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Sun Q, Ding H, Lu C, Yan L, Cao B. Association between serum and urinary environmental metal levels and major depressive disorder: a study based on logistic regression and quantile regression. Front Public Health 2024; 12:1450983. [PMID: 39228853 PMCID: PMC11369418 DOI: 10.3389/fpubh.2024.1450983] [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: 06/27/2024] [Accepted: 08/19/2024] [Indexed: 09/05/2024] Open
Abstract
Background Major depressive disorder (MDD) is a prevalent mental disorder globally. Increasing evidence suggests that Environmental Metal (EM) play a crucial role in MDD. Therefore, this study investigated the roles of barium (Ba), cesium (Cs), nickel (Ni), manganese (Mn), lead (Pb), mercury (Hg), cadmium (Cd), and tin (Sn) in the etiology of MDD. Methods The study included 72 MDD patients and 75 healthy controls (HCs) from the Second People's Hospital of Zhumadian, China. Inductively coupled plasma mass spectrometer (ICP-MS) measured the metal levels in serum and urine samples from both groups. Results Significant differences in serum and urine levels of EMs were observed between MDD patients and HCs. After adjusting for age, gender, and BMI, logistic regression and quantile regression models revealed significant associations between EMs and MDD. In serum samples, higher Sn levels (OR = 1.22, p = 0.044) increased MDD risk, whereas higher Cs levels (OR = 0.02, p < 0.001), Cd (OR = 0.06, p = 0.047), and Mn (OR = 0.54, p = 0.016) decreased MDD risk. In urine samples, higher Ba levels (OR = 0.94, p = 0.015), Ni (OR = 0.87, p = 0.0024), Sn (OR = 1.62, p < 0.001), and Mn (OR = 0.77, p = 0.037) were significantly associated with MDD. Sn significantly positively predicted HAMD-24 scores at the 0.50 and 0.75 quantiles (β = 0.96, p = 0.018; β = 1.25, p = 0.008) as did Pb (β = 5.15, p = 0.001; β = 4.19, p = 0.004). Ba positively predicted depressive symptoms across all quantiles (all p < 0.05). Hg positively predicted HAMD-24 scores at the 0.50 quantile (β = 9.20, p = 0.050). Conclusion These findings underscore EMs' importance in depression, aiding in targeted interventions for varying degrees of depression and necessitating future studies to clarify causality and mechanisms.
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Affiliation(s)
- Qixuan Sun
- Key Laboratory of Cognition and Personality, Faculty of Psychology, Ministry of Education, Southwest University, Chongqing, China
- College of Computer and Information Science, Southwest University, Chongqing, China
| | - Haiyang Ding
- Key Laboratory of Cognition and Personality, Faculty of Psychology, Ministry of Education, Southwest University, Chongqing, China
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
- Department of Psychology, University of Chinese Academy of Sciences, Beijing, China
| | - Chenxuan Lu
- Key Laboratory of Cognition and Personality, Faculty of Psychology, Ministry of Education, Southwest University, Chongqing, China
| | - Lailai Yan
- Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, China
| | - Bing Cao
- Key Laboratory of Cognition and Personality, Faculty of Psychology, Ministry of Education, Southwest University, Chongqing, China
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2
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Kowalewska PM, Fletcher J, Jackson WF, Brett SE, Kim MS, Mironova GY, Haghbin N, Richter DM, Tykocki NR, Nelson MT, Welsh DG. Genetic ablation of smooth muscle K IR2.1 is inconsequential to the function of mouse cerebral arteries. J Cereb Blood Flow Metab 2022; 42:1693-1706. [PMID: 35410518 PMCID: PMC9441723 DOI: 10.1177/0271678x221093432] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
Cerebral blood flow is a finely tuned process dependent on coordinated changes in arterial tone. These changes are strongly tied to smooth muscle membrane potential and inwardly rectifying K+ (KIR) channels are thought to be a key determinant. To elucidate the role of KIR2.1 in cerebral arterial tone development, this study examined the electrical and functional properties of cells, vessels and living tissue from tamoxifen-induced smooth muscle cell (SMC)-specific KIR2.1 knockout mice. Patch-clamp electrophysiology revealed a robust Ba2+-sensitive inwardly rectifying K+ current in cerebral arterial myocytes irrespective of KIR2.1 knockout. Immunolabeling clarified that KIR2.1 expression was low in SMCs while KIR2.2 labeling was remarkably abundant at the membrane. In alignment with these observations, pressure myography revealed that the myogenic response and K+-induced dilation were intact in cerebral arteries post knockout. At the whole organ level, this translated to a maintenance of brain perfusion in SMC KIR2.1-/- mice, as assessed with arterial spin-labeling MRI. We confirmed these findings in superior epigastric arteries and implicated KIR2.2 as more functionally relevant in SMCs. Together, these results suggest that subunits other than KIR2.1 play a significant role in setting native current in SMCs and driving arterial tone.
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Affiliation(s)
- Paulina M Kowalewska
- Robarts Research Institute and the Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada
| | - Jacob Fletcher
- Robarts Research Institute and the Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada
| | - William F Jackson
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - Suzanne E Brett
- Robarts Research Institute and the Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada
| | - Michelle Sm Kim
- Robarts Research Institute and the Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada
| | - Galina Yu Mironova
- Robarts Research Institute and the Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada
| | - Nadia Haghbin
- Robarts Research Institute and the Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada
| | - David M Richter
- Robarts Research Institute and the Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada
| | - Nathan R Tykocki
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - Mark T Nelson
- Department of Pharmacology, University of Vermont, Burlington, VT, USA
| | - Donald G Welsh
- Robarts Research Institute and the Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada
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3
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Trinity JD, Kwon OS, Broxterman RM, Gifford JR, Kithas AC, Hydren JR, Jarrett CL, Shields KL, Bisconti AV, Park SH, Craig JC, Nelson AD, Morgan DE, Jessop JE, Bledsoe AD, Richardson RS. The role of the endothelium in the hyperemic response to passive leg movement: looking beyond nitric oxide. Am J Physiol Heart Circ Physiol 2020; 320:H668-H678. [PMID: 33306447 DOI: 10.1152/ajpheart.00784.2020] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Passive leg movement (PLM) evokes a robust and predominantly nitric oxide (NO)-mediated increase in blood flow that declines with age and disease. Consequently, PLM is becoming increasingly accepted as a sensitive assessment of endothelium-mediated vascular function. However, a substantial PLM-induced hyperemic response is still evoked despite nitric oxide synthase (NOS) inhibition. Therefore, in nine young healthy men (25 ± 4 yr), this investigation aimed to determine whether the combination of two potent endothelium-dependent vasodilators, specifically prostaglandin (PG) and endothelium-derived hyperpolarizing factor (EDHF), account for the remaining hyperemic response to the two variants of PLM, PLM (60 movements) and single PLM (sPLM, 1 movement), when NOS is inhibited. The leg blood flow (LBF, Doppler ultrasound) response to PLM and sPLM following the intra-arterial infusion of NG-monomethyl-l-arginine (l-NMMA), to inhibit NOS, was compared to the combined inhibition of NOS, cyclooxygenase (COX), and cytochrome P-450 (CYP450) by l-NMMA, ketorolac tromethamine (KET), and fluconazole (FLUC), respectively. NOS inhibition attenuated the overall LBF [area under the curve (LBFAUC)] response to both PLM (control: 456 ± 194, l-NMMA: 168 ± 127 mL, P < 0.01) and sPLM (control: 185 ± 171, l-NMMA: 62 ± 31 mL, P = 0.03). The combined inhibition of NOS, COX, and CYP450 (i.e., l-NMMA+KET+FLUC) did not further attenuate the hyperemic responses to PLM (LBFAUC: 271 ± 97 mL, P > 0.05) or sPLM (LBFAUC: 72 ± 45 mL, P > 0.05). Therefore, PG and EDHF do not collectively contribute to the non-NOS-derived NO-mediated, endothelium-dependent hyperemic response to either PLM or sPLM in healthy young men. These findings add to the mounting evidence and understanding of the vasodilatory pathways assessed by the PLM and sPLM vascular function tests.NEW & NOTEWORTHY Passive leg movement (PLM) evokes a highly nitric oxide (NO)-mediated hyperemic response and may provide a novel evaluation of vascular function. The contributions of endothelium-dependent vasodilatory pathways, beyond NO and including prostaglandins and endothelium-derived hyperpolarizing factor, to the PLM-induced hyperemic response to PLM have not been evaluated. With intra-arterial drug infusion, the combined inhibition of nitric oxide synthase (NOS), cyclooxygenase, and cytochrome P-450 (CYP450) pathways did not further diminish the hyperemic response to PLM compared with NOS inhibition alone.
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Affiliation(s)
- Joel D Trinity
- Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs Medical Center, Salt Lake City, Utah.,Department of Internal Medicine, University of Utah, Salt Lake City, Utah.,Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah
| | - Oh Sung Kwon
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah.,Department of Kinesiology, University of Connecticut, Storrs, Connecticut
| | - Ryan M Broxterman
- Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs Medical Center, Salt Lake City, Utah.,Department of Internal Medicine, University of Utah, Salt Lake City, Utah
| | - Jayson R Gifford
- Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs Medical Center, Salt Lake City, Utah.,Department of Exercise Science, Brigham Young University, Provo, Utah
| | - Andrew C Kithas
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah
| | - Jay R Hydren
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah
| | - Catherine L Jarrett
- Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs Medical Center, Salt Lake City, Utah
| | - Katherine L Shields
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah
| | - Angela V Bisconti
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah
| | - Soung Hun Park
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah
| | - Jesse C Craig
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah
| | - Ashley D Nelson
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah
| | - David E Morgan
- Department of Anesthesiology, University of Utah, Salt Lake City, Utah
| | - Jacob E Jessop
- Department of Anesthesiology, University of Utah, Salt Lake City, Utah
| | - Amber D Bledsoe
- Department of Anesthesiology, University of Utah, Salt Lake City, Utah
| | - Russell S Richardson
- Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs Medical Center, Salt Lake City, Utah.,Department of Internal Medicine, University of Utah, Salt Lake City, Utah.,Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah
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4
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Sancho M, Welsh DG. K IR channels in the microvasculature: Regulatory properties and the lipid-hemodynamic environment. CURRENT TOPICS IN MEMBRANES 2020; 85:227-259. [PMID: 32402641 DOI: 10.1016/bs.ctm.2020.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
Basal tone and perfusion control is set in cerebral arteries by the sensing of pressure and flow, key hemodynamic stimuli. These forces establish a contractile foundation within arterial networks upon which local neurovascular stimuli operate. This fundamental process is intimately tied to arterial VM and the rise in cytosolic [Ca2+] by the graded opening of voltage-operated Ca2+ channels. Arterial VM is in turn controlled by a dynamic interaction among several resident ion channels, KIR being one of particular significance. As the name suggests, KIR displays strong inward rectification, retains a small outward component, potentiated by extracellular K+ and blocked by micromolar Ba2+. Cerebrovascular KIR is unique from other K+ currents as it is present in both smooth muscle and endothelium yet lacking in classical regulatory modulation. Such observations have fostered the view that KIR is nothing more than a background conductance, activated by extracellular K+ and which passively facilitates dilation. Recent work in cell model systems has; however, identified two membrane lipids, phosphatidylinositol 4,5-bisphosphate (PIP2) and cholesterol, that interact with KIR2.x, to stabilize the channel in the preferred open or silent state, respectively. Translating this unique form of regulation, recent studies have demonstrated that specific lipid-protein interactions enable unique KIR populations to sense distinct hemodynamic stimuli and set basal tone. This review summarizes the current knowledge of vascular KIR channels and how the lipid and hemodynamic impact their activity.
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Affiliation(s)
- Maria Sancho
- Robarts Research Institute and the Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada
| | - Donald G Welsh
- Robarts Research Institute and the Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada.
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Hearon CM, Richards JC, Racine ML, Luckasen GJ, Larson DG, Dinenno FA. Amplification of endothelium-dependent vasodilatation in contracting human skeletal muscle: role of K IR channels. J Physiol 2018; 597:1321-1335. [PMID: 30506579 DOI: 10.1113/jp276998] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 11/29/2018] [Indexed: 12/14/2022] Open
Abstract
KEY POINTS In humans, the vasodilatory response to skeletal muscle contraction is mediated in part by activation of inwardly rectifying potassium (KIR ) channels. Evidence from animal models suggest that KIR channels serve as electrical amplifiers of endothelium-dependent hyperpolarization (EDH). We found that skeletal muscle contraction amplifies vasodilatation to the endothelium-dependent agonist ACh, whereas there was no change in the vasodilatory response to sodium nitroprusside, an endothelium-independent nitric oxide donor. Blockade of KIR channels reduced the exercise-induced amplification of ACh-mediated vasodilatation. Conversely, pharmacological activation of KIR channels in quiescent muscle via intra-arterial infusion of KCl independently amplified the vasodilatory response to ACh. This study is the first in humans to demonstrate that specific endothelium-dependent vasodilatory signalling is amplified in the vasculature of contracting skeletal muscle and that KIR channels may serve as amplifiers of EDH-like vasodilatory signalling in humans. ABSTRACT The local vasodilatory response to muscle contraction is due in part to the activation of inwardly rectifying potassium (KIR ) channels. Evidence from animal models suggest that KIR channels function as 'amplifiers' of endothelium-dependent vasodilators. We tested the hypothesis that contracting muscle selectively amplifies endothelium-dependent vasodilatation via activation of KIR channels. We measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to local intra-arterial infusion of ACh (endothelium-dependent dilator) during resting conditions, handgrip exercise (5% maximum voluntary contraction) or sodium nitroprusside (SNP; endothelium-independent dilator) which served as a high-flow control condition (n = 7, young healthy men and women). Trials were performed before and after blockade of KIR channels via infusion of barium chloride. Exercise augmented peak ACh-mediated vasodilatation (ΔFVC saline: 117 ± 14; exercise: 236 ± 21 ml min-1 (100 mmHg)-1 ; P < 0.05), whereas SNP did not impact ACh-mediated vasodilatation. Blockade of KIR channels attenuated the exercise-induced augmentation of ACh. In eight additional subjects, SNP was administered as the experimental dilator. In contrast to ACh, exercise did not alter SNP-mediated vasodilatation (ΔFVC saline: 158 ± 35; exercise: 121 ± 22 ml min-1 (100 mmHg)-1 ; n.s.). Finally, in a subset of six subjects, direct pharmacological activation of KIR channels in quiescent muscle via infusion of KCl amplified peak ACh-mediated vasodilatation (ΔFVC saline: 97 ± 15, KCl: 142 ± 16 ml min-1 (100 mmHg)-1 ; respectively; P < 0.05). These findings indicate that skeletal muscle contractions selectively amplify endothelium-dependent vasodilatory signalling via activation of KIR channels, and this may be an important mechanism contributing to the normal vasodilatory response to exercise in humans.
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Affiliation(s)
- Christopher M Hearon
- Human Cardiovascular Physiology Laboratory, Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, 80523, USA
| | - Jennifer C Richards
- Human Cardiovascular Physiology Laboratory, Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, 80523, USA
| | - Mathew L Racine
- Human Cardiovascular Physiology Laboratory, Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, 80523, USA
| | - Gary J Luckasen
- Medical Center of the Rockies Foundation, University of Colorado Health, Loveland, CO, USA
| | - Dennis G Larson
- Medical Center of the Rockies Foundation, University of Colorado Health, Loveland, CO, USA
| | - Frank A Dinenno
- Human Cardiovascular Physiology Laboratory, Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, 80523, USA.,Center for Cardiovascular Research, Colorado State University, Fort Collins, CO, 80523, USA
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6
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Tykocki NR, Boerman EM, Jackson WF. Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles. Compr Physiol 2017; 7:485-581. [PMID: 28333380 DOI: 10.1002/cphy.c160011] [Citation(s) in RCA: 241] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Vascular tone of resistance arteries and arterioles determines peripheral vascular resistance, contributing to the regulation of blood pressure and blood flow to, and within the body's tissues and organs. Ion channels in the plasma membrane and endoplasmic reticulum of vascular smooth muscle cells (SMCs) in these blood vessels importantly contribute to the regulation of intracellular Ca2+ concentration, the primary determinant of SMC contractile activity and vascular tone. Ion channels provide the main source of activator Ca2+ that determines vascular tone, and strongly contribute to setting and regulating membrane potential, which, in turn, regulates the open-state-probability of voltage gated Ca2+ channels (VGCCs), the primary source of Ca2+ in resistance artery and arteriolar SMCs. Ion channel function is also modulated by vasoconstrictors and vasodilators, contributing to all aspects of the regulation of vascular tone. This review will focus on the physiology of VGCCs, voltage-gated K+ (KV) channels, large-conductance Ca2+-activated K+ (BKCa) channels, strong-inward-rectifier K+ (KIR) channels, ATP-sensitive K+ (KATP) channels, ryanodine receptors (RyRs), inositol 1,4,5-trisphosphate receptors (IP3Rs), and a variety of transient receptor potential (TRP) channels that contribute to pressure-induced myogenic tone in resistance arteries and arterioles, the modulation of the function of these ion channels by vasoconstrictors and vasodilators, their role in the functional regulation of tissue blood flow and their dysfunction in diseases such as hypertension, obesity, and diabetes. © 2017 American Physiological Society. Compr Physiol 7:485-581, 2017.
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Affiliation(s)
- Nathan R Tykocki
- Department of Pharmacology, University of Vermont, Burlington, Vermont, USA
| | - Erika M Boerman
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri, USA
| | - William F Jackson
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA
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Schinzari F, Tesauro M, Cardillo C. Vascular hyperpolarization in human physiology and cardiovascular risk conditions and disease. Acta Physiol (Oxf) 2017; 219:124-137. [PMID: 28009486 DOI: 10.1111/apha.12630] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Revised: 10/05/2015] [Accepted: 11/05/2015] [Indexed: 12/11/2022]
Abstract
Hyperpolarization causing smooth muscle relaxation contributes to the maintenance of vascular homeostasis, particularly in small-calibre arteries and arterioles. It may also become a compensatory vasodilator mechanism upregulated in states with impaired nitric oxide (NO) availability. Bioassay of vascular hyperpolarization in the human circulation has been hampered by the complexity of mechanisms involved and the limited availability of investigational tools. Firm evidence, however, supports the notion that hyperpolarization participates in the regulation of resting vasodilator tone and vascular reactivity in healthy subjects. In addition, an enhanced endothelium-derived hyperpolarization contributes to both resting and agonist-stimulated vasodilation in a variety of cardiovascular risk conditions and disease. Thus, hyperpolarization mediated by epoxyeicosatrienoic acids (EETs) and H2 O2 has been observed in coronary arterioles of patients with coronary artery disease. Similarly, ouabain-sensitive and EETs-mediated hyperpolarization has been observed to compensate for NO deficiency in patients with essential hypertension. Moreover, in non-hypertensive patients with multiple cardiovascular risk factors and in hypercholesterolaemia, KCa channel-mediated vasodilation appears to be activated. A novel paradigm establishes that perivascular adipose tissue (PVAT) is an additional regulator of vascular tone/function and endothelium is not the only agent in vascular hyperpolarization. Indeed, some PVAT-derived relaxing substances, such as adiponectin and angiotensin 1-7, may exert anticontractile and vasodilator actions by the opening of KCa channels in smooth muscle cells. Conversely, PVAT-derived factors impair coronary vasodilation via differential inhibition of some K+ channels. In view of adipose tissue abnormalities occurring in human obesity, changes in PVAT-dependent hyperpolarization may be relevant for vascular dysfunction also in this condition.
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Affiliation(s)
- F. Schinzari
- Department of Internal Medicine; Catholic University; Rome Italy
| | - M. Tesauro
- Department of Internal Medicine; Tor Vergata University; Rome Italy
| | - C. Cardillo
- Department of Internal Medicine; Catholic University; Rome Italy
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8
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Effect of potassium supplementation on vascular function: A meta-analysis of randomized controlled trials. Int J Cardiol 2016; 228:225-232. [PMID: 27865190 DOI: 10.1016/j.ijcard.2016.10.119] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 10/31/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND Effects of potassium supplementation on vascular function remain conflicting. This meta-analysis aimed to summarized current literature to fill the gaps in knowledge. METHODS A literature search was performed on PubMed database through April, 2016. The measurements of vascular function included pulse wave velocity (PWV), augmentation index (AI), pulse pressure (PP), flow mediated dilatation (FMD), glycerol trinitrate responses (GTN), and intercellular cell adhesion molecule-1 (ICAM-1). Data were pooled as standardized mean difference (SMD) with 95% confidence intervals. RESULTS Seven randomized controlled trials examining 409 participants were included, with dosage of potassium ranging from 40 to 150mmol/day, and duration of intervention from 6days to 12months. Pooling results revealed a significant improvement in PP (SMD -0.280, 95% CI -0.493 to -0.067, p=0.010), but no improvement in PWV (SMD -0.342, 95% CI -1.123 to 0·440, p=0.391), AI (SMD -0.114, 95% CI -0.282 to 0.054, p=0.184), FMD (SMD 0·278, 95% CI -0.321 to 0.877, p=0.363), GTN (SMD -0.009, 95% CI -0.949 to 0.930, p=0.984), and ICAM-1 (SMD -0.238, 95% CI -0.720 to 0.244, p=0.333). CONCLUSIONS Potassium supplementation was associated with significant improvement of PP, rather than other measurements of vascular function. However, the small number of researches and wide variation of evidences make it difficult to make a definitive conclusion.
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9
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Hearon CM, Kirby BS, Luckasen GJ, Larson DG, Dinenno FA. Endothelium-dependent vasodilatory signalling modulates α 1 -adrenergic vasoconstriction in contracting skeletal muscle of humans. J Physiol 2016; 594:7435-7453. [PMID: 27561916 DOI: 10.1113/jp272829] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 08/17/2016] [Indexed: 11/08/2022] Open
Abstract
KEY POINTS 'Functional sympatholysis' describes the ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction, and is critical to ensure proper blood flow and oxygen delivery to metabolically active skeletal muscle. The signalling mechanism responsible for sympatholysis in healthy humans is unknown. Evidence from animal models has identified endothelium-derived hyperpolarization (EDH) as a potential mechanism capable of attenuating sympathetic vasoconstriction. In this study, increasing endothelium-dependent signalling during exercise significantly enhanced the ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction in humans. This is the first study in humans to identify endothelium-dependent regulation of sympathetic vasoconstriction in contracting skeletal muscle, and specifically supports a role for EDH-like vasodilatory signalling. Impaired functional sympatholysis is a common feature of cardiovascular ageing, hypertension and heart failure, and thus identifying fundamental mechanisms responsible for sympatholysis is clinically relevant. ABSTRACT Stimulation of α-adrenoceptors elicits vasoconstriction in resting skeletal muscle that is blunted during exercise in an intensity-dependent manner. In humans, the underlying mechanisms remain unclear. We tested the hypothesis that stimulating endothelium-dependent vasodilatory signalling will enhance the ability of contracting skeletal muscle to blunt α1 -adrenergic vasoconstriction. Changes in forearm vascular conductance (FVC; Doppler ultrasound, brachial intra-arterial pressure via catheter) to local intra-arterial infusion of phenylephrine (PE; α1 -adrenoceptor agonist) were calculated during (1) infusion of the endothelium-dependent vasodilators acetylcholine (ACh) and adenosine triphosphate (ATP), the endothelium-independent vasodilator (sodium nitroprusside, SNP), or potassium chloride (KCl) at rest; (2) mild or moderate intensity handgrip exercise; and (3) combined mild exercise + ACh, ATP, SNP, or KCl infusions in healthy adults. Robust vasoconstriction to PE was observed during vasodilator infusion alone and mild exercise, and this was blunted during moderate intensity exercise (ΔFVC: -34 ± 4 and -34 ± 3 vs. -13 ± 2%, respectively, P < 0.05). Infusion of ACh or ATP during mild exercise significantly attenuated PE vasoconstriction similar to levels observed during moderate exercise (ACh: -3 ± 4; ATP: -18 ± 4%). In contrast, infusion of SNP or KCl during mild exercise did not attenuate PE-mediated vasoconstriction (-32 ± 5 and -46 ± 3%). To further study the role of endothelium-dependent hyperpolarization (EDH), ACh trials were repeated with combined nitric oxide synthase and cyclooxygenase inhibition. Here, PE-mediated vasoconstriction was blunted at rest (blockade: -20 ± 5 vs. CONTROL -31 ± 3% vs.; P < 0.05) and remained blunted during exercise (blockade: -15 ± 5 vs. CONTROL -14 ± 5%). We conclude that stimulation of EDH-like vasodilatation can blunt α1 -adrenergic vasoconstriction in contracting skeletal muscle of humans.
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Affiliation(s)
- Christopher M Hearon
- Human Cardiovascular Physiology Laboratory, Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, 80523, USA
| | - Brett S Kirby
- Human Cardiovascular Physiology Laboratory, Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, 80523, USA
| | - Gary J Luckasen
- Medical Center of the Rockies Foundation, University of Colorado Health System, Loveland, CO, 80538, USA
| | - Dennis G Larson
- Medical Center of the Rockies Foundation, University of Colorado Health System, Loveland, CO, 80538, USA
| | - Frank A Dinenno
- Human Cardiovascular Physiology Laboratory, Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, 80523, USA.,Center for Cardiovascular Research, Colorado State University, Fort Collins, CO, 80523, USA
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10
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Hearon CM, Racine ML. Integration of vasodilatory stimuli in skeletal muscle vasculature: subtraction by addition? J Physiol 2016; 594:3181-2. [DOI: 10.1113/jp272019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 01/29/2016] [Indexed: 11/08/2022] Open
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11
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Uluganyan M, Ekmekçi A, Murat A, Avşar Ş, Ulutaş TK, Uyarel H, Bozbay M, Çiçek G, Karaca G, Eren M. Admission serum potassium level is associated with in-hospital and long-term mortality in ST-elevation myocardial infarction. Anatol J Cardiol 2016; 16:10-5. [PMID: 26467357 PMCID: PMC5336698 DOI: 10.5152/akd.2015.5706] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/09/2015] [Indexed: 11/22/2022] Open
Abstract
OBJECTIVE Current guidelines recommend a serum potassium (sK) level of 4.0-5.0 mmol/L in acute myocardial infarction patients. Recent trials have demonstrated an increased mortality rate with an sK level of>4.5 mmol/L. The aim of this study was to figure out the relation between admission sK level and in-hospital and long-term mortality and ventricular arrhythmias. METHODS Retrospectively, 611 patients with ST-elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention were recruited. Admission sK levels were categorized accordingly: <3.5, 3.5-<4, 4-<4.5, 4.5-<5, and ≥5 mmol/L. RESULTS The lowest in-hospital and long-term mortality occurred in patients with sK levels of 3.5 to <4 mmol/L. The long-term mortality risk increased for admission sK levels of >4.5 mmol/L [odds ratio (OR), 1.58; 95% confidence interval (CI) 0.42-5.9 and OR, 2.27; 95% CI 0.44-11.5 for sK levels of 4.5-<5 mmol/L and ≥5 mmol/L, respectively]. At sK levels <3 mmol/L and ≥5 mmol/L, the incidence of ventricular arrhythmias was higher (p=0.019). CONCLUSION Admission sK level of >4.5 mmol/L was associated with increased long-term mortality in STEMI. A significant relation was found between sK level of <3 mmol/L and ≥5 mmol/L and ventricular arrhythmias.
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Affiliation(s)
- Mahmut Uluganyan
- Clinic of Cardiology, Kadirli Government Hospital; Osmaniye-Turkey.
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Yang L, Mäki-Petäjä K, Cheriyan J, McEniery C, Wilkinson IB. The role of epoxyeicosatrienoic acids in the cardiovascular system. Br J Clin Pharmacol 2015; 80:28-44. [PMID: 25655310 PMCID: PMC4500322 DOI: 10.1111/bcp.12603] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Revised: 01/19/2015] [Accepted: 01/23/2015] [Indexed: 12/29/2022] Open
Abstract
There is increasing evidence suggesting that epoxyeicosatrienoic acids (EETs) play an important role in cardioprotective mechanisms. These include regulating vascular tone, modulating inflammatory responses, improving cardiomyocyte function and reducing ischaemic damage, resulting in attenuation of animal models of cardiovascular risk factors. This review discusses the current knowledge on the role of EETs in endothelium-dependent control of vascular tone in the healthy and in subjects with cardiovascular risk factors, and considers the pharmacological potential of targeting this pathway.
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Affiliation(s)
- L Yang
- Experimental Medicine and Immunotherapeutics, Department of Medicine, Box 110, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - K Mäki-Petäjä
- Experimental Medicine and Immunotherapeutics, Department of Medicine, Box 110, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - J Cheriyan
- Experimental Medicine and Immunotherapeutics, Department of Medicine, Box 110, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - C McEniery
- Experimental Medicine and Immunotherapeutics, Department of Medicine, Box 110, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - I B Wilkinson
- Experimental Medicine and Immunotherapeutics, Department of Medicine, Box 110, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
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Blanch N, Clifton PM, Keogh JB. A systematic review of vascular and endothelial function: effects of fruit, vegetable and potassium intake. Nutr Metab Cardiovasc Dis 2015; 25:253-266. [PMID: 25456155 DOI: 10.1016/j.numecd.2014.10.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Revised: 10/02/2014] [Accepted: 10/04/2014] [Indexed: 01/16/2023]
Abstract
AIM To review the relationships between: 1) Potassium and endothelial function; 2) Fruits and vegetables and endothelial function; 3) Potassium and other measures of vascular function; 4) Fruits and vegetables and other measures of vascular function. DATA SYNTHESIS An electronic search for intervention trials investigating the effect of potassium, fruits and vegetables on vascular function was performed in MEDLINE, EMBASE and the Cochrane Library. Potassium appears to improve endothelial function with a dose of >40 mmol/d, however the mechanisms for this effect remain unclear. Potassium may improve measures of vascular function however this effect may be dependent on the effect of potassium on blood pressure. The effect of fruit and vegetables on endothelial function independent of confounding variables is less clear. Increased fruit and vegetable intake may improve vascular function only in high risk populations. CONCLUSION Increasing dietary potassium appears to improve vascular function but the effect of increasing fruit and vegetable intake per se on vascular function is less clear.
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Affiliation(s)
- N Blanch
- School of Pharmacy and Medical Science, University of South Australia, Australia
| | - P M Clifton
- School of Pharmacy and Medical Science, University of South Australia, Australia
| | - J B Keogh
- School of Pharmacy and Medical Science, University of South Australia, Australia.
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Palacios J, Nwokocha CR, Cifuentes F. Arsenic exposure decreases rhythmic contractions of vascular tone through sodium transporters and K + channels. World J Pharmacol 2014; 3:18-23. [DOI: 10.5497/wjp.v3.i2.18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2014] [Revised: 06/24/2014] [Accepted: 07/15/2014] [Indexed: 02/06/2023] Open
Abstract
Arsenic-contaminated drinking water is a public health problem in countries such as Taiwan, Bangladesh, United States, Mexico, Argentina, and Chile. The chronic ingestion of arsenic-contaminated drinking water increases the risk for ischemic heart disease, cerebrovascular disease, and prevalence of hypertension. Although toxic arsenic effects are controversial, there is evidence that a high concentration of arsenic may induce hypertension through increase in vascular tone and resistance. Vascular tone is regulated by the rhythmic contractions of the blood vessels, generated by calcium oscillations in the cytosol of vascular smooth muscle cells. To regulate the cytosolic calcium oscillations, the membrane oscillator model involves the participation of Ca2+ channels, calcium-activated K+ channels, Na+/Ca2+ exchange, plasma membrane Ca2+-ATPase, and the Na+/K+-ATPase. However, little is known about the role of K+ uptake by sodium transporters [Na+/K+-ATPase or Na+-K+-2Cl- (NKCC1)] on the rhythmic contractions. Vascular rhythmic contractions, or vasomotion are a local mechanism to regulate vascular resistance and blood flow. Since vascular rhythmic contractions of blood vessels are involved in modulating the vascular resistance, the blood flow, and the systemic pressure, we suggest a model explaining the participation of the sodium pump and NKCC1 co-transporter in low dose arsenic exposure effects on vasomotion and vascular dysfunction.
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Crecelius AR, Richards JC, Luckasen GJ, Larson DG, Dinenno FA. Reactive hyperemia occurs via activation of inwardly rectifying potassium channels and Na+/K+-ATPase in humans. Circ Res 2013; 113:1023-32. [PMID: 23940309 DOI: 10.1161/circresaha.113.301675] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
RATIONALE Reactive hyperemia (RH) in the forearm circulation is an important marker of cardiovascular health, yet the underlying vasodilator signaling pathways are controversial and thus remain unclear. OBJECTIVE We hypothesized that RH occurs via activation of inwardly rectifying potassium (KIR) channels and Na(+)/K(+)-ATPase and is largely independent of the combined production of the endothelial autocoids nitric oxide (NO) and prostaglandins in young healthy humans. METHODS AND RESULTS In 24 (23±1 years) subjects, we performed RH trials by measuring forearm blood flow (FBF; venous occlusion plethysmography) after 5 minutes of arterial occlusion. In protocol 1, we studied 2 groups of 8 subjects and assessed RH in the following conditions. For group 1, we studied control (saline), KIR channel inhibition (BaCl2), combined inhibition of KIR channels and Na(+)/K(+)-ATPase (BaCl2 and ouabain, respectively), and combined inhibition of KIR channels, Na(+)/K(+)-ATPase, NO, and prostaglandins (BaCl2, ouabain, L-NMMA [N(G)-monomethyl-L-arginine] and ketorolac, respectively). Group 2 received ouabain rather than BaCl2 in the second trial. In protocol 2 (n=8), the following 3 RH trials were performed: control; L-NMMA plus ketorolac; and L-NMMA plus ketorolac plus BaCl2 plus ouabain. All infusions were intra-arterial (brachial). Compared with control, BaCl2 significantly reduced peak FBF (-50±6%; P<0.05), whereas ouabain and L-NMMA plus ketorolac did not. Total FBF (area under the curve) was attenuated by BaCl2 (-61±3%) and ouabain (-44±12%) alone, and this effect was enhanced when combined (-87±4%), nearly abolishing RH. L-NMMA plus ketorolac did not impact total RH FBF before or after administration of BaCl2 plus ouabain. CONCLUSIONS Activation of KIR channels is the primary determinant of peak RH, whereas activation of both KIR channels and Na(+)/K(+)-ATPase explains nearly all of the total (AUC) RH in humans.
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Affiliation(s)
- Anne R Crecelius
- From the Human Cardiovascular Physiology Laboratory, Department of Health and Exercise Science, and Vascular Physiology Research Group, Department of Biomedical Sciences, Colorado State University, Fort Collins, CO; and Medical Center of the Rockies Foundation, University of Colorado Health, Loveland, CO
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Crecelius AR, Kirby BS, Luckasen GJ, Larson DG, Dinenno FA. Mechanisms of rapid vasodilation after a brief contraction in human skeletal muscle. Am J Physiol Heart Circ Physiol 2013; 305:H29-40. [PMID: 23645465 DOI: 10.1152/ajpheart.00298.2013] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
A monophasic increase in skeletal muscle blood flow is observed after a brief single forearm contraction in humans, yet the underlying vascular signaling pathways remain largely undetermined. Evidence from experimental animals indicates an obligatory role of vasodilation via K⁺-mediated smooth muscle hyperpolarization, and human data suggest little to no independent role for nitric oxide (NO) or vasodilating prostaglandins (PGs). We tested the hypothesis that K⁺-mediated vascular hyperpolarization underlies the rapid vasodilation in humans and that combined inhibition of NO and PGs would have a minimal effect on this response. We measured forearm blood flow (Doppler ultrasound) and calculated vascular conductance 10 s before and for 30 s after a single 1-s dynamic forearm contraction at 10%, 20%, and 40% maximum voluntary contraction in 16 young adults. To inhibit K⁺-mediated vasodilation, BaCl₂ and ouabain were infused intra-arterially to inhibit inwardly rectifying K⁺ channels and Na⁺-K⁺-ATPase, respectively. Combined enzymatic inhibition of NO and PG synthesis occurred via NG-monomethyl-L-arginine (L-NMMA; NO synthase) and ketorolac (cyclooxygenase), respectively. In protocol 1 (n = 8), BaCl₂ + ouabain reduced peak vasodilation (range: 30-45%, P < 0.05) and total postcontraction vasodilation (area under the curve, ~55-75% from control) at all intensities. Contrary to our hypothesis, L-NMMA + ketorolac had a further impact (peak: ~60% and area under the curve: ~80% from control). In protocol 2 (n = 8), the order of inhibitors was reversed, and the findings were remarkably similar. We conclude that K⁺-mediated hyperpolarization and NO and PGs, in combination, significantly contribute to contraction-induced rapid vasodilation and that inhibition of these signaling pathways nearly abolishes this phenomenon in humans.
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Affiliation(s)
- Anne R Crecelius
- Human Cardiovascular Physiology Laboratory, Department of Health and Exercise Science, Colorado State University, Fort Collins, CO 80523, USA
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Crecelius AR, Kirby BS, Luckasen GJ, Larson DG, Dinenno FA. ATP-mediated vasodilatation occurs via activation of inwardly rectifying potassium channels in humans. J Physiol 2012; 590:5349-59. [PMID: 22777673 DOI: 10.1113/jphysiol.2012.234245] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Circulating ATP possesses unique vasomotor properties in humans and has been hypothesized to play a role in vascular control under a variety of physiological conditions. However, the primary downstream signalling mechanisms underlying ATP-mediated vasodilatation remain unclear. The purpose of the present experiment was to determine whether ATP-mediated vasodilatation is independent of nitric oxide (NO) and prostaglandin (PG) synthesis and occurs primarily via the activation of Na(+)/K(+)-ATPase and inwardly rectifying potassium (K(IR)) channels in humans. In all protocols, young healthy adults were studied and forearm vascular conductance (FVC) was calculated from forearm blood flow (measured via venous occlusion plethysmography) and intra-arterial blood pressure to quantify local vasodilatation. Vasodilator responses (%FVC) during intra-arterial ATP infusions were unchanged following combined inhibition of NO and PGs (n = 8; P > 0.05) whereas the responses to KCl were greater (P < 0.05). Combined infusion of ouabain (to inhibit Na(+)/K(+)-ATPase) and barium chloride (BaCl(2); to inhibit K(IR) channels) abolished KCl-mediated vasodilatation (n = 6; %FVC = 134 ± 13 vs. 4 ± 5%; P < 0.05), demonstrating effective blockade of direct vascular hyperpolarization. The vasodilator responses to three different doses of ATP were inhibited on average 56 ± 5% (n = 16) following combined ouabain plus BaCl(2) infusion. In follow-up studies, BaCl(2) alone inhibited the vasodilator responses to ATP on average 51 ± 3% (n = 6), which was not different than that observed for combined ouabain plus BaCl(2) administration. Our novel results indicate that the primary mechanism of ATP-mediated vasodilatation is vascular hyperpolarization via activation of K(IR) channels. These observations translate in vitro findings to humans in vivo and may help explain the unique vasomotor properties of intravascular ATP in the human circulation.
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Affiliation(s)
- Anne R Crecelius
- Human Cardiovascular Physiology Laboratory, Department of Health and Exercise Science, Vascular Physiology Research Group, Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523-1582, USA
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Ozkor MA, Quyyumi AA. Endothelium-derived hyperpolarizing factor and vascular function. Cardiol Res Pract 2011; 2011:156146. [PMID: 21876822 PMCID: PMC3157651 DOI: 10.4061/2011/156146] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2011] [Revised: 05/27/2011] [Accepted: 05/27/2011] [Indexed: 01/20/2023] Open
Abstract
Endothelial function refers to a multitude of physiological processes that maintain healthy homeostasis of the vascular wall. Exposure of the endothelium to cardiac risk factors results in endothelial dysfunction and is associated with an alteration in the balance of vasoactive substances produced by endothelial cells. These include a reduction in nitric oxide (NO), an increase in generation of potential vasoconstrictor substances and a potential compensatory increase in other mediators of vasodilation. The latter has been surmised from data demonstrating persistent endothelium-dependent vasodilatation despite complete inhibition of NO and prostaglandins. This remaining non-NO, non-prostaglandin mediated endothelium-dependent vasodilator response has been attributed to endothelium-derived hyperpolarizing factor/s (EDHF). Endothelial hyperpolarization is likely due to several factors that appear to be site and species specific. Experimental studies suggest that the contribution of the EDHFs increase as the vessel size decreases, with a predominance of EDHF activity in the resistance vessels, and a compensatory up-regulation of hyperpolarization in states characterized by reduced NO availability. Since endothelial dysfunction is a precursor for atherosclerosis development and its magnitude is a reflection of future risk, then the mechanisms underlying endothelial dysfunction need to be fully understood, so that adequate therapeutic interventions can be designed.
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Affiliation(s)
- Muhiddin A Ozkor
- The Heart Hospital, University College London, London WIG 8PH, UK
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Bellien J, Joannides R, Richard V, Thuillez C. Modulation of cytochrome-derived epoxyeicosatrienoic acids pathway: A promising pharmacological approach to prevent endothelial dysfunction in cardiovascular diseases? Pharmacol Ther 2011; 131:1-17. [DOI: 10.1016/j.pharmthera.2011.03.015] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2011] [Accepted: 03/21/2011] [Indexed: 01/11/2023]
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Miura H, Toyama K, Pratt PF, Gutterman DD. Cigarette smoking impairs Na+-K+-ATPase activity in the human coronary microcirculation. Am J Physiol Heart Circ Physiol 2010; 300:H109-17. [PMID: 21076023 DOI: 10.1152/ajpheart.00237.2010] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The extracellular K(+) concentration ([K(+)](o)) has been proposed to link cardiac metabolism with coronary perfusion and arrhythmogenesis, particularly during ischemia. Several animal studies have also supported K(+) as an EDHF that activates Na(+)-K(+)-ATPase and/or inwardly rectifying K(+) (K(ir)) channels. Therefore, we examined the vascular reactivity of human coronary arterioles (HCAs) to small elevations in [K(+)](o), the influence of risk factors for coronary disease, and the role of K(+) as an EDHF. Changes in the internal diameter of HCAs were recorded with videomicroscopy. Most vessels dilated to increases in [K(+)](o) with a maximal dilation of 55 ± 6% primarily at 12.5-20.0 mM KCl (n = 38, average: 16 ± 1 mM). Ouabain, a Na(+)-K(+)-ATPase inhibitor, alone reduced the dilation, and the addition of Ba(2+), a K(ir) channel blocker, abolished the remaining dilation, whereas neither endothelial denudation nor Ba(2+) alone reduced the dilation. Multivariate analysis revealed that cigarette smoking was the only risk factor associated with impaired dilation to K(+). Ouabain significantly reduced the vasodilation in HCAs from subjects without cigarette smoking but not in those with smoking. Cigarette smoking downregulated the expression of the Na(+)-K(+)-ATPase catalytic α(1)-subunit but not Kir2.1 in the vessels. Ouabain abolished the dilation in endothelium-denuded vessels to a same extent to that with the combination of ouabain and Ba(2+) in endothelium-intact vessels, whereas neither ouabain nor ouabain plus Ba(2+) reduced EDHF-mediated dilations to bradykinin and ADP. A rise in [K(+)](o) dilates HCAs primarily via the activation of Na(+)-K(+)-ATPase in vascular smooth muscle cells with a considerable contribution of K(ir) channels in the endothelium, indicating that [K(+)](o) may modify coronary microvascular resistance in humans. Na(+)-K(+)-ATPase activity is impaired in subjects who smoke, possibly contributing to dysregulation of the coronary microcirculation, excess ischemia, and arrhythmogenesis in those subjects. K(+) does not likely serve as an EDHF in the human coronary arteriolar dilation to bradykinin and ADP.
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Affiliation(s)
- Hiroto Miura
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
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Büssemaker E, Hillebrand U, Hausberg M, Pavenstädt H, Oberleithner H. Pathogenesis of Hypertension: Interactions Among Sodium, Potassium, and Aldosterone. Am J Kidney Dis 2010; 55:1111-20. [DOI: 10.1053/j.ajkd.2009.12.022] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2009] [Accepted: 12/03/2009] [Indexed: 01/11/2023]
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Ulusoy HB, Kaya MG. Potassium induced dilation in bovine coronary artery involves both inward rectifier potassium channels and Na+ /K+ ATPase. ACTA ACUST UNITED AC 2010; 96:427-36. [PMID: 19942549 DOI: 10.1556/aphysiol.96.2009.4.3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Increases in extracellular potassium (K+) concentration (up to 20 mM) cause dilation in some blood vessels. This may be particularly important in myocardial ischemia because in this condition K+ is released from ischemic cells. In this study, we investigated mechanisms of effect of increased K+ concentration on the tone of isolated bovine coronary artery. Bovine coronary arteries were isolated and mounted in organ baths for isometric tension recording. After an equilibration period, arteries were contracted with serotonin (1 microM). When serotonin contraction reached a steady-state, K+ concentration of organ baths was increased from physiological levels to 10 mM, 14 mM, 18 mM or 22 mM in four groups of the arteries. After a washout period, this procedure was repeated in presence of ouabain, a blocker of Na+ /K+ ATPase or a K+ channel blocker (tetraethylammonium, 4-aminopyridine, glibenclamide or barium). Increasing K+ concentration of the organ baths to 10 mM, 14 mM and 18 mM caused dilation in the arteries. Ouabain abolished the dilation and barium (a blocker of inward rectifier K + channels) inhibited the dilation significantly.According to our results there is K+ -induced dilation in bovine coronary artery and it involves activation of both Na+ /K+ ATPase and inward rectifier K+ channels.
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Affiliation(s)
- H B Ulusoy
- Department of Pharmacology, Faculty of Medicine, Erciyes University, Kayseri, Turkey.
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Bellien J, Thuillez C, Joannides R. Contribution of endothelium-derived hyperpolarizing factors to the regulation of vascular tone in humans. Fundam Clin Pharmacol 2008; 22:363-77. [DOI: 10.1111/j.1472-8206.2008.00610.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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Park WS, Han J, Earm YE. Physiological role of inward rectifier K+ channels in vascular smooth muscle cells. Pflugers Arch 2008; 457:137-47. [DOI: 10.1007/s00424-008-0512-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2007] [Revised: 03/19/2008] [Accepted: 03/25/2008] [Indexed: 10/22/2022]
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Juel C, Olsen S, Rentsch RL, González-Alonso J, Rosenmeier JB. K+ as a vasodilator in resting human muscle: implications for exercise hyperaemia. Acta Physiol (Oxf) 2007; 190:311-8. [PMID: 17394572 DOI: 10.1111/j.1748-1716.2007.01678.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
AIM Potassium (K(+)) released from contracting skeletal muscle is considered a vasodilatory agent. This concept is mainly based on experiments infusing non-physiological doses of K(+). The aim of the present study was to investigate the role of K(+) in blood flow regulation. METHODS We measured leg blood flow (LBF) and arterio-venous (A-V) O(2) difference in 13 subjects while infusing K(+) into the femoral artery at a rate of 0.2, 0.4, 0.6 and 0.8 mmol min(-1). RESULTS The lowest dose increased the calculated femoral artery plasma K(+) concentration by approx.1 mmol L(-1). Graded K(+) infusions increased LBF from 0.39 +/- 0.06 to 0.56 +/- 0.13, 0.58 +/- 0.17, 0.61 +/- 0.11 and 0.71 +/- 0.17 L min(-1), respectively, whereas the leg A-V O(2) difference decreased from 74 +/- 9 to 60 +/- 12, 52 +/- 11, 53 +/- 9 and 45 +/- 7 mL L(-1), respectively (P < 0.05). Mean arterial pressure was unchanged, indicating that the increase in LBF was associated with vasodilatation. The effect of K(+) was totally inhibited by infusion (27 micromol min(-1)) of Ba(2+), an inhibitor of Kir2.1 channels. Simultaneous infusion of ATP and K(+) evoked an increase in LBF equalled to the sum of their effects. CONCLUSIONS Physiological infusions of K(+) induce significant increases in resting LBF, which are completely blunted by inhibition of the Kir2.1 channels. The present findings in resting skeletal muscle suggest that K(+) released from contracting muscle might be involved in exercise hyperaemia. However, the magnitude of increase in LBF observed with K(+) infusion suggests that K(+) only accounts for a limited fraction of the hyperaemic response to exercise.
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Affiliation(s)
- C Juel
- Institute of Molecular Biology and Physiology, Copenhagen Muscle Research Centre, University of Copenhagen, Copenhagen, Denmark.
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Li J, Gao Z, Kehoe V, Sinoway LI. Interstitial K+ concentration in active muscle after myocardial infarction. Am J Physiol Heart Circ Physiol 2006; 292:H808-13. [PMID: 17012361 PMCID: PMC2291533 DOI: 10.1152/ajpheart.00295.2006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Previous work demonstrated that Na(+)-K(+) pump activity within skeletal muscle is attenuated in myocardial infarction (MI). This may lead to enhanced interstitial K(+) concentration ([K(+)](o)) in the muscle. We tested the hypothesis that [K(+)](o) rises with muscle contraction and that, in rats with MI, the rate of rise in [K(+)](o) is greater than it is in control animals. Microdialysis probes were inserted in the skeletal muscle of six healthy control and six MI rats. The ends of the probes were then attached to the K(+) electrodes, and [K(+)](o) was continuously measured. Muscle contraction was induced by electrical stimulation of the sciatic nerves for 1 min. Stimulation at 1 and 3 Hz increased muscle [K(+)](o) by 14.2% and 44.7% in controls and by 22.9% and 62.8% in MI rats (P < 0.05 vs. controls), respectively. When ouabain, an inhibitor of Na(+)-K(+) pump, was added to the perfusate, muscle [K(+)](o) rose significantly. This effect of ouabain was significantly attenuated in MI animals. In conclusion, when compared with that in control animals, an increase of [K(+)](o) in exercising muscle is augmented in MI rats, likely due to an attenuation of Na(+)-K(+) pump activity.
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Affiliation(s)
- Jianhua Li
- Division of Cardiology, Pennsylvania State University College of Medicine, 500 University Dr., Hershey, PA 17033, USA.
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Fujita T, Ogino M, Daigo F, Yamaguchi T, Majima M. Intracellular Ca2+ contributes to K+-induced increase in renal kallikrein secretion. Int Immunopharmacol 2006; 6:1487-95. [PMID: 16846843 DOI: 10.1016/j.intimp.2006.05.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2005] [Revised: 01/26/2006] [Accepted: 05/24/2006] [Indexed: 11/23/2022]
Abstract
We have reported that natriuretic effects of K(+) are involved in enhancement of renal kallikrein-kinin system. The study was aimed to examine 1) comparison of augmentative effects of K(+) on urinary KK excretion with non-specific washout effects by trichlormethiazide (thiazide), polyethyleneglycol 200 (PEG) and rapid physiological saline infusion, 2) contribution of Ca(2+) on the K(+)-induced increase in renal kallikrein secretion. Renal kallikrein activities were measured as fluorescence activities of methylcoumarinylamide-labeled synthetic substrate of tissue kallikrein (TK). Increases in urinary TK excretion were simultaneously observed with diuresis caused by thiazide, PEG, and rapid saline infusion. K(+) infusion increased urinary TK excretion with a diuretic response same as the control. K(+), but not thiazide, showed an early increase in renal TK secretion dose dependently in the kidney slices. Increases in renal TK secretion persisted during treatment with K(+). Neither voltage-dependent Ca(2+)-channel blockers such as verapamil and nifedipine nor simultaneous treatment of EDTA affected on the K(+)-induced increase in renal TK secretion. While, EDTA decreased the K(+)-induced increases in renal TK secretion with time. Caffeine also had an early effect on the increase in renal TK secretion. K(+)-induced increases in renal TK secretion was demonstrated even after treatment with ryanodine or depletion of caffeine-sensitive intracellular Ca(2+) by thapsigargin. It was indicated that the increase in renal TK secretion by K(+) depends on the intracellular Ca(2+) and the caffeine-sensitive release of intracellular Ca(2+) may not be involved in this response. Mechanisms for the K(+)-induced increase in renal TK secretion needs to be further elucidated.
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Affiliation(s)
- Tomoe Fujita
- Department of Pharmacology, Kitasato University, School of Medicine, Kitasato 1-15-1, Sagamihara, Kanagawa 228-8555, Japan.
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Haddy FJ, Vanhoutte PM, Feletou M. Role of potassium in regulating blood flow and blood pressure. Am J Physiol Regul Integr Comp Physiol 2006; 290:R546-52. [PMID: 16467502 DOI: 10.1152/ajpregu.00491.2005] [Citation(s) in RCA: 197] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Unlike sodium, potassium is vasoactive; for example, when infused into the arterial supply of a vascular bed, blood flow increases. The vasodilation results from hyperpolarization of the vascular smooth muscle cell subsequent to potassium stimulation by the ion of the electrogenic Na+-K+ pump and/or activating the inwardly rectifying Kir channels. In the case of skeletal muscle and brain, the increased flow sustains the augmented metabolic needs of the tissues. Potassium ions are also released by the endothelial cells in response to neurohumoral mediators and physical forces (such as shear stress) and contribute to the endothelium-dependent relaxations, being a component of endothelium-derived hyperpolarization factor-mediated responses. Dietary supplementation of potassium can lower blood pressure in normal and some hypertensive patients. Again, in contrast to NaCl restriction, the response to potassium supplementation is slow to appear, taking approximately 4 wk. Such supplementation reduces the need for antihypertensive medication. "Salt-sensitive" hypertension responds particularly well, perhaps, in part, because supplementation with potassium increases the urinary excretion of sodium chloride. Potassium supplementation may even reduce organ system complications (e.g., stroke).
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Affiliation(s)
- Francis J Haddy
- Department of Physiology and Biomedical Engineering, Mayo Clinic, College of Medicine, Rochester, Minnesota, USA
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Li J, Sinoway LI, Ng YC. Aging augments interstitial K+concentrations in active muscle of rats. J Appl Physiol (1985) 2006; 100:1158-63. [PMID: 16322369 DOI: 10.1152/japplphysiol.00639.2005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Skeletal muscle performance declines with advancing age, and the underlying mechanism is not completely understood. A large body of convincing evidence has demonstrated a crucial role for interstitial K+concentration ([K+]o) in modulating contractile function of skeletal muscle. The present study tested the hypothesis that during muscle contraction there is a greater accumulation of [K+]oin aged compared with adult skeletal muscle. Twitch muscle contraction was induced by electrical stimulation of the sciatic nerves of 8- and 32-mo-old Fischer 344 × Brown Norway rats. Levels of [K+]owere measured continuously by a microdialysis technique with the probes inserted into the gastrocnemius muscle. Stimulation at 1, 3, and 5 Hz elevated muscle [K+]oby 52, 64, and 88% in adult rats, and by 78, 98, and 104% in aged rats, respectively, and the increase was significantly higher in aged than in adult rats. Recovery for [K+]o, as measured by the time for [K+]oto recover by 20 and 50% from peak response after stimulation, was slower in aged rats. Ouabain (5 mM), a specific inhibitor of the Na+-K+pump, was added in the perfusate to inhibit the reuptake of K+into the cells to assess the role of the pump in the overall K+balance. Ouabain elevated muscle [K+]oat rest, and the effect was significantly attenuated in aged animals. The present data demonstrated an augmented [K+]oin aged skeletal muscle compared with adult skeletal muscle, and the data suggested that an alteration in the function of the Na+-K+pump may contribute, in part, to the deficiency in K+balance in skeletal muscle of aged rats.
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Affiliation(s)
- Jianhua Li
- Division of Cardiology, Pennsylvania State College of Medicine, Milton S. Hershey Medical Center, 500 University Dr., Hershey, PA 17033, USA
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31
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Van Beekvelt MCP, Drost G, Rongen G, Stegeman DF, Van Engelen BGM, Zwarts MJ. Na+-K+-ATPase is not involved in the warming-up phenomenon in generalized myotonia. Muscle Nerve 2006; 33:514-23. [PMID: 16382442 DOI: 10.1002/mus.20483] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The initial temporary weakness that occurs in autosomal-recessive generalized myotonia diminishes with repetitive contractions. Physiological understanding of this phenomenon is incomplete. The underlying hypothesis of our study was that the "warming-up" phenomenon relates to the exercise-related activation of Na(+)-K(+)-ATPase. Three patients performed isometric exercise of the brachioradialis muscle on two separate days. Randomly, on one of these days the contraction was preceded by a 30-min infusion of the Na(+)-K(+)-ATPase inhibitor ouabain into the brachial artery of the exercising arm (0.4 mug.min(-1).dl(-1)). Force was measured simultaneously with electrical muscle activity using high-density surface electromyography (HD-sEMG). A transient rapid decline in force occurred after initiation of exercise, accompanied by electrophysiological changes indicating sarcolemmal conduction block. Ouabain infusion did not affect the recovery from transient paresis or the accompanying electromyographic changes, indicating that the warming-up phenomenon in generalized myotonia is not mediated by Na(+)-K(+)-ATPase.
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Affiliation(s)
- Mireille C P Van Beekvelt
- Department of Clinical Neurophysiology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
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Goto K, Rummery NM, Grayson TH, Hill CE. Attenuation of conducted vasodilatation in rat mesenteric arteries during hypertension: role of inwardly rectifying potassium channels. J Physiol 2004; 561:215-31. [PMID: 15550469 PMCID: PMC1665331 DOI: 10.1113/jphysiol.2004.070458] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The present study was designed to elucidate whether the conduction of vasomotor responses mediated by endothelium-derived hyperpolarizing factor (EDHF) in rat mesenteric arteries is altered during hypertension. Iontophoresed acetylcholine (ACh; 500 ms) caused EDHF-mediated hyperpolarization and vasodilatation at the local site and these responses spread through the endothelium to remote sites in 12-week-old Wistar-Kyoto rats (WKY). Conducted responses were significantly attenuated in age-matched spontaneously hypertensive rats (SHR) although the rate of decay with distance did not change. Inhibition of inwardly rectifying potassium (Kir) channels (30 microM barium) eliminated the difference between WKY and SHR by attenuating conducted responses in WKY but not SHR. At the local site, barium (30 microM) significantly reduced the duration but not the amplitude of ACh-induced hyperpolarization in WKY only. Barium had no effect when the iontophoretic stimulus was reduced to 350 ms. After blockade of EDHF in SHR, ACh elicited a depolarization which our indirect data suggest spreads along the vessel in the endothelium. Messenger RNA expression of Kir2.0 genes did not differ between the strains nor did the amplitude of K(+)-induced hyperpolarization, which was abolished by disruption of the endothelium. Immunohistochemistry revealed a decrease in connexin (Cx)37 but not Cx40 or Cx43 protein in endothelial cells of SHR compared to WKY. Results suggest that conduction of EDHF-mediated responses in WKY, but not in SHR, is facilitated by activation of Kir channels at the site of ACh application and not by differences in endothelial connexin expression. Lack of Kir channel involvement in hypertension may result from reduction in the duration of the hyperpolarization due to the development of ACh-mediated depolarization, rather than to any difference in Kir subunit expression or function.
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Affiliation(s)
- Kenichi Goto
- Division of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT, 0200, Australia.
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Abstract
Humans are prone to sodium overload and potassium depletion. This electrolyte imbalance is important in the pathogenesis of cardiovascular disease and sudden cardiac death. Avoiding hypokalemia is beneficial in several cardiovascular disease states including acute myocardial infarction, heart failure, and hypertension. The evidence highlighting the importance of potassium homeostasis in cardiovascular disease and possible mechanisms explaining potassium's benefits are reviewed. Targets for serum potassium concentration are suggested.
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Affiliation(s)
- John E Macdonald
- Department of Clinical Pharmacology, Ninewells Hospital, Dundee, United Kingdom.
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van Ginneken EEM, Meijer P, Verkaik N, Smits P, Rongen GA. ATP-induced vasodilation in human skeletal muscle. Br J Pharmacol 2004; 141:842-50. [PMID: 14769779 PMCID: PMC1574250 DOI: 10.1038/sj.bjp.0705589] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
1. The purine nucleotide adenosine-5'-triphosphate (ATP) exerts pronounced effects on the cardiovascular system. The mechanism of action of the vasodilator response to ATP in humans has not been elucidated yet. The proposed endothelium-derived relaxing factors (EDRFs) were studied in a series of experiments, using the perfused forearm technique. 2. Adenosine 5'-triphosphate (0.2, 0.6, 6 and 20 nmol dl(-1) forearm volume min(-1)) evoked a dose-dependent forearm vasodilator response, which could not be inhibited by separate infusion of the nonselective COX inhibitor indomethacin (5 microg dl(-1) min(-1), n=10), the blocker of Na(+)/K(+)-ATPase ouabain (0.2 microg dl(-1) min(-1), n=8), the blocker of K(Ca) channels tetraethylammonium chloride (TEA, 0.1 microg dl(-1) min(-1), n=10), nor by the K(ATP)-channel blocker glibenclamide (2 microg dl(-1) min(-1), n=10). All blockers, except glibenclamide, caused a significant increase in baseline vascular tone. The obtained results might be due to compensatory actions of unblocked EDRFs. Combined infusion of TEA, indomethacin and l-NMMA (n=6) significantly increased the baseline forearm vascular resistance. The ATP-induced relative decreases in forearm vascular resistance were 48+/-5, 67+/-3, 88+/-2, and 92+/-2% in the absence and 23+/-7, 62+/-4, 89+/-2, and 93+/-1% in the presence of the combination of TEA, indomethacin and l-NMMA (P<0.05, repeated-measures ANOVA, n=6). A similar inhibition was obtained for sodium nitroprusside (SNP, P<0.05 repeated-measures ANOVA, n=6), indicating a nonspecific interaction due to the blocker-induced vasoconstriction. 3. ATP-induced vasodilation in the human forearm cannot be inhibited by separate infusion of indomethacin, ouabain, glibenclamide or TEA, or by a combined infusion of TEA, indomethacin, and l-NMMA. Endothelium-independent mechanisms and involvement of unblocked EDRFs, such as CO, might play a role, and call for further studies.
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Affiliation(s)
- E E M van Ginneken
- Department of General Internal Medicine, University Medical Centre Nijmegen, P.O. Box 9101, Nijmegen, 6500 HB, The Netherlands
| | - P Meijer
- Department of Pharmacology-Toxicology, University Medical Centre Nijmegen, P.O. Box 9101, Nijmegen, 6500 HB, The Netherlands
| | - N Verkaik
- Department of Pharmacology-Toxicology, University Medical Centre Nijmegen, P.O. Box 9101, Nijmegen, 6500 HB, The Netherlands
| | - P Smits
- Department of Pharmacology-Toxicology, University Medical Centre Nijmegen, P.O. Box 9101, Nijmegen, 6500 HB, The Netherlands
| | - G A Rongen
- Department of Pharmacology-Toxicology, University Medical Centre Nijmegen, P.O. Box 9101, Nijmegen, 6500 HB, The Netherlands
- Author for correspondence:
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Avogaro A, de Kreutzenberg S, Kiwanuka E, Tiengo A. Nonesterified fatty acids and endothelial dysfunction. ACTA ACUST UNITED AC 2003. [DOI: 10.1016/s0531-5131(02)01282-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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de Kreutzenberg SV, Puato M, Kiwanuka E, Del Prato S, Pauletto P, Pasini L, Tiengo A, Avogaro A. Elevated non-esterified fatty acids impair nitric oxide independent vasodilation, in humans: evidence for a role of inwardly rectifying potassium channels. Atherosclerosis 2003; 169:147-53. [PMID: 12860261 DOI: 10.1016/s0021-9150(03)00153-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
UNLABELLED To evaluate the role of elevation of non-esterified fatty acids on forearm nitric oxide (NO) dependent and independent relaxation, four studies were performed in the forearms of 14 normals: (1). endothelium-dependent and -independent vasodilations were assessed during acetylcholine (Ach) and sodium nitroprusside (SNP) infusions; (2). flow-mediated vasodilation (FMD) was assessed; (3) .bradykinin (BK) was infused during NO and prostaglandin inhibition (NO clamp); (4). blood flow (FBF) was measured during Ouabain, a Na(+)/K(+) ATPase, and BaCl(2), rectifying potassium channel (K(IR)) blockers, respectively. All studies were performed before and after 120 min. Intralipid+heparin (high-NEFA) infusion. Ach-mediated FBF increase was lower at high-NEFA (332+/-34 vs. 436+/-44% at 45 microg l forearm(-1) min(-1); % of ratio infused: control arm P<0.05), while SNP response was similar. FMD did not differ before and during high-NEFA, which induced a blunted response of FBF during BK with or without NO clamp. Ouabain and BaCl(2)-mediated FBF inhibition was lower (P<0.01) at high-NEFA. During ouabain alone FBF decreased slightly. IN CONCLUSION High-NEFA exerts a negative role on both NO-dependent and independent vasodilations. The decrease in FBF, mediated by K(IR) inhibition, is blunted by high-NEFA: these substrates interfere with hemodynamic/metabolism coupling, possibly through the inhibition of these channels.
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Affiliation(s)
- Saula Vigili de Kreutzenberg
- Department of Clinical and Experimental Medicine, Cattedra di Malattie del Metabolismo, University of Padova, Via Giustiniani 2, 35128 Padua, Italy
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Büssemaker E, Popp R, Binder J, Busse R, Fleming I. Characterization of the endothelium-derived hyperpolarizing factor (EDHF) response in the human interlobar artery. Kidney Int 2003; 63:1749-55. [PMID: 12675850 DOI: 10.1046/j.1523-1755.2003.00910.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND In addition to nitric oxide (NO) and prostacyclin (PGI2), the vascular endothelium can influence local vascular tone by a mechanism involving the hyperpolarization of vascular smooth muscle cells. This response is attributed to the release of an endothelium-derived hyperpolarizing factor (EDHF). The present study was performed to determine the characteristics of the EDHF that mediates the NO/PGI2-independent hyperpolarization and relaxation of human renal interlobar arteries. METHODS Acetylcholine-induced, EDHF-mediated hyperpolarization and relaxation were assessed using sharp microelectrodes impaled into interlobar smooth muscle cells and in organ chamber experiments, respectively. All experiments were performed in the combined presence of NO synthase (NOS) and cyclooxygenase inhibitors and the thromboxane analog U46619. RESULTS Interlobar arteries demonstrated pronounced NO/PGI2-independent relaxations and hyperpolarizations that were sensitive to the blockade of calcium-activated K+-channels (KCa+ channels) by the combination of charybdotoxin and apamin and to the inhibition of the Na-K-ATPase by ouabain. Exogenously applied KCl also exhibited relaxations and hyperpolarizations that were sensitive to ouabain but insensitive to the combined inclusion of charybdotoxin and apamin. Relaxations induced by KCl were also observed in endothelium-denuded interlobar arteries. CONCLUSION These results indicate that in the human renal interlobar artery, EDHF-mediated responses display the pharmacologic characteristics of K+ ions released through endothelial KCa+ channels. Smooth muscle cell hyperpolarization and relaxation appear to be dependent on the activation of ouabain-sensitive subunits of the Na-K-ATPase.
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Affiliation(s)
- Eckhart Büssemaker
- Institut für Kardiovaskuläre Physiologie, and Klinik für Urologie und Kinderurologie, Klinikum der J.W.G.-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany
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Busse R, Edwards G, Félétou M, Fleming I, Vanhoutte PM, Weston AH. EDHF: bringing the concepts together. Trends Pharmacol Sci 2002; 23:374-80. [PMID: 12377579 DOI: 10.1016/s0165-6147(02)02050-3] [Citation(s) in RCA: 590] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Endothelial cells synthesize and release vasoactive mediators in response to various neurohumoural substances (e.g. bradykinin or acetylcholine) and physical stimuli (e.g. cyclic stretch or fluid shear stress). The best-characterized endothelium-derived relaxing factors are nitric oxide and prostacyclin. However, an additional relaxant pathway associated with smooth muscle hyperpolarization also exists. This hyperpolarization was originally attributed to the release of an endothelium-derived hyperpolarizing factor (EDHF) that diffuses to and activates smooth muscle K(+) channels. More recent evidence suggests that endothelial cell receptor activation by these neurohumoural substances opens endothelial cell K(+) channels. Several mechanisms have been proposed to link this pivotal step to the subsequent smooth muscle hyperpolarization. The main concepts are considered in detail in this review.
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Affiliation(s)
- Rudi Busse
- Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Frankfurt, Germany
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