylorus and filled with approximately 0.1 mL warm water in anesthetized normal rats or rats with diarrhea or constipation. The heterotopic acupoints including LI11 (Quchi), ST37 (Shangjuxu), BL25 (Dachangshu), and the homotopic acupoint ST25 (Tianshu), were stimulated for 60 s by rotating acupuncture needles right and left at a frequency of 2 Hz. To determine the type of afferent fibers mediating the regulation of jejunal motility by manual acupuncture, the ipsilateral sciatic A or C fibers of ST37 were inactivated by local application of the A-fiber selective demyelination agent cobra venom or the C fiber blocker capsaicin. Methoctramine, a selective M2 receptor antagonist, was injected intravenously to identify a specific role of M2 receptors in mediating the effect of acupuncture on jejunal motility.
RESULTS: Acupuncture at heterotopic acupoints, such as LI11 and ST37, increased jejunal motility not only in normal rats, but also in rats with constipation or diarrhea. In normal rats, manual acupuncture at LI11 or ST37 enhanced jejunal pressure from 7.34 ± 0.19 cmH2O to 7.93 ± 0.20 cmH2O, an increase of 9.05% ± 0.82% (P < 0.05), and from 6.95 ± 0.14 cmH2O to 8.97 ± 0.22 cmH2O, a significant increase of 27.44% ± 1.96% (P < 0.01), respectively. In constipated rats, manual acupuncture at LI11 or ST37 increased intrajejunal pressure from 8.17 ± 0.31 cmH2O to 9.86 ± 0.36 cmH2O, an increase of 20.69% ± 2.10% (P < 0.05), and from 8.82 ± 0.28 cmH2O to 10.83 ± 0.28 cmH2O, an increase of 22.81% ± 1.46% (P < 0.05), respectively. In rats with diarrhea, MA at LI11 or ST37 increased intrajejunal pressure from 11.95 ± 0.35 cmH2O to 13.96 ± 0.39 cmH2O, an increase of 16.82% ± 2.35% (P < 0.05), and tended to increase intrajejunal pressure (from 12.42 ± 0.38 cmH2O to 13.05 ± 0.38 cmH2O, an increase of 5.07% ± 1.08%, P > 0.05), respectively. In contrast, acupuncture ST25, a homotopic acupoint, not only decreased intrajejunal pressure, but also significantly decreased frequency in normal rats and rats with constipation or diarrhea. Following demyelination of Aδ fibers, acupuncture at ST37 again augmented intrajejunal pressure to 121.48% ± 3.06% of baseline. Following capsaicin application for 24 h, acupuncture at ipsilateral ST37 increased intrajejunal pressure to 106.63% ± 1.26% of basal levels when compared to measurements prior to capsaicin treatment (P < 0.05). Acupuncture at LI11, ST37, or BL25 significantly rescued methoctramine-mediated inhibition of jejunal motility amplitude from 42.83% ± 1.65% to 53.43% ± 1.95% of baseline (P < 0.05), from 45.15% ± 2.22% to 70.51% ± 2.34% of baseline (P < 0.01), and from 38.03% ± 2.34% to 70.12% ± 2.22% of baseline (P < 0.01), respectively.
CONCLUSION: Acupuncture at heterotopic acupoints increases the amplitude of jejunal motility in rats. C fibers and M2 receptors predominantly and (or) partially mediate the regulation of jejunal motility by acupuncture, respectively.
Collapse
|
|
35
|
Valle RGL, Godoy FL. Neostigmine for acute colonic pseudo-obstruction: A meta-analysis. Ann Med Surg (Lond) 2014; 3:60-4. [PMID: 25568788 PMCID: PMC4284455 DOI: 10.1016/j.amsu.2014.04.002] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Revised: 04/01/2014] [Accepted: 04/09/2014] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Acute colonic pseudo-obstruction (ACPO) is an uncommon condition that occasionally develops in hospitalized patients with serious underlying ailments. Its early recognition is essential to reduce life-threatening complications. Few low-powered randomized clinical trials (RCTs) have confirmed the effectiveness of neostigmine for treatment. AIM To analyse the effectiveness and main side effects of neostigmine in the treatment of ACPO. EXPERIMENTAL A literature search was performed for all published RCTs, reporting on neostigmine as treatment for ACPO. RESULTS Four studies fulfilled the inclusion criteria, evaluating 127 patients: treatment group = 65, control group = 62. Neostigmine effectiveness to resolve ACPO with only one dose was 89.2% versus 14.65% (P < 0.001, NNT = 1 [95% CI 1-2]). CONCLUSIONS Neostigmine is a safe and effective option for patients with ACPO who failed to respond to conservative management.
Collapse
Affiliation(s)
- Raul Guillermo Lopez Valle
- Corresponding author. Affinity Medical Associates, 11550 Louetta Suite 1200, Houston, TX 77070, USA. Tel.: +1 281 320 1196; fax: +1 281 320 1209.
| | | |
Collapse
|
|
36
|
Abstract
Urine differs greatly in ion and solute composition from plasma and contains harmful and noxious substances that must be stored for hours and then eliminated when it is socially convenient to do so. The urinary tract that handles this output is composed of a series of pressurizable muscular compartments separated by sphincteric structures. With neural input, these structures coordinate the delivery, collection, and, ultimately, expulsion of urine. Despite large osmotic and chemical gradients in this waste fluid, the bladder maintains a highly impermeable surface in the face of a physically demanding biomechanical environment, which mandates recurring cycles of surface area expansion and increased wall tension during filling, followed by rapid wall compression during voiding. Afferent neuronal inflow from mucosa and submucosa communicates sensory information about bladder fullness, and voiding is initiated consciously through coordinated central and spinal efferent outflow to the detrusor, trigonal internal sphincter, and external urethral sphincter after periods of relative quiescence. Provocative new findings suggest that in some cases, lower urinary tract symptoms, such as incontinence, urgency, frequency, overactivity, and pain may be viewed as a consequence of urothelial defects (either urothelial barrier breakdown or inappropriate signaling from urothelial cells to underlying sensory afferents and potentially interstitial cells). This review describes the physiologic and anatomic mechanisms by which urine is moved from the kidney to the bladder, stored, and then released. Relevant clinical examples of urinary tract dysfunction are also discussed.
Collapse
Affiliation(s)
- Warren G Hill
- Laboratory of Voiding Dysfunction, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
| |
Collapse
|
|
37
|
|
|
38
|
Bashashati M, McCallum RW. Neurochemical mechanisms and pharmacologic strategies in managing nausea and vomiting related to cyclic vomiting syndrome and other gastrointestinal disorders. Eur J Pharmacol 2013; 722:79-94. [PMID: 24161560 DOI: 10.1016/j.ejphar.2013.09.075] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2013] [Revised: 09/24/2013] [Accepted: 09/27/2013] [Indexed: 12/18/2022]
Abstract
Nausea and vomiting are common gastrointestinal complaints which could be triggered by stimuli in both the peripheral and central nervous systems. They may be considered as defense mechanisms when threatening toxins/agents enter the gastrointestinal tract or there is excessive retention of gastrointestinal contents due to obstruction. The pathophysiology of nausea and vomiting is complex and much still remains unknown. Therefore, treatments are restricted or ineffective in many cases. Nausea and vomiting with functional etiologies including cyclic vomiting syndrome are challenging in gastroenterology. In this article, we review potential pathways, neurochemical transmitters, and their receptors which are possibly involved in the pathophysiology of nausea and vomiting including the entity cyclic vomiting syndrome.
Collapse
Affiliation(s)
- Mohammad Bashashati
- Hotchkiss Brain Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
| | - Richard W McCallum
- Department of Internal Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA.
| |
Collapse
|
|
39
|
Al-Shboul O, Mustafa A, Al-hashimi F. Non-genomic effects of progesterone on Rho kinase II in rat gastric smooth muscle cells. J Smooth Muscle Res 2013; 49:55-62. [PMID: 24133695 PMCID: PMC5137272 DOI: 10.1540/jsmr.49.55] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Various studies have shown that pregnancy is associated with gastrointestinal complaints
that might result from disturbance of the normal contractile pattern of smooth muscle.
Progesterone is an important steroid hormone, which plays a crucial role in female
pregnancy. Progesterone affects muscle cells by genomic mechanisms, through nuclear
receptors, and non-genomic mechanisms, through unidentified pathways. Non-genomic actions
were defined as those occurring within 10 min of progesterone exposure. The aim of the
present study was to investigate the non-genomic effect of progesterone on Rho kinase II
activity in gastric smooth muscle. Single smooth muscle cells of the stomach obtained from
Sprague Dawley rats were used. Dispersed gastric smooth muscle cells were treated with
progesterone or acetylcholine (ACh) separately. Cells designated for progesterone
treatment were incubated with 1 μM progesterone for 10 min. Rho kinase II expression and
both basal and ACh-induced Rho kinase II activity were measured via specifically designed
enzyme-linked immunosorbent assay (ELISA) and activity assay kits respectively in both
control and progesterone-treated groups. Progesterone inhibited the ACh-induced, but not
the basal, Rho kinase II activity in dispersed gastric smooth muscle cells without
affecting its expression level. This study suggested that progesterone can rapidly affect
the contractile activity of isolated gastric smooth muscle cells in rats via inhibition of
the Rho kinase II pathway.
Collapse
|
|
40
|
Wang ZP, Liu HZ, Zhu L, Hu YM, Cui YY, Niu YY, Lu Y, Chen HZ. The effect of absolute configuration on activity, subtype selectivity (M3/M2) of 3α-acyloxy-6β-acetoxyltropane derivatives as muscarinic M3 receptor antagonists. Bioorg Med Chem 2013; 21:1234-9. [DOI: 10.1016/j.bmc.2012.12.052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Revised: 12/19/2012] [Accepted: 12/20/2012] [Indexed: 10/27/2022]
|
|
41
|
Leone Roberti Maggiore U, Salvatore S, Alessandri F, Remorgida V, Origoni M, Candiani M, Venturini PL, Ferrero S. Pharmacokinetics and toxicity of antimuscarinic drugs for overactive bladder treatment in females. Expert Opin Drug Metab Toxicol 2012; 8:1387-408. [PMID: 22871042 DOI: 10.1517/17425255.2012.714365] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Antimuscarinics (AMs) are the mainstay of pharmacological treatment of overactive bladder (OAB), a symptom complex defined by the presence of urinary urgency, usually associated with frequency and nocturia, with or without urgency urinary incontinence. The AMs used to treat OAB differ in their pharmacological profiles, which may affect their potential for causing adverse effects (AEs). AREAS COVERED The present article aims to review the literature about pharmacokinetics (PK) of the different AMs used in the treatment of OAB. Furthermore, the AEs related to the use of these drugs and their incidence are presented. This systematic review is based on material searched and obtained via Medline, Pubmed and EMBASE up to March 2012 using the search terms "adverse events, pharmacokinetics, tolerability" in combination with "darifenacin, fesoterodine, imidafenacin, oxybutynin, propiverine, solifenacin, tolterodine, and trospium." EXPERT OPINION Antimuscarinics are the first-line pharmacological treatment for OAB. Despite the development of new molecules that improve their efficacy/safety profile, there are some drugs that are pharmacokinetically more appropriate to be prescribed in specific populations such as patients with neurological disease or the elderly. Moreover, research should be encouraged in evaluating antimuscarinics in conjunction with other drugs such as estrogens or beta-agonists. The identification of prognostic criteria for pharmacological therapy would be helpful.
Collapse
Affiliation(s)
- Umberto Leone Roberti Maggiore
- University of Genoa, San Martino Hospital and National Institute for Cancer Research, Department of Obstetrics and Gynaecology, Genoa, Italy
| | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Yang S, Xiong CJ, Sun HM, Li XS, Zhang GQ, Wu B, Zhou DS. The distribution of HCN2-positive cells in the gastrointestinal tract of mice. J Anat 2012; 221:303-10. [PMID: 22803609 DOI: 10.1111/j.1469-7580.2012.01546.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/27/2012] [Indexed: 01/19/2023] Open
Abstract
HCN2 channels are involved in the spontaneous rhythmic activities of some CNS neurons and act by generating I(f) current. The gastrointestinal (GI) tract is known to be capable of spontaneous rhythmic activity; however, the possible role of HCN2 channels in this organ has not yet been elucidated. This study investigated the distribution of HCN2-positive cells in the mouse GI tract using immunohistochemistry. To identify the nature of these HCN2 cells, anti-ChAT and anti-Kit antibodies were used to co-label neurons and the interstitial cells of Cajal (ICCs), respectively. Additionally, differences in the distribution of HCN2-positive cells within the GI tract were also analyzed. Our results showed that HCN2 channels were mainly located within the myenteric neurons of the enteric nervous system in the GI tract. Double-staining revealed that HCN2-positive neurons were labeled by ChAT, indicating that these HCN2-positive cells are also cholinergic neurons. Although the HCN2-positive cells were not stained by the anti-Kit antibody, their processes were in close proximity to ICCs around the myenteric plexus region. Moreover, several differences in the distribution of HCN2 in the stomach, small intestine and colon were partly consistent with the regional differences in the spontaneous rhythmic activities of these organs. Basing on the role HCN2, we suggested that HCN2 channels facilitate the release of Ach from cholinergic neurons to affect the GI peristalsis by acting on M receptors on the ICCs. However, the HCN2 channels are not directly involved in spontaneous slow-wave initiation by ICCs.
Collapse
Affiliation(s)
- Shu Yang
- Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | | | | | | | | | | | | |
Collapse
|
|
43
|
Chen J, Wen J, Cai W. Smooth muscle adaptation and recovery of contractility after massive small bowel resection in rats. Exp Biol Med (Maywood) 2012; 237:578-84. [PMID: 22581812 DOI: 10.1258/ebm.2012.011338] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Previous studies have suggested that massive small bowel resection (mSBR) compromises the normal intestinal processes of digestion and absorption, and requires an adaptive response to regain full function and reinstate coordinated contractile activity of the circular smooth muscle. This study was designed to investigate spontaneous contractile activity of circular smooth muscle using the mSBR rat model and to determine the functional role of M(2) and M(3) muscarinic acetylcholine receptors (mAChR) in this process. Male Sprague-Dawley rats underwent an 80% proximal SBR or sham operation. Markers of adaptation, including villus and microvillus height, were analyzed by hematoxylin and eosin staining and transmission electron microscopy. Contractility was measured by attaching the distal ileum strips to strain gauge transducers and exposing the tissue to varying doses of the cholinergic agonist carbachol. Protein expressions of M(2)- and M(3)-mAChR in intestinal smooth muscle (ISM) were detected by Western blot. Following mSBR, the ISM showed perturbed spontaneous rhythmic contraction, irregular amplitude and slow frequency by muscle strip test. However, by two weeks after mSBR, the contractile function of circular smooth muscle was found to have returned to normal levels. Protein expression of M(2)-mAChR was down-regulated following mSBR but up-regulated during the adaptive process when contractile activity of circular smooth muscle was regained. These results indicate that smooth muscle contractility was spontaneously restored in rats following mSBR, and involved the acetylcholine receptors M(2) and M(3). Thus, the disrupted contractile response of smooth muscle in short bowel syndrome may be corrected by therapeutic intervention to restore the expressions of M(2)- and M(3)-mAChR to pre-mSBR levels.
Collapse
Affiliation(s)
- Jie Chen
- Department of Pediatric Surgery, School of Medicine, Xin Hua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University, 1665 Kong Jiang Road 200092, Shanghai, China
| | | | | |
Collapse
|
|
44
|
Hu J, Gao WY, Ma L, Man SL, Huang LQ, Liu CX. Activation of M3 muscarinic receptor and Ca²⁺ influx by crude fraction from Crotonis Fructus in isolated rabbit jejunum. JOURNAL OF ETHNOPHARMACOLOGY 2012; 139:136-141. [PMID: 22107834 DOI: 10.1016/j.jep.2011.10.041] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2011] [Revised: 09/15/2011] [Accepted: 10/25/2011] [Indexed: 05/31/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Crotonis Fructus is the mature fruit of Croton tiglium L. (Euphorbiaceae), which has been used in traditional Chinese medicine for the treatment of gastrointestinal (GI) diseases, such as constipation, abdominal pain, peptic ulcer, and intestinal inflammation for thousands of years. The aim of this study was to investigate the pharmacological effect of extracts and fractions from Crotonis Fructus on GI tract. MATERIALS AND METHODS The activities of methanol extract and fractions from Crotonis Fructus on the smooth muscle contractions were evaluated using isolated rabbit jejunum model. RESULTS The results suggest that the n-BuOH and H(2)O fractions showed spasmolytic activity, while the MeOH extract, PE and EtOAc fractions exerted spasmogenic effect. Moreover, bioassay-guided fractionation verified that the EtOAc fraction was more potent than others, followed by PE fraction and methanol extract. Additionally, atropine (10μM), 4-DAMP (10μM) and verapamil (0.1μM) produced a significant inhibition of contractions caused by EtOAc fraction, while either hexamethonium (10μM) or methoctramine (10μM) was inactive. Additionally, a HPLC fingerprint of EtOAc fraction was appraised to ensure its chemical consistency and the main component has been identified as phorbol 12-acetate-13-tiglate. CONCLUSIONS These data indicate that the regulatory effect of EtOAc fraction on GI motility are medicated via the activation of M3 muscarinic receptor and Ca(2+) influx through L-type Ca(2+) channel. These provide a scientific basis for the traditional use of Crotonis Fructus in GI disorders.
Collapse
Affiliation(s)
- Jing Hu
- Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | | | | | | | | | | |
Collapse
|
|
45
|
Joo MC, Kim YS, Choi ES, Oh JT, Park HJ, Lee MY. Changes in the muscarinic receptors on the colonic smooth muscles of rats with spinal cord injury. Ann Rehabil Med 2011; 35:589-98. [PMID: 22506180 PMCID: PMC3309258 DOI: 10.5535/arm.2011.35.5.589] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2010] [Accepted: 05/22/2011] [Indexed: 11/29/2022] Open
Abstract
Objective To investigate changes in (1) the colonic response to acetylcholine (Ach), (2) the muscarinic (M) receptors in the colon, and (3) the levels of colonic contraction-related proteins after a spinal cord injury (SCI). Method We divided 16 Sprague-Dawley rats into 2 groups: the control group and the SCI group. A spinal cord transection was performed surgically at the T10 vertebral level. After 1 week, the entire colon was divided into 2 segments, the proximal and distal colon. Each segment was mounted in a longitudinal or circular muscle direction in a 10-ml organ bath. We determined the intergroup differences as percentage changes in contractility after Ach treatment alone, Ach treatment with M2 receptor antagonist (AQ-RA741) pretreatment, and Ach treatment with M3 receptor antagonist (4-DAMP) pretreatment. Western blot analyses were performed to determine the expression level of RhoA, and heat shock protein 27 (HSP27). Results Compared to the control rats, the SCI rats showed an increased response to Ach along both the directions in the proximal colon (p<0.05). Compared to the control group, in the SCI group, the Ach response was significantly different in the proximal segment under AQ-RA741 pretreatment (p<0.05) and in the distal segment under 4-DAMP pretreatment (p<0.05). Findings of the western blot analyses showed a significant decrease in the level of protein gene product 9.5 in the proximal and distal colon and a significant increase in the level of RhoA and HSP27 in the proximal colon of the SCI rats. Conclusion Our results suggest that changes in colonic contractility after SCI are partly attributable to changes in the M receptor subtypes.
Collapse
Affiliation(s)
- Min Cheol Joo
- Department of Rehabilitation Medicine and Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, Iksan 570-749, Korea
| | | | | | | | | | | |
Collapse
|
|
46
|
Yang JM, Ip PSP, Che CT, Yeung JHK. Relaxant effects of Schisandra chinensis and its major lignans on agonists-induced contraction in guinea pig ileum. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2011; 18:1153-1160. [PMID: 21764275 DOI: 10.1016/j.phymed.2011.06.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2010] [Revised: 03/08/2011] [Accepted: 06/09/2011] [Indexed: 05/31/2023]
Abstract
In this study, the herbal extracts of Schisandra chinensis were demonstrated to inhibit the contractions induced by acetylcholine (ACh) and serotonin (5-HT) in guinea pig ileum, and the 95% ethanol extract was more effective than the aqueous extract. Analysis with High Performance Liquid Chromatography (HPLC) indicated that schisandrin, schisandrol B, schisandrin A and schisandrin B were the major lignans of Schisandra chinensis, and the ethanol extract contained higher amount of these lignans than the aqueous extract. All four lignans inhibited the contractile responses to ACh, with EC(20) values ranging from 2.2±0.4μM (schisandrin A) to 13.2±4.7μM (schisandrin). The effectiveness of these compounds in relaxing the 5-HT-induced contraction was observed with a similar magnitude. Receptor binding assay indicated that Schisandra lignans did not show significant antagonistic effect on muscarinic M3 receptor. In Ca(2+)-free preparations primed with ACh or KCl, schisandrin A (50μM) attenuated the contractile responses to cumulative addition of CaCl(2) by 37%. In addition, schisandrin A also concentration-dependently inhibited ACh-induced contractions in Ca(2+)-free buffer. This study demonstrates that Schisandra chinensis exhibited relaxant effects on agonist-induced contraction in guinea pig ileum, with schisandrin, schisandrol B, schisandrin A and schisandrin B being the major active ingredients. The antispasmodic action of schisandrin A involved inhibitions on both Ca(2+) influx through L-type Ca(2+) channels and intracellular Ca(2+) mobilization, rather than specific antagonism of cholinergic muscarinic receptors.
Collapse
Affiliation(s)
- Jia-Ming Yang
- School of Chinese Medicine, Faculty of Science, The Chinese University of Hong Kong, Shatin, Hong Kong
| | | | | | | |
Collapse
|
|
47
|
On benzofuroindole analogues as smooth muscle relaxants. J Biomed Biotechnol 2011; 2011:389056. [PMID: 21941431 PMCID: PMC3177241 DOI: 10.1155/2011/389056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Accepted: 07/14/2011] [Indexed: 11/18/2022] Open
Abstract
At least two laboratories have independently reported the synthesis of benzofuroindole compounds having potential therapeutic implications in many disease states including those that involve smooth muscle hyperactivity. Through a series of in vitro screenings, they demonstrated the efficacy (and selectivity) of these compounds to potentiate large conductance calcium- (Ca2+-) activated K+ (BKCa) channels, by far, the most characterized of all Ca2+-dependent K+ channels. Interestingly, promising benzofuroindole derivatives such as compound 7 (10H-benzo[4,5]furo[3,2-b]indole) and compound 22 (4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid) both exhibited high bladder (versus aorta) selectivity, making them attractive alternative treatments for bladder overactivity. In recent reports, compound 22 (LDD175 or TBIC) also showed inhibition of ileum and uterine contractions, indicating multiple target tissues, which is not surprising as BKCa channels are ubiquitously expressed in the animal and human tissues. In this paper, the authors discuss the value of benzofuroindole compounds and the challenges that need to be overcome if they were considered as smooth muscle relaxants.
Collapse
|
|
48
|
Fry CH, Bayliss M, Young JS, Hussain M. Influence of age and bladder dysfunction on the contractile properties of isolated human detrusor smooth muscle. BJU Int 2010; 108:E91-6. [PMID: 21070581 DOI: 10.1111/j.1464-410x.2010.09845.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVE To test the hypothesis that the in vitro contractile properties of human detrusor smooth muscle are dependent on the age, gender and lower urinary tract pathology of the patient. MATERIALS AND METHODS Contractions were elicited in isolated human detrusor smooth muscle preparations by nerve-mediated electrical field stimulation, agonist application (carbachol, α,β-methylene ATP and high-K solutions) or direct muscle electrical stimulation. Biopsies (n = 227) were obtained from four groups of patients with: stable bladders (control), bladder outlet obstruction (BOO), idiopathic (IDO), or neurogenic (NDO) detrusor overactivity. RESULTS The magnitude of nerve-mediated contractions declined as a function of patients' age in each of the BOO, IDO and NDO groups but not in the control group. Contractions elicited by direct muscle activation (10 µM carbachol or electrical stimulation with 20 ms pulses in the presence of 1 µM tetrodotoxin) did not vary with patient age. Carbachol contractions were significantly smaller in samples from NDO bladders. Atropine resistance was more prevalent in the pathology groups compared with the control group and was greatest in the IDO group. There was no influence of age in the prevalence or magnitude of atropine-resistant contractions in any group. Muscle excitability to direct electrical stimulation was similar in all groups. CONCLUSIONS In the human bladder there is no evidence for a decline of detrusor smooth muscle contractility or excitability as a function of age, nor any gender difference or presence of pathology. In the pathology groups there was evidence for a decline of functional innervation with age.
Collapse
|
|
49
|
Harrington AM, Peck CJ, Liu L, Burcher E, Hutson JM, Southwell BR. Localization of muscarinic receptors M1R, M2R and M3R in the human colon. Neurogastroenterol Motil 2010; 22:999-1008, e262-3. [PMID: 20146726 DOI: 10.1111/j.1365-2982.2009.01456.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Muscarinic acetylcholine receptors (MR) are involved in multiple intestinal reflexes. The cellular localization of subtypes of MRs within enteric circuits mediating muscle and mucosal reflexes remains to be demonstrated. This study aimed to localize the three functionally significant subtypes of MRs in human colon. METHODS Reverse transcriptase-PCR was used to determine expression levels of muscarinic receptor subtype (MRs) M1Rs, M2Rs and M3Rs in human colon. Indirect immunofluorescence and confocal microscopy was used to localize MRs in cryostat-cut sections of human colon. Sections were double labeled for multiple cellular and neurochemical markers. Western blotting was used to confirm specificity of the muscarinic antisera used. KEY RESULTS All three MR subtypes were expressed in human colon. Immunoreactivity (IR) for M2Rs and M3Rs was most abundant in circular and longitudinal muscle. M1R-IR was most abundant on myenteric and submucosal nerve cells, both cholinergic and nitrergic. M3R-IR was also present on populations on myenteric nerve cell bodies. Immunoreactivity for all three receptors was present on nerve fibers in the circular muscle. CONCLUSIONS & INFERENCES In the human colon, subtypes of MRs were present on multiple cell types within the enteric circuits underlying motility, secretory and vasoactive reflexes. The cellular distribution for MRs found in this study agrees with data from functional studies, providing insight into the role MRs have in mediating enteric cholinergic neurotransmission.
Collapse
Affiliation(s)
- A M Harrington
- F. Douglas Stephens Surgical Research Laboratory, Murdoch Children's Research Institute, Parkville, Australia
| | | | | | | | | | | |
Collapse
|
|
50
|
Ameer OZ, Salman IM, Siddiqui MJA, Yam MF, Sriramaneni RN, Sadikun A, Ismail Z, Shah AM, Asmawi MZ. In vitro cholinomimetic effect of Loranthus ferrugineus in isolated guinea pig ileum. J Acupunct Meridian Stud 2010; 2:288-93. [PMID: 20633504 DOI: 10.1016/s2005-2901(09)60070-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2009] [Accepted: 09/29/2009] [Indexed: 12/27/2022] Open
Abstract
This study aimed to elucidate the mechanism(s) of the spasmogenic action of Loranthus ferrugineus in isolated guinea pig ileum. Thus the contractile responses of guinea pig ileum to graded additions of either L. ferrugineus methanol extract or its n-butanol fraction were tested in the presence and absence of various pharmacological interventions. The data showed that L. ferrugineus methanol extract and the n-butanol fraction produced a concentration-dependent spasmogenic effect in isolated guinea pig ileum segments. These effects were significantly inhibited in the presence of 1 microM atropine. In contrast, the response to the lowest concentrations of L. ferrugineus methanol extract (0.25, 0.5 and 1 mg/mL) and n-butanol fraction of L. ferrugineus (0.125, 0.25 and 0.5 mg/mL) were considerably enhanced in the presence of 0.05 microM neostigmine. Neither L. ferrugineus methanol extract nor n-butanol fraction contractile responses were affected upon the incubation of the ileal segments with 100 microM hexamethonium. The results of this study show that the spasmogenic effect of L. ferrugineus is possibly mediated through a direct action on intestinal muscarinic receptors. It is suggested that the bioactive constituents of L. ferrugineus serve as a substrate for acetylcholinesterase.
Collapse
Affiliation(s)
- Omar Ziad Ameer
- Department of Physiology & Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia.
| | | | | | | | | | | | | | | | | |
Collapse
|