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Katunaric B, SenthilKumar G, Stehula FJ, Werthman A, Bordas-Murphy H, Freed JK. Noninvasive assessment of human microvascular function in health and disease using incident dark-field microscopy. Am J Physiol Heart Circ Physiol 2024; 327:H261-H267. [PMID: 38787388 PMCID: PMC11380954 DOI: 10.1152/ajpheart.00292.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 05/22/2024] [Accepted: 05/22/2024] [Indexed: 05/25/2024]
Abstract
Reduced peripheral microvascular reactivity is associated with an increased risk for major adverse cardiac events (MACEs). Tools for noninvasive assessment of peripheral microvascular function are limited, and existing technology is poorly validated in both healthy populations and patients with cardiovascular disease (CVD). Here, we used a handheld incident dark-field imaging tool (CytoCam) to test the hypothesis that, compared with healthy individuals (no risk factors for CVD), subjects formally diagnosed with coronary artery disease (CAD) or those with ≥2 risk factors for CAD (at risk) would exhibit impaired peripheral microvascular reactivity. A total of 17 participants (11 healthy, 6 at risk) were included in this pilot study. CytoCam was used to measure sublingual microvascular total vessel density (TVD), perfused vessel density (PVD), and microvascular flow index (MFI) in response to the topical application of acetylcholine (ACh) and sublingual administration of nitroglycerin (NTG). Baseline MFI and PVD were significantly reduced in the at-risk cohort compared with healthy individuals. Surprisingly, following the application of acetylcholine and nitroglycerin, both groups showed a significant improvement in all three microvascular perfusion parameters. These results suggest that, despite baseline reductions in both microvascular density and perfusion, human in vivo peripheral microvascular reactivity to both endothelial-dependent and -independent vasoactive agents remains intact in individuals with CAD or multiple risk factors for disease.NEW & NOTEWORTHY To our knowledge, this is the first study to comprehensively characterize in vivo sublingual microvascular structure and function (endothelium-dependent and -independent) in healthy patients and those with CVD. Importantly, we used an easy-to-use handheld device that can be easily translated to clinical settings. Our results indicate that baseline microvascular impairments in structure and function can be detected using the CytoCam technology, although reactivity to acetylcholine may be maintained even during disease in the peripheral microcirculation.
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Affiliation(s)
- Boran Katunaric
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Gopika SenthilKumar
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Forrest J Stehula
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Alec Werthman
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Henry Bordas-Murphy
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Julie K Freed
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
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Nóbrega OT, Campos-Staffico AM, Oliveira EK, Munhoz DB, Moura FA, Carvalho LSF, Soares AASM, Gomes CM, Tonet-Furioso AC, Sposito AC. Defective Allele of the Neuronal Nitric Oxide Synthase Gene Increases Insulin Resistance During Acute Phase of Myocardial Infarction. Int J Gen Med 2021; 14:3669-3676. [PMID: 34321912 PMCID: PMC8312503 DOI: 10.2147/ijgm.s313661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Accepted: 06/30/2021] [Indexed: 11/23/2022] Open
Abstract
Background Glycemic disorders are strong predictors of mortality in ST-elevation myocardial infarction (STEMI) patients, and disruption in nitric oxide (NO) production is associated with insulin-resistant states. We evaluated whether a defective allele of the neuronal nitric oxide synthase (nNOS) gene (NOS1) might influence insulin response and blood-glucose balance during the acute phase of STEMI and if post-infarction total plasma-NO levels and vasodilation scores varied across nNOS genotypes. Methods Consecutive patients with STEMI (n=354) underwent clinical evaluations and genotyping for the promoter variation rs41279104. In-hospital clinical and blood evaluations were performed at admission and five days after STEMI, with glycemic, insulinemic, and disposition indices assessed at the same times. Flow-mediated dilation (FMD) was assessed by reactive hyperemia on the 30th day. Results Homozygotes for the defective allele (A) showed lower glycemia and insulin sensitivity on day 1 while showing the highest β-cell function and no changes in the circulating NO pool, which is compatible with hyperresponsive β cells counteracting the inherent glucose-resistant state of AA patients. At day 5, glycemic scores had shifted to indicate greater insulin sensitivity among A homozygotes, paralleled by a significant yet poor increase in NO bioavailability compared to that among G carriers. All in all, defective homozygotes showed greater insulin resistance at admission that had reversed by 5 days after STEMI. Even so, A carriers developed lower FMD scores compared to G homozygotes after the acute phase. Conclusion A defective nNOS allele (and due decline in NO production) seemed to elicit a hyperinsulinemia response to compensate for an insulin-resistant state during the acute phase of STEMI and to be associated with poor endothelial function after the acute phase.
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Affiliation(s)
- Otávio T Nóbrega
- Programa de Pós-Graduação em Ciências Médicas, Faculdade de Medicina, Universidade de Brasília (UnB), Brasília, DF, Brazil
| | | | - Elayne Kelen Oliveira
- Departamento de Cardiologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brazil
| | - Daniel B Munhoz
- Departamento de Cardiologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brazil
| | - Filipe A Moura
- Departamento de Cardiologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brazil
| | - Luis Sérgio F Carvalho
- Centro de Inovação, Ensino e Pesquisa, Instituto de Gestão Estratégica em Saúde do Distrito Federal, Brasília, DF, Brazil
| | - Alexandre Anderson S M Soares
- Programa de Pós-Graduação em Ciências Médicas, Faculdade de Medicina, Universidade de Brasília (UnB), Brasília, DF, Brazil.,Serviço de Cardiologia, Instituto Biocárdios, Brasília, DF, Brazil
| | - Ciro M Gomes
- Programa de Pós-Graduação em Ciências Médicas, Faculdade de Medicina, Universidade de Brasília (UnB), Brasília, DF, Brazil.,Laboratório de Dermatomicologia, Faculdade de Medicina, Universidade de Brasília (UnB), Brasília, DF, Brazil
| | - Audrey C Tonet-Furioso
- Programa de Pós-Graduação em Gerontologia, Universidade Católica de Brasília (UCB-DF), Taguatinga, DF, Brazil
| | - Andrei C Sposito
- Programa de Pós-Graduação em Ciências Médicas, Faculdade de Medicina, Universidade de Brasília (UnB), Brasília, DF, Brazil.,Departamento de Cardiologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brazil
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Al-Badri A, Kim JH, Liu C, Mehta PK, Quyyumi AA. Peripheral Microvascular Function Reflects Coronary Vascular Function. Arterioscler Thromb Vasc Biol 2019; 39:1492-1500. [PMID: 31018659 PMCID: PMC6594879 DOI: 10.1161/atvbaha.119.312378] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Objectives- Coronary endothelial dysfunction is a precursor of atherosclerosis and adverse outcomes. Whether endothelial dysfunction is a localized or generalized phenomenon in humans remains uncertain. We simultaneously measured femoral and coronary vascular function with the hypothesis that peripheral vascular endothelial function will be reflective of coronary endothelial function. Approach and Results- Eighty-five subjects underwent coronary angiography for evaluation of chest pain or abnormal stress tests. Endothelium-dependent and -independent vascular function were measured using intracoronary and intrafemoral infusions of acetylcholine and sodium nitroprusside, respectively. Coronary flow reserve was assessed using intracoronary adenosine infusion. Flow velocity was measured in each circulation using a Doppler wire (FloWire, EndoSonics). Coronary vascular resistance and femoral vascular resistance were calculated as mean arterial pressure (mm Hg)/coronary blood flow (mL/min) and mean arterial pressure (mm Hg)/femoral average peak velocity (cm/s), respectively. Mean age was 53±11 years, 37% were female, 44% had hypertension, 12% had diabetes mellitus, and 38% had obstructive coronary artery disease. There was a correlation between the change in femoral vascular resistance with acetylcholine and acetylcholine-mediated changes in both the coronary vascular resistance ( r=0.27; P=0.014) and in the epicardial coronary artery diameter ( r=-0.25; P=0.021), indicating that subjects with normal endothelial function in the femoral circulation had normal endothelial function in the coronary epicardial and microcirculation and vice versa. The coronary vasodilator response to adenosine also correlated with the femoral vasodilatation with acetylcholine ( r=0.4; P=0.0002). There was no correlation between the coronary and femoral responses to sodium nitroprusside. Conclusions- Endothelial functional changes in the peripheral and coronary circulations were modestly correlated. Thus, peripheral microvascular endothelial function reflects endothelium-dependent coronary epicardial and microvascular function and the coronary flow reserve. Visual Overview- An online visual overview is available for this article.
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Affiliation(s)
- Ahmed Al-Badri
- From the Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Jeong Hwan Kim
- From the Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Chang Liu
- From the Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Puja K Mehta
- From the Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Arshed A Quyyumi
- From the Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA
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Baselet B, Sonveaux P, Baatout S, Aerts A. Pathological effects of ionizing radiation: endothelial activation and dysfunction. Cell Mol Life Sci 2019; 76:699-728. [PMID: 30377700 PMCID: PMC6514067 DOI: 10.1007/s00018-018-2956-z] [Citation(s) in RCA: 157] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 10/19/2018] [Accepted: 10/23/2018] [Indexed: 01/13/2023]
Abstract
The endothelium, a tissue that forms a single layer of cells lining various organs and cavities of the body, especially the heart and blood as well as lymphatic vessels, plays a complex role in vascular biology. It contributes to key aspects of vascular homeostasis and is also involved in pathophysiological processes, such as thrombosis, inflammation, and hypertension. Epidemiological data show that high doses of ionizing radiation lead to cardiovascular disease over time. The aim of this review is to summarize the current knowledge on endothelial cell activation and dysfunction after ionizing radiation exposure as a central feature preceding the development of cardiovascular diseases.
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Affiliation(s)
- Bjorn Baselet
- Radiobiology Unit, Belgian Nuclear Research Centre (SCK•CEN), Mol, Belgium
- Institute of Experimental and Clinical Research (IREC), Pole of Pharmacology and Therapeutics, Université catholique de Louvain (UCL), Brussels, Belgium
| | - Pierre Sonveaux
- Institute of Experimental and Clinical Research (IREC), Pole of Pharmacology and Therapeutics, Université catholique de Louvain (UCL), Brussels, Belgium
| | - Sarah Baatout
- Radiobiology Unit, Belgian Nuclear Research Centre (SCK•CEN), Mol, Belgium
- Department of Molecular Biotechnology, Ghent University, Ghent, Belgium
| | - An Aerts
- Radiobiology Unit, Belgian Nuclear Research Centre (SCK•CEN), Mol, Belgium.
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Brown RA, Shantsila E, Varma C, Lip GYH. Current Understanding of Atherogenesis. Am J Med 2017; 130:268-282. [PMID: 27888053 DOI: 10.1016/j.amjmed.2016.10.022] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Revised: 10/13/2016] [Accepted: 10/14/2016] [Indexed: 12/20/2022]
Abstract
Scientific understanding of atherogenesis is constantly developing. From Virchow's observations 160 years ago we now recognize the endothelial response to injury as inflammatory, involved in all stages of atherosclerosis. Endothelial activation may cause reversible injury or dysfunction, or lead to irreparable damage. Indeed, early atherosclerosis is reversible. The introduction of genome-wide association testing has furthered the identification of potentially important genetic variants that help explain the heritability of coronary artery disease as well as spontaneous cases of severe coronary artery disease in patients with otherwise minimal risk factors. However, the mechanisms by which many of the newer variants exert their influence remain unknown.
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Affiliation(s)
- Richard A Brown
- Department of Medicine, University of Birmingham Institute of Cardiovascular Sciences, City Hospital, United Kingdom
| | - Eduard Shantsila
- Department of Medicine, University of Birmingham Institute of Cardiovascular Sciences, City Hospital, United Kingdom; Cardiology Department at Sandwell and West Birmingham Hospitals NHS Trust, City Hospital and Sandwell Hospital, West Bromwich, United Kingdom
| | - Chetan Varma
- Cardiology Department at Sandwell and West Birmingham Hospitals NHS Trust, City Hospital and Sandwell Hospital, West Bromwich, United Kingdom
| | - Gregory Y H Lip
- Department of Medicine, University of Birmingham Institute of Cardiovascular Sciences, City Hospital, United Kingdom; Cardiology Department at Sandwell and West Birmingham Hospitals NHS Trust, City Hospital and Sandwell Hospital, West Bromwich, United Kingdom.
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Gutterman DD, Chabowski DS, Kadlec AO, Durand MJ, Freed JK, Ait-Aissa K, Beyer AM. The Human Microcirculation: Regulation of Flow and Beyond. Circ Res 2016; 118:157-72. [PMID: 26837746 DOI: 10.1161/circresaha.115.305364] [Citation(s) in RCA: 203] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The microcirculation is responsible for orchestrating adjustments in vascular tone to match local tissue perfusion with oxygen demand. Beyond this metabolic dilation, the microvasculature plays a critical role in modulating vascular tone by endothelial release of an unusually diverse family of compounds including nitric oxide, other reactive oxygen species, and arachidonic acid metabolites. Animal models have provided excellent insight into mechanisms of vasoregulation in health and disease. However, there are unique aspects of the human microcirculation that serve as the focus of this review. The concept is put forth that vasculoparenchymal communication is multimodal, with vascular release of nitric oxide eliciting dilation and preserving normal parenchymal function by inhibiting inflammation and proliferation. Likewise, in disease or stress, endothelial release of reactive oxygen species mediates both dilation and parenchymal inflammation leading to cellular dysfunction, thrombosis, and fibrosis. Some pathways responsible for this stress-induced shift in mediator of vasodilation are proposed. This paradigm may help explain why microvascular dysfunction is such a powerful predictor of cardiovascular events and help identify new approaches to treatment and prevention.
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Affiliation(s)
- David D Gutterman
- From the Cardiovascular Center (A.M.B., A.O.K., D.D.G., D.S.C., J.K.F., K.A.-A., M.J.D.), Departments of Medicine (A.M.B., A.O.K., D.D.G., D.S.C., J.K.F., K.A.-A.), Pharmacology and Toxicology (D.S.C., J.K.F.), Physiology (A.M.B., A.O.K.), Physical Medicine and Rehabilitation (M.J.D.), and Anesthesiology (J.K.F.), Medical College of Wisconsin, Milwaukee.
| | - Dawid S Chabowski
- From the Cardiovascular Center (A.M.B., A.O.K., D.D.G., D.S.C., J.K.F., K.A.-A., M.J.D.), Departments of Medicine (A.M.B., A.O.K., D.D.G., D.S.C., J.K.F., K.A.-A.), Pharmacology and Toxicology (D.S.C., J.K.F.), Physiology (A.M.B., A.O.K.), Physical Medicine and Rehabilitation (M.J.D.), and Anesthesiology (J.K.F.), Medical College of Wisconsin, Milwaukee
| | - Andrew O Kadlec
- From the Cardiovascular Center (A.M.B., A.O.K., D.D.G., D.S.C., J.K.F., K.A.-A., M.J.D.), Departments of Medicine (A.M.B., A.O.K., D.D.G., D.S.C., J.K.F., K.A.-A.), Pharmacology and Toxicology (D.S.C., J.K.F.), Physiology (A.M.B., A.O.K.), Physical Medicine and Rehabilitation (M.J.D.), and Anesthesiology (J.K.F.), Medical College of Wisconsin, Milwaukee
| | - Matthew J Durand
- From the Cardiovascular Center (A.M.B., A.O.K., D.D.G., D.S.C., J.K.F., K.A.-A., M.J.D.), Departments of Medicine (A.M.B., A.O.K., D.D.G., D.S.C., J.K.F., K.A.-A.), Pharmacology and Toxicology (D.S.C., J.K.F.), Physiology (A.M.B., A.O.K.), Physical Medicine and Rehabilitation (M.J.D.), and Anesthesiology (J.K.F.), Medical College of Wisconsin, Milwaukee
| | - Julie K Freed
- From the Cardiovascular Center (A.M.B., A.O.K., D.D.G., D.S.C., J.K.F., K.A.-A., M.J.D.), Departments of Medicine (A.M.B., A.O.K., D.D.G., D.S.C., J.K.F., K.A.-A.), Pharmacology and Toxicology (D.S.C., J.K.F.), Physiology (A.M.B., A.O.K.), Physical Medicine and Rehabilitation (M.J.D.), and Anesthesiology (J.K.F.), Medical College of Wisconsin, Milwaukee
| | - Karima Ait-Aissa
- From the Cardiovascular Center (A.M.B., A.O.K., D.D.G., D.S.C., J.K.F., K.A.-A., M.J.D.), Departments of Medicine (A.M.B., A.O.K., D.D.G., D.S.C., J.K.F., K.A.-A.), Pharmacology and Toxicology (D.S.C., J.K.F.), Physiology (A.M.B., A.O.K.), Physical Medicine and Rehabilitation (M.J.D.), and Anesthesiology (J.K.F.), Medical College of Wisconsin, Milwaukee
| | - Andreas M Beyer
- From the Cardiovascular Center (A.M.B., A.O.K., D.D.G., D.S.C., J.K.F., K.A.-A., M.J.D.), Departments of Medicine (A.M.B., A.O.K., D.D.G., D.S.C., J.K.F., K.A.-A.), Pharmacology and Toxicology (D.S.C., J.K.F.), Physiology (A.M.B., A.O.K.), Physical Medicine and Rehabilitation (M.J.D.), and Anesthesiology (J.K.F.), Medical College of Wisconsin, Milwaukee
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Neuman RB, Hayek SS, Poole JC, Rahman A, Menon V, Kavtaradze N, Polhemus D, Veledar E, Lefer DJ, Quyyumi AA. Nitric Oxide Contributes to Vasomotor Tone in Hypertensive African Americans Treated With Nebivolol and Metoprolol. J Clin Hypertens (Greenwich) 2016; 18:223-31. [PMID: 26285691 PMCID: PMC4760906 DOI: 10.1111/jch.12649] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 06/30/2015] [Accepted: 07/05/2015] [Indexed: 11/29/2022]
Abstract
Endothelial dysfunction is more prevalent in African Americans (AAs) compared with whites. The authors hypothesized that nebivolol, a selective β1 -antagonist that stimulates nitric oxide (NO), will improve endothelial function in AAs with hypertension when compared with metoprolol. In a double-blind, randomized, crossover study, 19 AA hypertensive patients were randomized to a 12-week treatment period with either nebivolol 10 mg or metoprolol succinate 100 mg daily. Forearm blood flow (FBF) was measured using plethysmography at rest and after intra-arterial infusion of acetylcholine and sodium nitroprusside to estimate endothelium-dependent and independent vasodilation, respectively. Physiologic vasodilation was assessed during hand-grip exercise. Measurements were repeated after NO blockade with L-N(G) -monomethylarginine (L-NMMA) and after inhibition of endothelium-derived hyperpolarizing factor (EDHF) with tetraethylammonium chloride (TEA). NO blockade with L-NMMA produced a trend toward greater vasoconstriction during nebivolol compared with metoprolol treatment (21% vs 12% reduction in FBF, P=.06, respectively). This difference was more significant after combined administration of L-NMMA and TEA (P<.001). Similarly, there was a contribution of NO to exercise-induced vasodilation during nebivolol but not during metoprolol treatment. There were significantly greater contributions of NO and EDHF to resting vasodilator tone and of NO to exercise-induced vasodilation with nebivolol compared with metoprolol in AAs with hypertension.
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Affiliation(s)
- Robert B. Neuman
- Division of CardiologyEmory University School of MedicineAtlantaGA
| | - Salim S. Hayek
- Division of CardiologyEmory University School of MedicineAtlantaGA
| | - Joseph C. Poole
- Division of CardiologyEmory University School of MedicineAtlantaGA
| | - Ayaz Rahman
- Division of CardiologyEmory University School of MedicineAtlantaGA
| | - Vivek Menon
- Division of CardiologyEmory University School of MedicineAtlantaGA
| | - Nino Kavtaradze
- Division of CardiologyEmory University School of MedicineAtlantaGA
| | - David Polhemus
- Department of PharmacologyLouisiana State University Health Sciences CenterNew OrleansLA
| | - Emir Veledar
- Division of CardiologyEmory University School of MedicineAtlantaGA
| | - David J. Lefer
- Department of PharmacologyLouisiana State University Health Sciences CenterNew OrleansLA
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Ozkor MA, Hayek SS, Rahman AM, Murrow JR, Kavtaradze N, Lin J, Manatunga A, Quyyumi AA. Contribution of endothelium-derived hyperpolarizing factor to exercise-induced vasodilation in health and hypercholesterolemia. Vasc Med 2015; 20:14-22. [PMID: 25648989 PMCID: PMC9135050 DOI: 10.1177/1358863x14565374] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The role of endothelium-derived hyperpolarizing factor (EDHF) in either the healthy circulation or in those with hypercholesterolemia is unknown. In healthy and hypercholesterolemic subjects, we measured forearm blood flow (FBF) using strain-gauge plethysmography at rest, during graded handgrip exercise, and after sodium nitroprusside infusion. Measurements were repeated after l-NMMA, tetraethylammonium (TEA), and combined infusions. At rest, l-NMMA infusion reduced FBF in healthy but not hypercholesterolemic subjects. At peak exercise, vasodilation was lower in hypercholesterolemic compared to healthy subjects (274% vs 438% increase in FBF, p=0.017). TEA infusion reduced exercise-induced vasodilation in both healthy and hypercholesterolemic subjects (27%, p<0.0001 and -20%, p<0.0001, respectively). The addition of l-NMMA to TEA further reduced FBF in healthy (-14%, p=0.012) but not in hypercholesterolemic subjects, indicating a reduced nitric oxide and greater EDHF-mediated contribution to exercise-induced vasodilation in hypercholesterolemia. In conclusion, exercise-induced vasodilation is impaired and predominantly mediated by EDHF in hypercholesterolemic subjects. CLINICAL TRIAL REGISTRATION IDENTIFIER NCT00166166:
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Affiliation(s)
- Muhiddin A Ozkor
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Salim S Hayek
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Ayaz M Rahman
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Jonathan R Murrow
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Nino Kavtaradze
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Ji Lin
- Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Amita Manatunga
- Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Arshed A Quyyumi
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
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Rahman AM, Murrow JR, Ozkor MA, Kavtaradze N, Lin J, De Staercke C, Hooper WC, Manatunga A, Hayek S, Quyyumi AA. Endothelium-derived hyperpolarizing factor mediates bradykinin-stimulated tissue plasminogen activator release in humans. J Vasc Res 2014; 51:200-8. [PMID: 24925526 DOI: 10.1159/000362666] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Accepted: 03/28/2014] [Indexed: 12/20/2022] Open
Abstract
AIMS Bradykinin (BK) stimulates tissue plasminogen activator (t-PA) release from human endothelium. Although BK stimulates both nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) release, the role of EDHF in t-PA release remains unexplored. This study sought to determine the mechanisms of BK-stimulated t-PA release in the forearm vasculature of healthy human subjects. METHODS In 33 healthy subjects (age 40.3 ± 1.9 years), forearm blood flow (FBF) and t-PA release were measured at rest and after intra-arterial infusions of BK (400 ng/min) and sodium nitroprusside (3.2 mg/min). Measurements were repeated after intra-arterial infusion of tetraethylammonium chloride (TEA; 1 µmol/min), fluconazole (0.4 µmol·min(-1)·l(-1)), and N(G)-monomethyl-L-arginine (L-NMMA, 8 µmol/min) to block nitric oxide, and their combination in separate studies. RESULTS BK significantly increased net t-PA release across the forearm (p < 0.0001). Fluconazole attenuated both BK-mediated vasodilation (-23.3 ± 2.7% FBF, p < 0.0001) and t-PA release (from 50.9 ± 9.0 to 21.3 ± 8.9 ng/min/100 ml, p = 0.02). TEA attenuated FBF (-14.7 ± 3.2%, p = 0.002) and abolished BK-stimulated t-PA release (from 22.9 ± 5.7 to -0.8 ± 3.6 ng/min/100 ml, p = 0.0002). L-NMMA attenuated FBF (p < 0.0001), but did not inhibit BK-induced t-PA release (nonsignificant). CONCLUSION BK-stimulated t-PA release is partly due to cytochrome P450-derived epoxides and is inhibited by K(+)Ca channel blockade. Thus, BK stimulates both EDHF-dependent vasodilation and t-PA release.
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Affiliation(s)
- Ayaz M Rahman
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Ga., USA
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Sasongko MB, Wong TY, Wang JJ. Retinal microvascular structure: determinants and potential utility of novel imaging measurements. EXPERT REVIEW OF OPHTHALMOLOGY 2014. [DOI: 10.1586/eop.10.27] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Eisenach JH, Gullixson LR, Kost SL, Joyner MJ, Turner ST, Nicholson WT. Sex differences in salt sensitivity to nitric oxide dependent vasodilation in healthy young adults. J Appl Physiol (1985) 2011; 112:1049-53. [PMID: 22194324 DOI: 10.1152/japplphysiol.01197.2011] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Dietary sodium and blood pressure regulation differs between normotensive men and women, an effect which may involve endothelial production of nitric oxide (NO). Therefore, we tested the hypothesis that differences in the NO component of endothelium-dependent vasodilation between low and high dietary sodium intake depend on sex. For 5 days prior to study, healthy adults consumed a controlled low-sodium diet (10 mmol/day, n = 30, mean age ± SE: 30 ± 1 yr, 16 men) or high-sodium diet (400 mmol/day, n = 36, age 23 ± 1 yr, 13 men). Forearm blood flow (FBF, plethysmography) responses to brachial artery administration of acetylcholine (ACh, 4 μg·100 ml tissue(-1)·min(-1)) were measured before and after endothelial NO synthase inhibition with N(G)-monomethyl-l-arginine (l-NMMA, 50 mg bolus + 1 mg/min infusion). The NO component of endothelium-dependent dilation was calculated as the response to ACh before and after l-NMMA accounting for changes in baseline FBF: [(FBF ACh - FBF baseline) - (FBF ACh(L-NMMA) - FBF baseline(L-NMMA))]. This value was 5.7 ± 1.3 and 2.5 ± 0.8 ml·100 ml forearm tissue(-1)·min(-1) for the low- and high-sodium diets, respectively (main effect of sodium, P = 0.019). The sodium effect was larger for the men, with values of 7.9 ± 2.0 and 2.2 ± 1.4 for men vs. 3.1 ± 1.3 and 2.7 ± 1.0 ml·100 ml forearm tissue(-1)·min(-1) for the women (P = 0.034, sex-by-sodium interaction). We conclude that the NO component of endothelium-dependent vasodilation is altered by dietary sodium intake based on sex, suggesting that endothelial NO production is sensitive to dietary sodium in healthy young men but not women.
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Affiliation(s)
- John H Eisenach
- Department of Anesthesiology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
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Ozkor MA, Murrow JR, Rahman AM, Kavtaradze N, Lin J, Manatunga A, Quyyumi AA. Endothelium-derived hyperpolarizing factor determines resting and stimulated forearm vasodilator tone in health and in disease. Circulation 2011; 123:2244-53. [PMID: 21555712 DOI: 10.1161/circulationaha.110.990317] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND We assessed the contribution of endothelium-derived hyperpolarizing factors to resting and agonist-stimulated vasodilator tone in health and disease. Tetraethylammonium chloride (TEA) was used to inhibit K(+)(Ca) channel activation and fluconazole was used to inhibit cytochrome P450 2C9-mediated epoxyeicosatrienoic acid synthesis. We hypothesized that endothelium-derived hyperpolarizing factors contribute to resting vascular tone by K(+)(Ca) channel activation and epoxyeicosatrienoic acid release and that endothelium-derived hyperpolarizing factors compensate for reduced nitric oxide bioavailability at rest and with endothelium-dependent vasodilators. METHODS AND RESULTS In 103 healthy subjects and 71 nonhypertensive subjects with multiple risk factors, we measured resting forearm blood flow (FBF) using venous occlusion plethysmography before and after intra-arterial infusions of N(G)-monomethyl-l-arginine (L-NMMA), TEA, fluconazole, and their combination. The effects of these antagonists on resting FBF and on bradykinin- and acetylcholine-mediated vasodilation were studied. Resting FBF decreased with TEA and L-NMMA in all subjects (P<0.001); however, the vasoconstrictor response to L-NMMA was greater (P=0.04) and to TEA was lower (P=0.04) in healthy subjects compared with those with risk factors. Fluconazole decreased resting FBF in all subjects, and the addition of TEA further reduced FBF after fluconazole, suggesting that cytochrome P450 metabolites and other hyperpolarizing factor(s) activate K(+)(Ca) channels. Both L-NMMA and TEA attenuated bradykinin-mediated vasodilation in healthy and hypercholesterolemic subjects (P<0.001). In contrast, acetylcholine-mediated vasodilation remained unchanged with TEA in healthy subjects but was significantly attenuated in hypercholesterolemia (P<0.04). CONCLUSIONS First, by activating TEA-inhibitable K(+)(Ca) channels, endothelium-derived hyperpolarizing factors, together with nitric oxide, contribute to resting microvascular dilator tone. The contribution of K(+)(Ca) channel activation compared with nitric oxide is greater in those with multiple risk factors compared with healthy subjects. Second, activation of K(+)(Ca) channels is only partly through epoxyeicosatrienoic acid release, indicating the presence of other hyperpolarizing mechanisms. Third, bradykinin, but not acetylcholine, stimulates K(+)(Ca) channel-mediated vasodilation in healthy subjects, whereas in hypercholesterolemia, K(+)(Ca) channel-mediated vasodilation compensates for the reduced nitric oxide activity. Thus, enhanced endothelium-derived hyperpolarizing factor activity in conditions of nitric oxide deficiency contributes to maintenance of resting and agonist-stimulated vasodilation. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00166166.
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Affiliation(s)
- Muhiddin A Ozkor
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, USA
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Long X, Bratz IN, Alloosh M, Edwards JM, Sturek M. Short-term exercise training prevents micro- and macrovascular disease following coronary stenting. J Appl Physiol (1985) 2010; 108:1766-74. [PMID: 20299615 PMCID: PMC2886674 DOI: 10.1152/japplphysiol.01014.2009] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2009] [Accepted: 03/16/2010] [Indexed: 12/16/2022] Open
Abstract
The purpose of this study was to determine the effects of exercise on coronary blood flow and macrovascular atherosclerosis in response to stent deployment. Male Yucatan swine were placed on a control diet (C); on a high-fat/cholesterol diet (hypercholesterolemic; H); or on a high-fat/cholesterol diet and aerobically exercise trained (HX) starting after 36 wk on the diet. All pigs underwent coronary angiography and intravascular ultrasound (IVUS) guided placement of a bare metal stent in the circumflex coronary artery after 40 wk on diets and 3 wk later pigs underwent repeat angiography and IVUS and coronary blood flow (CBF) measurement. Average peak velocity (APV) was measured under basal conditions and in response to intracoronary application of the endothelium-independent vasodilator adenosine and the endothelium-dependent vasodilator bradykinin. There was a similar approximately 8-fold increase in total cholesterol in H and HX compared with control. Baseline CBF was increased above control and H in HX (P<0.05). At all doses adenosine-induced CBF was impaired in H, but preserved in HX. Similarly, bradykinin-induced CBF was impaired in H vs. control, yet was potentiated in HX. Microvessel density was decreased in H and preserved in HX vs. control. Native atheroma in HX was lower relative to H and control, while in-stent stenosis in HX was not different from H. Hyperlipidemia-induced microvascular dysfunction after stent deployment may be a result of reduction in microvessel density. This is the first report that short-term exercise training near the time of stenting prevents stent-induced microvascular dysfunction and attenuates native atheroma independent of changes in plasma cholesterol in this porcine model.
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Affiliation(s)
- Xin Long
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Dr., MS 385, Indianapolis, IN 46202-5120, USA
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15
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Andrade ACM, Cesena FHY, Consolim-Colombo FM, Coimbra SR, Benjó AM, Krieger EM, Luz PLD. Short-term red wine consumption promotes differential effects on plasma levels of high-density lipoprotein cholesterol, sympathetic activity, and endothelial function in hypercholesterolemic, hypertensive, and healthy subjects. Clinics (Sao Paulo) 2009; 64:435-42. [PMID: 19488610 PMCID: PMC2694248 DOI: 10.1590/s1807-59322009000500011] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2009] [Accepted: 03/04/2009] [Indexed: 01/22/2023] Open
Abstract
OBJECTIVES To compare the metabolic, hemodynamic, autonomic, and endothelial responses to short-term red wine consumption in subjects with hypercholesterolemia or arterial hypertension, and healthy controls. METHODS Subjects with hypercholesterolemia (n=10) or arterial hypertension (n=9), or healthy controls (n=7) were given red wine (250 mL/night) for 15 days. Analyses were performed before and after red wine intake. RESULTS Red wine significantly increased the plasma levels of HDL-cholesterol in the controls, but not in the other groups. The effects on hemodynamic measurements were mild, non-significantly more prominent in healthy subjects, and exhibited high interindividual variability. Across all participants, mean blood pressure decreased 7 mmHg (p <0.01) and systemic vascular resistance decreased 7% (p = 0.05). Heart rate and cardiac output did not significantly change in any group. Red wine enhanced muscle sympathetic fibular nerve activity in hypercholesterolemic and hypertensive patients, but not in controls. At baseline, brachial artery flow-mediated dilation was impaired in patients with hypercholesterolemia and arterial hypertension; red wine restored the dilation in the hypercholesterolemic group but not in the hypertensive group. CONCLUSIONS Red wine elicits different metabolic, autonomic, and endothelial responses among individuals with hypercholesterolemia or arterial hypertension and healthy controls. Our findings highlight the need to consider patient characteristics when evaluating the response to red wine.
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Affiliation(s)
- Ana C M Andrade
- Heart Institute, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
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Casey DP, Curry TB, Joyner MJ. Measuring muscle blood flow: a key link between systemic and regional metabolism. Curr Opin Clin Nutr Metab Care 2008; 11:580-6. [PMID: 18685453 PMCID: PMC3462349 DOI: 10.1097/mco.0b013e32830b5b34] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
PURPOSE OF REVIEW To provide a brief overview of the main techniques to measure muscle blood flow in humans and highlight some of the strengths and weaknesses associated with each technique. RECENT FINDINGS Peak muscle blood flow values of 300 ml/min per 100 g are possible in humans during heavy exercise performed with small muscle mass. This value is far higher than that which appears in most textbooks. Accurate and reliable techniques are therefore essential in measuring muscle blood flow. Current invasive techniques commonly used include indicator dilution (thermodilution and dye dilution) and radiolabel tracer washout (e.g. 133Xe washout) methods. Although invasive techniques have provided valuable insight into tissue blood flow, noninvasive techniques such as venous occlusion plethysmography and Doppler ultrasound are frequently used and provide accurate measurements of blood flow. Newer imaging techniques (MRI, positron emission tomography, and contrast-enhanced ultrasonography) promise increased resolution of measurements of local blood flow, including in discrete tissues in which more classical techniques are not able to be used. SUMMARY Muscle blood flow is a key link in the interplay and regulation of systemic and local muscle metabolism. Recognizing the advantages and limitations of each technique is essential to translational researchers studying the effects of nutrition and metabolism on muscle blood flow.
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Affiliation(s)
- Darren P Casey
- Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota 55905, USA.
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Van Guilder GP, Stauffer BL, Greiner JJ, Desouza CA. Impaired endothelium-dependent vasodilation in overweight and obese adult humans is not limited to muscarinic receptor agonists. Am J Physiol Heart Circ Physiol 2008; 294:H1685-92. [PMID: 18281379 PMCID: PMC3686114 DOI: 10.1152/ajpheart.01281.2007] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Muscarinic receptor agonists have primarily been used to characterize endothelium-dependent vasodilator dysfunction with overweight/obesity. Reliance on a single class of agonist, however, yields limited, and potentially misleading, information regarding endothelial vasodilator capacity. The aims of this study were to determine 1) whether the overweight/obesity-related reduction in endothelium-dependent vasodilation extends beyond muscarinic receptor agonists and 2) whether the contribution of nitric oxide (NO) to endothelium-dependent vasodilation is reduced in overweight/obese adults. Eighty-six middle-aged and older adults were studied: 42 normal-weight (54 +/- 1 yr, 21 men and 21 women, body mass index = 23.4 +/- 0.3 kg/m(2)) and 44 overweight/obese (54 +/- 1 yr, 28 men and 16 women, body mass index = 30.3 +/- 0.6 kg/m(2)) subjects. Forearm blood flow (FBF) responses to intra-arterial infusions of acetylcholine in the absence and presence of the endothelial NO synthase inhibitor N(G)-monomethyl-l-arginine, methacholine, bradykinin, substance P, isoproterenol, and sodium nitroprusside were measured by strain-gauge plethysmography. FBF responses to each endothelial agonist were significantly blunted in the overweight/obese adults. Total FBF (area under the curve) to acetylcholine (50 +/- 5 vs. 79 +/- 4 ml/100 ml tissue), methacholine (55 +/- 4 vs. 86 +/- 5 ml/100 ml tissue), bradykinin (62 +/- 5 vs. 85 +/- 4 ml/100 ml tissue), substance P (37 +/- 4 vs. 57 +/- 5 ml/100 ml tissue), and isoproterenol (62 +/- 4 vs. 82 +/- 6 ml/100 ml tissue) were 30%-40% lower in the overweight/obese than normal-weight adults. N(G)-monomethyl-l-arginine significantly reduced the FBF response to acetylcholine to the same extent in both groups. There were no differences between the groups in the FBF responses to sodium nitroprusside. These results indicate that agonist-stimulated endothelium-dependent vasodilation is universally impaired with overweight/obesity. Moreover, this impairment appears to be independent of NO.
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Affiliation(s)
- Gary P Van Guilder
- Dept. of Integrative Physiology, Univ. of Colorado, 354 UCB, Boulder, CO 80309. )
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McGuire JJ, Van Vliet BN, Giménez J, King JC, Halfyard SJ. Persistence of PAR-2 vasodilation despite endothelial dysfunction in BPH/2 hypertensive mice. Pflugers Arch 2007; 454:535-43. [PMID: 17318644 DOI: 10.1007/s00424-007-0226-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2006] [Revised: 01/18/2007] [Accepted: 01/29/2007] [Indexed: 11/25/2022]
Abstract
This study investigated relaxation of vascular smooth muscle by acetylcholine, bradykinin and protease-activated receptor 2 (PAR-2) to characterise endothelial dysfunction in spontaneously hypertensive mice (BPH/2). We hypothesised that PAR-2 induced vasodilation would be preserved in BPH/2 despite the presence of hypertension and impaired vasodilator responses to acetylcholine and bradykinin. Mean arterial blood pressure (MAP), heart rate and locomotor activity were assessed in conscious mice over 24-h periods by radiotelemetry. Relaxation responses of small mesenteric arteries to acetylcholine, bradykinin and the PAR-2 agonist, 2-furoyl-LIGRLO-amide (2fly), were assessed using wire myographs. MAP and heart rate of BPH/2 were 15 and 18%, respectively, higher than in controls (BPN/3). BPH/2 also exhibited increased locomotor activity. Maximal relaxations of arteries by acetylcholine and bradykinin in BPH/2 were reduced by 25-50% relative to BPN/3. In contrast, relaxation responses to 2fly were only slightly (6%), albeit significantly, reduced. Sodium nitroprusside-induced relaxations were not different between strains. Treatment of BPH/2 arteries with inhibitors of calcium-activated K(+) channels was sufficient to block persistent 2fly- and residual ACh- and bradykinin-induced relaxations, whereas NO synthase inhibitor failed to inhibit these relaxations. In BPH/2 mice, vascular smooth muscle relaxation by PAR-2 is well preserved despite the presence of hypertension and impaired vasodilation responses to acetylcholine and bradykinin.
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Affiliation(s)
- John J McGuire
- Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada.
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Heare T, Alp NJ, Priestman DA, Kulkarni AB, Qasba P, Butters TD, Dwek RA, Clarke K, Channon KM, Platt FM. Severe endothelial dysfunction in the aorta of a mouse model of Fabry disease; partial prevention by N-butyldeoxynojirimycin treatment. J Inherit Metab Dis 2007; 30:79-87. [PMID: 17189993 DOI: 10.1007/s10545-006-0473-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2006] [Revised: 11/06/2006] [Accepted: 11/29/2006] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Fabry disease results from alpha-gala-ctosidase A deficiency and is characterized by the lysosomal accumulation of globotriaosylceramide. Globotriaosylceramide storage predominantly affects endothelial cells, altering vascular wall morphology and vasomotor function. Our objective was to investigate aortic globotriaosylceramide levels, morphology and function in a mouse model of Fabry disease, and the effect of substrate reduction therapy, using the glycosphingolipid biosynthesis inhibitor N-butyldeoxynojirimycin. METHODS AND RESULTS Mice used were C57BL/6J and alpha-galactosidase A knockout (Fabry). We show progressive accumulation of aortic globotriaosylceramide throughout the lifespan of untreated Fabry mice (55-fold elevation at 2 months increasing to 187-fold by 19 months), localized to endothelial and vascular smooth-muscle cells; there was no effect on vascular wall morphology in young Fabry mice. In old mice, storage resulted in intimal thickening. Endothelial function declined with age in Fabry mouse aorta. Aortae from N-butyldeoxynojirimycin-treated Fabry mice at 19 months of age had reduced endothelial globotriaosylceramide storage, fewer morphological abnormalities and less severe vasomotor dysfunction compared with untreated littermates. CONCLUSION We provide evidence of a novel vascular phenotype in the Fabry mouse that has relevance to vascular disease in Fabry patients. N-Butyldeoxynojirimycin treatment partially prevented the phenotype in the Fabry mouse by reducing endothelial globotriaosylceramide storage.
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Affiliation(s)
- T Heare
- Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, UK
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Rossi GP, Taddei S, Ghiadoni L, Virdis A, Zavattiero S, Favilla S, Versari D, Sudano I, Azizi M, Vedie B, Pessina AC, Salvetti A, Jeunemaitre X. Tissue kallikrein gene polymorphisms induce no change in endothelium-dependent or independent vasodilation in hypertensive and normotensive subjects. J Hypertens 2006; 24:1955-63. [PMID: 16957554 DOI: 10.1097/01.hjh.0000244943.34546.40] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Tissue kallikrein (TK) generates Lys-bradykinin, which is then converted to bradykinin and releases nitric oxide (NO) from endothelial cells via B2 receptors. TK gene inactivation in mice causes severe endothelial dysfunction, which is also a hallmark of human primary hypertension (PH). Healthy carriers of a loss-of-function Arg to His substitution at position 53 (R53H) of the TK gene exhibit paradoxical arterial eutrophic remodeling. We therefore investigated the impact of this and other TK gene single nucleotide polymorphisms (SNPs) on endothelium-dependent vasodilatation (EDV) and endothelium-independent vasodilatation (EIV) in PH patients and normotensive (NT) subjects. METHODS The TK gene SNPs were genotyped blind to the phenotype by sequencing. We compared EDV and EIV vasodilatation across TK genotypes in 131 uncomplicated PH patients and 51 healthy NT subjects. EDV and EIV were assessed as the forearm blood flow response to a graded infusion of acetylcholine and sodium nitroprusside, respectively. We also evaluated the impact of the SNPs on NO-mediated EDV and on reactive oxygen species (ROS)-induced NO breakdown with the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-L-arginine or vitamin C, respectively. RESULTS Genotypes and allele frequencies were in Hardy-Weinberg equilibrium and similar in PH and NT. EDV was lower in PH patients than in NT subjects. No TK genotype affected either EDV or EIV per se, or via interaction with gender and age. NO inhibition and scavenging of ROS showed no TK genotype effect on EDV. Similar conclusions were obtained with haplotype analysis. CONCLUSIONS These results do not support the contention that TK gene SNPs have a major impact in determining NO-mediated responses to acetylcholine.
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Takase B, Hamabe A, Satomura K, Akima T, Uehata A, Ohsuzu F, Ishihara M, Kurita A. Close relationship between the vasodilator response to acetylcholine in the brachial and coronary artery in suspected coronary artery disease. Int J Cardiol 2006; 105:58-66. [PMID: 16207546 DOI: 10.1016/j.ijcard.2004.12.021] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2004] [Revised: 11/19/2004] [Accepted: 12/30/2004] [Indexed: 10/25/2022]
Abstract
BACKGROUND Vasodilator response to acetylcholine (endothelium-dependent dilation) is impaired in the peripheral and coronary circulation in patients with coronary artery disease (CAD). The purpose of this study is to investigate if the vasodilator response to acetylcholine in the brachial artery (BA) correlates with the same response in the coronary artery (CA). STUDY We measured the flow responses of BA and CA in 57 patients with suspected CAD. Doppler guidewire was placed into the proximal portion of the left BA and the major branch of CA. Acetylcholine was infused at 7.5, 15, and 30 mug/min for 5 min into BA and at 10(-8), 10(-7), 10(-6) M for 3 min into CA, respectively. The flow was calculated by multiplying average peak velocity by cross sectional areas obtained from quantitative angiography. Vasodilator response to acetylcholine was assessed by ratio of acetylcholine-induced flow/baseline flow. RESULTS A total of 33 CAD patients (CAD group, 61+/-8 years old) and 24 normal coronary patients (NL group, 57+/-12 years old) were investigated. A strong correlation between the vasodilator response to acetylcholine in BA and CA was observed in both CAD and NL groups, only at two moderate doses of acetylcholine (CAD group, r=0.64, p<0.001, NL group, r=0.87, p<0.001, 15 microg/min vs. 10(-7) M; CAD group, r=0.68, p<0.001, NL group, r=0.72, p<0.001, 30 microg/min vs. 10(-6) M). No significant correlation was obtained during low dose acetylcholine infusion. CONCLUSIONS The brachial artery vasodilator response to optimal acetylcholine doses is a useful surrogate for coronary endothelial function studies.
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Affiliation(s)
- Bonpei Takase
- National Defense Medical College Research Institute, Division of Biomedical Engineering, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
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Sen M, Anadol AZ, Oğuz M. Effect of hypercholesterolemia on experimental colonic anastomotic wound healing in rats. World J Gastroenterol 2006; 12:1225-8. [PMID: 16534875 PMCID: PMC4124433 DOI: 10.3748/wjg.v12.i8.1225] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the mechanical and biochemical parameters of colonic anastomotic healing in hypercholesterolemic rats.
METHODS: Sixty rats were divided into two groups of 30 each according to their dietary regimens. The test group was fed with a high cholesterol-containing diet for two months while the control group had standard diet. These two groups were further divided into three subgroups consisting of ten rats each. After hypercholesterolemia was established, left colon resection and anastomosis were performed in both groups and samples from liver and abdominal aorta were taken to evaluate the systemic effects of hypercholesterolemia. Anastomotic wound healing, blow-out pressures and tissue hydroxyproline levels were evaluated.
RESULTS: The test group had a significant weight gain in two months. Microscopic examination of the abdominal aorta revealed no atherosclerotic change in none of the groups, but liver tissue specimens showed significant steatosis in the test group. Tissue hydroxyproline levels and anastomotic blow-out pressures were significantly lower in the test group than in the controls.
CONCLUSION: Hypercholesterolemia not only increases hydroxyproline levels and blow-out pressures but also worsens anastomotic wound healing.
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Affiliation(s)
- Meral Sen
- Department of Surgery, School of Medicine, Fatih University, 06500 Ankara, Turkey.
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Leung H, Wang JJ, Rochtchina E, Wong TY, Klein R, Mitchell P. Dyslipidaemia and microvascular disease in the retina. Eye (Lond) 2006; 19:861-8. [PMID: 15359242 DOI: 10.1038/sj.eye.6701668] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
PURPOSE There are few data on the effect of serum lipids on microvascular disease. This study assessed the relationships between serum lipid levels and microvascular disease, as seen in the retina, among participants who attended a population-based study in Australia (n=3654, aged 49+years). METHODS Diameters of retinal arterioles and venules were measured from digitised photographs of each participant to obtain an estimate of generalised arteriolar narrowing. Focal arteriolar narrowing, arteriovenous nicking, and retinopathy lesions (microaneurysms, haemorrhages, hard/soft exudates) were graded using a standard protocol. Fasting blood tests were performed in 89% of subjects. Adjusted means were calculated using general linear models. Logistic regression models were used to determine the odds ratios for retinal microvascular signs. RESULTS After controlling for age, sex, body mass index, smoking, and mean arterial blood pressure, elevated high-density lipoprotein cholesterol was associated with narrower retinal arterioles (Ptrend=0.002) and venules (Ptrend=0.03) and with increased odds of generalised arteriolar narrowing (odds ratio 1.6, 95% confidence interval 1.1-2.2 for the highest vs the lowest quintile of high-density lipoprotein cholesterol). Serum triglyceride had a U-shaped relationship with venular diameter (Ptrend=0.003). We found no consistent pattern of association between serum total cholesterol or low-density lipoprotein cholesterol and any retinal microvascular signs. CONCLUSIONS These findings suggest that microvascular disease in the retina may result from processes distinct from dyslipidaemia.
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Affiliation(s)
- H Leung
- Department of Ophthalmology and the Westmead Millennium Institutes, Centre for Vision Research, The University of Sydney, Australia
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Entok E, Unalir A, Cavusoglu Y, Timuralp B, Vardareli E. Long-term effects of antilipidaemic therapy on left ventricular function in patients with dyslipidaemia: multigated radionuclide ventriculography study. Nucl Med Commun 2005; 26:773-9. [PMID: 16096580 DOI: 10.1097/01.mnm.0000172740.98369.ed] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
AIM It has been reported that dyslipidaemia impairs left ventricular systolic (LVs) and diastolic (LVd) functions, irrespective of atherogenic effects, in the setting of coronary artery disease. The aim of the present study was to evaluate the effects of anti-lipidaemic therapy on LVs and LVd functions by means of multigated radionuclide ventriculography (RNV) in subjects with signs of dyslipidaemia and with preserved left ventricular function. METHODS Eighteen patients with dyslipidaemia (eight men, 10 women, mean age 50+/-10 years) were included in the study. While the clinical examination and treadmill exercise test results were normal in all patients, low-density lipoprotein levels exceeded 160 mg . dl. Patients with medical conditions including coronary artery disease, hypertension, diabetes, cardiomyopathy and valvular heart disease which would influence left ventricular function were excluded from the study. RNV was performed in all subjects, taking into account the best septal position to differentiate the left ventricle from the right ventricle. The following parameters were calculated: ejection fraction, peak ejection rate (PER), time to peak ejection (TPER), a ejection rate (aER), a ejection fraction (aEF), Peak filling rate (PFR), time to peak filling rate (TPFR), a filling rate (aFR), a filling fraction (aFF). RESULTS The low-density lipoprotein value decreased and the high-density lipoprotein value increased after statin therapy (P<0.001 and P<0.003, respectively). PER, aER and aFF significantly increased and TPER decreased as a consequence of statin therapy (respectively, P<0.05, P<0.05, P<0.05 P<0.05). CONCLUSION Anti-lipidaemic therapy is effective in dyslipidaemic patients. RNV is a useful and non-invasive method for monitoring changes in ventricular function following anti-lipidaemic treatment strategies.
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Affiliation(s)
- Emre Entok
- Department of Nuclear Medicine, Osmangazi University Medical Faculty, 26480 Eskişehir, Turkey.
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25
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Mittermayer F, Schaller G, Pleiner J, Vychytil A, Sunder-Plassmann G, Hörl WH, Wolzt M. Asymmetrical dimethylarginine plasma concentrations are related to basal nitric oxide release but not endothelium-dependent vasodilation of resistance arteries in peritoneal dialysis patients. J Am Soc Nephrol 2005; 16:1832-8. [PMID: 15857920 DOI: 10.1681/asn.2004121109] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Vascular dysfunction in chronic renal failure may be linked to reduced nitric oxide (NO) bioactivity and increased circulating concentrations of the endogenous NO synthase inhibitor asymmetrical dimethyl L-arginine (ADMA). The association between ADMA and basal endothelial NO release and endothelium-dependent vasodilation in resistance arteries of chronic renal failure patients is unknown. Forearm blood flow responses to the endothelium-dependent vasodilator acetylcholine, the endothelium-independent vasodilator nitroglycerine, and the endothelium-dependent vasoconstrictor N(G)-monomethyl-L-arginine (L-NMMA) were assessed in 37 peritoneal dialysis patients. L-arginine and ADMA plasma concentrations were measured by HPLC. ADMA (mean +/- SEM: 0.68 +/- 0.02 micromol/L) was associated with basal forearm blood flow (r = -0.33; P < 0.05) and L-NMMA induced vasoconstriction (r = -0.55; P < 0.0005), but not with dilator effects of acetylcholine or nitroglycerine. L-arginine (68 +/- 3 micromol/L) tended to correlate with acetylcholine-induced vasodilation (r = 0.32; P = 0.05) but was not associated with other parameters. ADMA is related to basal but not to acetylcholine-stimulated NO bioactivity in patients on peritoneal dialysis. Impaired endothelium-dependent vasodilation found in chronic renal failure is not explained by elevated circulating NO synthase inhibitors in renal failure.
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Affiliation(s)
- Friedrich Mittermayer
- Medical University Vienna, Department of Clinical Pharmacology, Division of Nephrology and Dialysis, AKH-Wien, Währinger Gürtel 18-20, Vienna, A-1090 Austria
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Edremitlioğlu M, Oner G. The role of cholesterol on the pressure sensing ability of kidneys in rats. J Basic Clin Physiol Pharmacol 2005; 14:345-58. [PMID: 15198306 DOI: 10.1515/jbcpp.2003.14.4.345] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
We studied the effect of hypercholesterolemia on the pressure-sensing and regulating ability of the kidneys, using an acute hemorrhage model to provide 40% and 60% reduction in the blood pressure of hypercholesterolemic and control rats. The control group (n = 22) was fed a normal rat pellet diet and tap water; the experimental group (n = 22) received a diet containing 2% cholesterol/0.2% thaurocholate. Half the animals were subjected to 6 mL/kg bw and the others to 12 mL/kg bw of bleeding for 1 min. Blood pressure recording and proper samplings were done before bleeding and during the 20 min post-hemorrhagic period for analysis. Despite a finding of hypercholesterolemia in the experimental group, kidney cholesterol content as well as its function remained unchanged. Following an initial 40% decrease in rats bled 6 mL/kg bw, 20 min later the mean blood pressure returned to 90% of its initial value in control rats and to 70% of its basal level in hypercholesterolemic rats. A similar delay in pressure normalization occurred in rats subjected to 12 mL/kg of bleeding. Plasma renin activity remained unaffected. We conclude that dietary hypercholesterolemia delays the normalization of blood pressure after hemorrhage without affecting the sensing ability of kidneys, and that the kidneys are less sensitive than other organs to plasma cholesterol levels.
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Volpe M, Cosentino F. Evolving Pathophysiological Perspectives in Endothelial Dysfunction. High Blood Press Cardiovasc Prev 2004. [DOI: 10.2165/00151642-200411020-00001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
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Deramo VA, Sergott RC, Augsburger JJ, Foroozan R, Savino PJ, Leone A. Ischemic optic neuropathy as the first manifestation of elevated cholesterol levels in young patients. Ophthalmology 2003; 110:1041-6; discussion 1046. [PMID: 12750110 DOI: 10.1016/s0161-6420(03)00079-4] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
PURPOSE To investigate the relationship between idiopathic nonarteritic ischemic optic neuropathy (NAION) and serum lipid levels in patients </= 50 years of age. DESIGN Case-control study. PARTICIPANTS Thirty-seven consecutive patients with NAION and 74 age- and gender-matched comparison patients. METHODS AND MAIN OUTCOME MEASURES Serum lipid levels and the presence of several historical diseases and exposures were abstracted from the medical records in cases and controls. RESULTS The mean total cholesterol level was significantly increased in patients with NAION compared with controls (235.4 vs. 204.0 mg/dl, P < 0.001). The odds ratio of having high blood cholesterol (>/= 240 mg/dl) with NAION was 3.3 (95% confidence interval, 1.4-7.8), and the likelihood increased when the comparison was restricted to nondiabetic patients. Diabetes mellitus was more common in cases than controls (P = 0.027), but systemic hypertension was not significantly different (P = 0.63). No patient (0 of 24) had a magnetic resonance imaging study consistent with optic neuritis or central nervous system demyelination. Visual improvement was uncommon. CONCLUSIONS This study demonstrates that hypercholesterolemia is associated with NAION in younger patients. NAION may be the first manifestation of a lipid disorder, a previously unrecognized syndrome. These patients have experienced a focal, microvascular central nervous system ischemic event at a relatively young age. Aggressive treatment of lipid abnormalities in these patients may be warranted.
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Affiliation(s)
- Vincent A Deramo
- Neuro-Ophthalmology Service, Wills Eye Hospital, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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Stokes KY, Cooper D, Tailor A, Granger DN. Hypercholesterolemia promotes inflammation and microvascular dysfunction: role of nitric oxide and superoxide. Free Radic Biol Med 2002; 33:1026-36. [PMID: 12374614 DOI: 10.1016/s0891-5849(02)01015-8] [Citation(s) in RCA: 172] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Relatively brief periods (days) of hypercholesterolemia can exert profound effects on endothelium-dependent functions of the microcirculation, including dilation of arterioles, fluid filtration across capillaries, and regulation of leukocyte recruitment in postcapillary venules. Hypercholesterolemia appears to convert the normal anti-inflammatory phenotype of the microcirculation to a proinflammatory phenotype. This phenotypic change appears to result from a decline in nitric oxide (NO) bioavailability that results from a reduction in NO biosynthesis, inactivation of NO by superoxide (O(2)(*)(-)), or both. A consequence of the hypercholesterolemia-induced microvascular responses is an enhanced vulnerability of the microcirculation to the deleterious effects of ischemia and other inflammatory conditions. Hence, therapeutic strategies that are directed towards preventing the early microcirculatory dysfunction and inflammation caused by hypercholesterolemia may prove effective in reducing the high mortality associated with ischemic tissue diseases. Agents that act to maintain the normal balance between NO and reactive oxygen species (ROS) in vascular endothelial cells may prove particularly useful in this regard.
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Affiliation(s)
- Karen Y Stokes
- Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, LA 71130-3932, USA
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30
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DeSouza CA, Clevenger CM, Greiner JJ, Smith DT, Hoetzer GL, Shapiro LF, Stauffer BL. Evidence for agonist-specific endothelial vasodilator dysfunction with ageing in healthy humans. J Physiol 2002; 542:255-62. [PMID: 12096067 PMCID: PMC2290401 DOI: 10.1113/jphysiol.2002.019166] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Endothelium-dependent vasodilatation declines with advancing age in humans independently of disease. The mechanisms responsible for this decline are not clear. We determined whether the age-related reduction in endothelium-dependent vasodilatation in response to acetylcholine reflects a specific agonist-related defect or rather a more general endothelial cell vasomotor abnormality. Twenty-two young (23-35 years) and 41 older (50-76 years) healthy men were studied. Forearm blood flow (FBF) responses to intra-arterial infusions of acetylcholine, bradykinin, substance P, isoproterenol (isoprenaline) and sodium nitroprusside were measured by strain-gauge plethysmography. There were no differences in resting FBF between the young (3.9 +/- 0.2 ml (100 ml tissue)(-1) x min(-1)) and older men (4.0 +/- 0.2 ml (100 ml tissue)(-1) x min(-1)). The increase in FBF at the highest dose of acetylcholine was approximately 30 % lower (P < 0.01) in the older (from 4.0 +/- 0.2 to 12.3 +/- 0.7 ml (100 ml tissue)(-1) x min(-1)) compared with young men (from 3.9 +/- 0.2 to 17.1 +/- 1.5 ml (100 ml tissue)(-1) x min(-1)). In contrast to acetylcholine, the FBF responses to the other endothelial agonists were not impaired with age. The maximum increases in FBF in response to bradykinin (19.2 +/- 1.0 vs. 20.2 +/- 0.9 ml (100 ml tissue)(-1) x min(-1)), substance P (15.1 +/- 0.8 vs. 16.8 +/- 0.7 ml (100 ml tissue)(-1) x min(-1)) and isoproterenol (17.5 +/- 0.9 vs. 17.5 +/- 0.9 ml (100 ml tissue)(-1) x min(-1)) were not significantly different between the older and young subjects. There were no age-related differences in the FBF responses to sodium nitroprusside. These results demonstrate that, although acetylcholine-induced vasodilatation is impaired with age, forearm endothelial vasodilatation in response to bradykinin, substance P and isoproterenol are well preserved in healthy men. Moreover, these findings suggest that agonist-stimulated endothelium-dependent vasodilatation is not universally impaired with age.
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Affiliation(s)
- Christopher A DeSouza
- Integrative Vascular Biology Laboratory, Department of Kinesiology and Applied Physiology, University of Colorado, Boulder, CO 80309, USA.
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Abstract
Studies using both in vitro and in vivo techniques have repeatedly shown that endothelium-dependent vasodilation (EDV) is impaired in different forms of experimental as well as human hypercholesterolemia. Clearly this impaired EDV can be reversed by lowering cholesterol levels by diet or medical therapy. Competitive blocking of L-arginine, changes in nitric oxide synthase activity, increased release of endothelin-1, and inactivation of nitric oxide due to superoxide ions all contribute to the impairment in EDV during dyslipidemia. The oxidation of low density lipoprotein, with its compound lysophosphatidylcholine, plays a critical role in these events. However, data on the role of triglycerides and fat-rich meals regarding EDV are not so consistent as data for cholesterol, although a view that the compositions of individual fatty acids and antioxidants are of major importance is emerging. Thus, this review shows that while impaired EDV is a general feature of hypercholesterolemia, the mechanisms involved and the therapeutic opportunities available still have to be investigated. Furthermore, discrepancies regarding the role of triglycerides and fat content in food may be explained by divergent effects of different fatty acids on the endothelium.
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Affiliation(s)
- Lars Lind
- Department of Medicine, Uppsala University Hospital and AstraZeneca R&D, Möndal, Sweden.
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Chan NN, Colhoun HM, Vallance P. Cardiovascular risk factors as determinants of endothelium-dependent and endothelium-independent vascular reactivity in the general population. J Am Coll Cardiol 2001; 38:1814-20. [PMID: 11738279 DOI: 10.1016/s0735-1097(01)01669-2] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
OBJECTIVES We examined to what extent the variation in risk factors for coronary heart disease (CHD) and the Framingham risk score (FRS) explain the variation in vascular reactivity in adults aged 30 to 53 years. BACKGROUND The role of risk factors in determining vascular reactivity in the general population has not been quantified. METHODS Risk factors for CHD were measured, and the FRS was calculated in 69 healthy volunteers. Lipoprotein particle size was measured using proton-nuclear magnetic resonance spectroscopy. Forearm plethysmography was used to assess blood flow responses to acetylcholine (ACh), bradykinin (BK), glyceryl trinitrate (GTN), noradrenaline and N(G)-monomethyl-L-arginine (L-NMMA). RESULTS Lower ACh and BK responses were associated with a higher body mass index (BMI), a higher total cholesterol to high-density lipoprotein (HDL) cholesterol ratio, lower HDL cholesterol and a cigarette smoking habit (all p < 0.05). Higher low-density lipoprotein (LDL) cholesterol was also associated with a lower BK response (p = 0.001). A decreased GTN response was associated with a higher BMI and total cholesterol to HDL cholesterol ratio (both p < 0.05). A decreased L-NMMA response was associated with a smoking habit (p < 0.001). Lipoprotein particle sizes did not independently predict any vascular response. A high FRS was associated with a reduced response to ACh (p = 0.07), BK (p = 0.003) and L-NMMA (p = 0.003), and the relationship was stronger in women than in men. Altogether, risk factors explained 13%, 9%, 8% and 15% of the response to ACh, BK, GTN and L-NMMA, respectively. CONCLUSIONS Lipids, BMI and smoking are important determinants of vascular reactivity. The FRS is predictive of agonist-stimulated, endothelium-dependent vasodilation and basal NO release. However, much of the variation in the vascular responses to these drugs, at this age, remains unexplained.
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Affiliation(s)
- N N Chan
- EURODIAB, Department of Epidemiology and Public HealthUniversity College London, London, United Kingdom
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Joyner MJ, Dietz NM, Shepherd JT. From Belfast to Mayo and beyond: the use and future of plethysmography to study blood flow in human limbs. J Appl Physiol (1985) 2001; 91:2431-41. [PMID: 11717202 DOI: 10.1152/jappl.2001.91.6.2431] [Citation(s) in RCA: 122] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Venous occlusion plethysmography is a simple but elegant technique that has contributed to almost every major area of vascular biology in humans. The general principles of plethysmography were appreciated by the late 1800s, and the application of these principles to measure limb blood flow occurred in the early 1900s. Plethysmography has been instrumental in studying the role of the autonomic nervous system in regulating limb blood flow in humans and important in studying the vasodilator responses to exercise, reactive hyperemia, body heating, and mental stress. It has also been the technique of choice to study how human blood vessels respond to a variety of exogenously administered vasodilators and vasoconstrictors, especially those that act on various autonomic and adrenergic receptors. In recent years, plethysmography has been exploited to study the role of the vascular endothelium in health and disease. Venous occlusion plethysmography is likely to continue to play an important role as investigators seek to understand the physiological significance of newly identified vasoactive factors and how genetic polymorphisms affect the cardiovascular system in humans.
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Affiliation(s)
- M J Joyner
- Department of Physiology, Mayo Clinic and Foundation, 200 First St. SW, Rochester, MN 55905, USA.
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34
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Halcox JP, Quyyumi AA. Coronary vascular endothelial function and myocardial ischemia: why should we worry about endothelial dysfunction? Coron Artery Dis 2001; 12:475-84. [PMID: 11696686 DOI: 10.1097/00019501-200109000-00006] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- J P Halcox
- Cardiology Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-1650, USA
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35
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Duffy SJ, O'Brien RC, New G, Harper RW, Meredith IT. Effect of anti-oxidant treatment and cholesterol lowering on resting arterial tone, metabolic vasodilation and endothelial function in the human forearm: a randomized, placebo-controlled study. Clin Exp Pharmacol Physiol 2001; 28:409-18. [PMID: 11380515 DOI: 10.1046/j.1440-1681.2001.03458.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
1. The aim of the present study was to determine whether anti-oxidant therapy with vitamin E and/or cholesterol-lowering therapy with simvastatin would augment resting forearm blood flow (FBF) and metabolic vasodilation in response to exercise and improve endothelial function in young patients with hypercholesterolaemia. 2. Endothelium-dependent and -independent, nitric oxide (NO)-mediated vasodilation have been shown to be impaired in young, otherwise healthy subjects with hypercholesterolaemia. Recent experimental and clinical studies suggest that vascular function may be improved with anti-oxidant or cholesterol- lowering therapy, although these treatments may be synergistic. 3. We compared FBF at rest, in response to isotonic exercise, the endothelium-dependent vasodilator acetylcholine (ACh), the endothelium-independent vasodilator sodium nitroprusside (SNP) and the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) in 26 young, otherwise healthy volunteers (mean (+/-SD) age 29+/-7 years; 14 female, 12 male) with hypercholesterolaemia, before and after 6 months treatment with vitamin E, simvastatin and/or placebo. Treatment was randomized, double-blinded in a 2 x 2 factorial design. Forearm blood flow was measured using venous occlusion plethysmography. 4. Vitamin E therapy increased plasma alpha-tocopherol from 39.5+/-9.6 to 75.7+/-33.8 micromol/L (P < 0.001). Simvastatin reduced total cholesterol from 6.9+/-1.7 to 4.9+/-0.8 mmol/L and low- density lipoprotein (LDL) from 4.8+/-1.7 to 3.0+/-0.7 mmol/L (both P < 0.001), although total and LDL-cholesterol also decreased slightly in the placebo group. Vitamin E increased resting FBF from 2.1+/-0.3 to 2.4+/-0.3 mL/100 mL per min (P = 0.04) and decreased resting forearm vascular resistance from 42.1+/-4.2 to 36.1+/-3.4 units (P = 0.01), but the reduction in resting FBF with L-NMMA was not affected. Vasodilation in response to isotonic exercise, ACh and SNP was similar before and after treatment in the placebo, vitamin E, simvastatin and in the combined vitamin E-simvastatin groups. NG-Monomethyl-L-arginine infusion reduced resting FBF and functional hyperaemia in response to exercise and these responses were not altered by treatment. 5. These data suggest that while vitamin E therapy augments resting FBF and reduces forearm vascular resistance in young hypercholesterolaemic subjects, these effects may not be via NO-dependent pathways. Metabolic vasodilation and responses to the NO-mediated vasodilators ACh and SNP were not favourably affected by anti-oxidant or cholesterol-lowering therapy, either alone or in combination.
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Affiliation(s)
- S J Duffy
- The Centre for Heart and Chest Research, Monash Medical Centre and Monash University, Melbourne, Victoria, Australia
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Kaur S, Frishman WH, Singh I, Tamirisa P, Kumar A. Endothelin as a therapeutic target in the treatment of cardiovascular disease. HEART DISEASE (HAGERSTOWN, MD.) 2001; 3:176-88. [PMID: 11975789 DOI: 10.1097/00132580-200105000-00008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Endothelins, a family of peptides derived from the vascular endothelium and smooth muscle cells possess vasoconstrictor and mitogenic properties. By acting predominantly in a paracrine fashion, these peptides activate specific receptors and have protean effects in normal and diseased organ systems. The wide distribution of these receptors in various tissues mediate the multiplicity of physiologic actions attributed to endothelins. Much of our understanding about endothelins has come from the development of an array of receptor-specific and mixed receptor antagonists. Based on the promising results from animal studies, active research and drug development programs are under way to investigate the clinical potential of endothelin antagonism for treatment of cardiovascular disease.
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Affiliation(s)
- S Kaur
- Division of General Internal Medicine, New York Medical College/Westchester Medical Center, Valhalla 10595, USA
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Prasad A, Husain S, Schenke W, Mincemoyer R, Epstein N, Quyyumi AA. Contribution of bradykinin receptor dysfunction to abnormal coronary vasomotion in humans. J Am Coll Cardiol 2000; 36:1467-73. [PMID: 11079644 DOI: 10.1016/s0735-1097(00)00892-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES The aim of our study was to investigate coronary vascular kinin receptor function in patients with atherosclerosis or its risk factors. BACKGROUND Although acetylcholine (ACH) is used as a probe for testing vascular function in vivo, endogenous bradykinin (BK) regulates resting and flow-mediated epicardial tone. METHODS In 53 patients with mild atherosclerosis or its risk factors and 9 control subjects, endothelium-dependent vasomotion was tested with intracoronary ACH (30 microg/min) and BK (62.5 ng/min and 4 microg/min), and endothelium-independent function with sodium nitroprusside. Metabolic vasodilation was assessed during cardiac pacing (n = 19). Correlation with serum angiotensin-converting enzyme (ACE) levels and the ACE insertion/deletion genotype was performed. RESULTS There was progressive impairment in ACH-mediated microvascular dilation with increasing numbers of risk factors (p = 0.025, analysis of variance). By contrast, BK- and sodium nitroprusside-mediated microvascular dilation was similar in all groups. Similarly, there was no correlation between epicardial coronary responses to ACH and BK; segments that constricted or dilated with ACH had similar dilator responses with BK. Bradykinin, but not ACH-mediated vasomotion, was depressed in epicardial segments that constricted with pacing. Finally, epicardial BK responses were depressed in patients with high ACE levels and in those with the ACE DD genotype. CONCLUSIONS Endothelial dysfunction in atherosclerosis appears to be receptor-specific, involving the muscarinic receptor with relative sparing of the kinin receptor pathways. Abnormal reactivity of epicardial coronary arteries during physiologic stress is better represented by BK and not by ACH responses. Bradykinin activity and, hence, physiologic coronary vasomotion appears to be influenced by serum ACE levels and the ACE insertion/deletion genotype.
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Affiliation(s)
- A Prasad
- Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1650, USA
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Jeremy RW, McCarron H. Effect of hypercholesterolemia on Ca(2+)-dependent K(+) channel-mediated vasodilatation in vivo. Am J Physiol Heart Circ Physiol 2000; 279:H1600-8. [PMID: 11009446 DOI: 10.1152/ajpheart.2000.279.4.h1600] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Nitric oxide (NO)-mediated and NO-independent mechanisms of endothelium-dependent vasodilatation involve Ca(2+)-dependent K(+) (K(Ca)) channels. We examined the role in vivo of K(Ca) channels in NO-independent vasodilatation in hypercholesterolemia. Hindlimb vascular conductance was measured at rest and after aortic injection of ACh, bradykinin (BK), and sodium nitroprusside in anesthetized control and cholesterol-fed rabbits. Conductances were measured before and after treatment with the NO synthase antagonist N(omega)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) or K(Ca) blockers tetraethylammonium (30 mg/kg), charybdotoxin (10 microgram/kg), and apamin (50 microgram/kg). The contribution of NO to basal conductance was greater in control than in cholesterol-fed rabbits [2.2 +/- 0.4 vs. 1.1 +/- 0.3 (SE) ml. min(-1). kg(-1). 100 mmHg(-1), P < 0.05], but the NO-independent K(Ca) channel-mediated component was greater in the cholesterol-fed than in the control group (1.1 + 0.4 vs. 0.3 +/- 0.1 ml. min(-1). kg(-1). 100 mmHg(-1), P < 0.05). Maximum conductance response to ACh and BK was less in cholesterol-fed than in control rabbits, and the difference persisted after L-NAME (ACh: 7.7 +/- 0.7 vs. 10.1 +/- 0.5 ml. min(-1). kg(-1). 100 mmHg(-1), P < 0.005). Blockade of K(Ca) channels with tetraethylammonium or charybdotoxin + apamin almost completely abolished L-NAME-resistant vasodilatation after ACh or BK. The magnitude of K(Ca)-mediated vasodilatation after ACh or BK was impaired in hypercholesterolemic rabbits. Vasodilator responses to nitroprusside did not differ between groups. In vivo, hypercholesterolemia is associated with an altered balance between NO-mediated and NO-independent K(Ca) channel contributions to resting vasomotor tone and impairment of both mechanisms of endothelium-dependent vasodilatation.
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Affiliation(s)
- R W Jeremy
- Department of Medicine, University of Sydney, Sydney, New South Wales 2006, Australia.
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Kaufmann P, Matter C, Mandinov L, Frielingsdorf J, Seiler C, Hess OM. High level of cholesterol increases coronary vasomotor tone during exercise. Coron Artery Dis 2000; 11:459-66. [PMID: 10966131 DOI: 10.1097/00019501-200009000-00003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Coronary vasomotor tone plays an important role in the regulation of myocardial perfusion and influences ischemic threshold significantly. Endothelial dysfunction occurs in the presence of coronary risk factors and is closely linked to the development of atherosclerosis affecting myocardial perfusion and decreasing ischemic threshold. OBJECTIVE To study the effect of hypercholesterolemia on coronary vasomotor tone in normal and stenotic coronary arteries at rest and during exercise. PATIENTS AND METHODS In total 48 patients were included in the present analysis. Patients were divided into two groups according to the actual levels of serum cholesterol: 18 patients had normal (mean 181 +/- 28 mg%; group 1) and 30 had elevated (mean 263 +/- 46 mg%; group 2) levels of serum cholesterol according to the 4S criteria with a cutoff level of 213 mg% (5.5 mmol/l). Coronary vasomotor tone at rest and during supine bicycle exercise was calculated by dividing mean aortic pressure by radius of coronary vessel obtained using biplanar quantitative coronary angiography. A normal as well as a stenotic vessel segment in each patient were studied. RESULTS Normal vessel segments in patients with normal levels of cholesterol (group 1) exhibited no exercise-induced change in coronary vascular tone (+3%, NS), whereas a significant increase in tone (+24%, P < 0.01 versus rest) occurred in those with high levels of cholesterol (group 2). In contrast, stenotic segments in members of both groups exhibited an increase in vascular tone irrespective of the actual level of serum cholesterol. CONCLUSIONS Hypercholesterolemia causes a pathologic increase in coronary vasomotor tone of angiographically normal vessel segments during exercise. A similar pathologic response occurs in stenotic arteries, but this is independent of the actual level of serum cholesterol. These findings suggest that hypercholesterolemia influences vasomotor tone of the nonstenosed coronary arteries in patients with coronary artery disease probably through the occurrence of endothelial dysfunction.
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Affiliation(s)
- P Kaufmann
- Cardiovascular Center, Division of Cardiology, University Hospital Zurich, Switzerland.
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Adams MR, Kinlay S, Blake GJ, Orford JL, Ganz P, Selwyn AP. Atherogenic lipids and endothelial dysfunction: mechanisms in the genesis of ischemic syndromes. Annu Rev Med 2000; 51:149-67. [PMID: 10774458 DOI: 10.1146/annurev.med.51.1.149] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Atherogenic lipids, particularly oxidized low-density lipoprotein, are responsible for a wide range of cellular dysfunctions within the vessel wall. The effects on endothelial cells disrupt normal control of vasomotion, with a reduction of effective nitric oxide activity, the development of a procoagulant surface, chronic low-grade inflammation, and abnormal cell growth. These changes are central not only in the development of atherosclerosis but also in the evolution of both stable and unstable ischemic syndromes. There is growing evidence that these abnormal changes in cell function respond rapidly to changes in the atherogenic lipids. Certain cell functions can improve within hours or days of cholesterol lowering.
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Affiliation(s)
- M R Adams
- Department of Cardiology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
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41
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Ogawa T, Sugidachi A, Asai F, Koike H. Reduced platelet serotonin content in rabbits with dietary hypercholesterolemia. Blood Coagul Fibrinolysis 2000; 11:313-9. [PMID: 10847417 DOI: 10.1097/00001721-200006000-00001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Serotonin [5-hydroxytryptamine (5-HT)] has been implicated in platelet activation and vasoconstriction, two processes that contribute to arterial thrombosis in atherosclerotic diseases. In the present study, Japanese White rabbits fed 1% cholesterol for 5 weeks were used to investigate the response of hypercholesterolemic vascular arteries and platelets to 5-HT. Contractions of the thoracic aorta induced by 5-HT were comparable between the cholesterol-fed group and the age-matched control group. However, acetylcholine-induced vasodilation in arteries preconstricted with 5-HT was moderately but significantly attenuated in the cholesterol-fed rabbits. Platelet aggregation responses to 5-HT (0.1-3 micromol/l) in combination with epinephrine (5 micromol/l), adenosine diphosphate (ADP) (0.3-10 micromol/l), 9,11-dideoxy-9alpha,11alpha-methanoepoxy-prostaglandin F2alpha (U-46619) (1-30 micromol/l) or collagen (3 microg/ml) were significantly enhanced in cholesterol-fed rabbits. In contrast, platelet 5-HT content determined with a high-performance liquid chromatography-electrochemical detector (HPLC-ECD) was significantly decreased in cholesterol-fed rabbits. These results suggest a possible association among the endothelial dysfunction, platelet aggregation and platelet 5-HT content in rabbits with dietary hypercholesterolemia.
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Affiliation(s)
- T Ogawa
- Pharmacology and Molecular Biology Research Laboratories, Sankyo Co. Ltd., Tokyo, Japan.
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Abstract
Coronary microvessels play a pivotal role in determining the supply of oxygen and nutrients to the myocardium by regulating the coronary flow conductance and substance transport. Direct approaches analyzing the coronary microvessels have provided a large body of knowledge concerning the physiological and pharmacological characteristics of the coronary circulation, as has the rapid accumulation of biochemical findings about the substances that mediate vascular functions. Myogenic and flow-induced intrinsic vascular controls that determine basal tone have been observed in coronary microvessels in vitro. Coronary microvascular responses during metabolic stimulation, autoregulation, and reactive hyperemia have been analyzed in vivo, and are known to be largely mediated by metabolic factors, although the involvement of other factors should also be taken into account. The importance of ATP-sensitive K(+) channels in the metabolic control has been increasingly recognized. Furthermore, many neurohumoral mediators significantly affect coronary microvascular control in endothelium-dependent and -independent manners. The striking size-dependent heterogeneity of microvascular responses to all of these intrinsic, metabolic, and neurohumoral factors is orchestrated for optimal perfusion of the myocardium by synergistic and competitive interactions. The regulation of coronary microvascular permeability is another important factor for the nutrient supply and for edema formation. Analyses of collateral microvessels and subendocardial microvessels are important for understanding the pathophysiology of ischemic hearts and hypertrophied hearts. Studies of the microvascular responses to drugs and of the impairment of coronary microvessels in diseased conditions provide useful information for treating microvascular dysfunctions. In this article, the endogenous regulatory system and pharmacological responses of the coronary circulation are reviewed from the microvascular point of view.
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Affiliation(s)
- T Komaru
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Japan.
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Li XP, Zhao SP, Zhang XY, Liu L, Gao M, Zhou QC. Protective effect of high density lipoprotein on endothelium-dependent vasodilatation. Int J Cardiol 2000; 73:231-6. [PMID: 10841964 DOI: 10.1016/s0167-5273(00)00221-7] [Citation(s) in RCA: 91] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Low concentrations of high-density lipoprotein cholesterol (HDL-C) have been associated with increased risk of coronary heart disease (CHD) even when the total cholesterol (TC) and triglyceride (TG) levels are not elevated. The mechanism by which HDL confers protection against atherosclerosis remains speculative. Using high-resolution ultrasound, we measured the dilatation changes of brachial arteries during reactive hyperemia and after sublingual glyceryl trinitrate (GTN) in 63 patients with established (CHD) and 45 controls, in which the serum TC level was normal. The results showed that both flow-mediated dilatation (FMD) and GTN-induced dilatation of brachial arteries in patients with CHD were much reduced compared with control group (2.31+/-2.46% vs. 7.43+/-4.10% and 16.41+/-6.15% vs. 22.44+/-8.63%, respectively, P<0.001 for all). Univariate analysis indicated that FMD of brachial arteries was inversely related to age (r=-0.226, P<0.05), hypertension (r=-0.229, P<0.05), baseline diameter (r=-0.299, P<0.01) and LDL-C (r=-0.237, P<0.05) and positively related to HDL-C (r=0.491, P<0.01). GTN induced vasodilatation was inversely related to age (r=-0.216, P<0. 05) and baseline diameter (-0.476, P<0.01). Multiple stepwise regression analyses in two groups taken together showed that HDL-C and age were the independent predictors of the FMD of brachial arteries (beta=0.466, P=0.000 and beta=-0.184, P=0.020, respectively). Baseline diameter was significant predictor of GTN-induced vasodilatation (beta=-0.390, P=0.000). The analysis in the group of CHD patients showed that only HDL-C was significantly relate to the FMD of brachial arteries (beta=0.295, P=0.018 ) and in controls that hypertension and HDL-C were significantly relate to the FMD of brachial arteries (beta=-0.395, P=0.004 and beta=0.344, P=0.011, respectively). These finding suggest that endothelium-dependent and endothelium-independent vasodilatation are impaired in the patients with CHD. HDL exerts a protective effect on endothelium-dependent vasodilatation in TC being relatively normal population.
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Affiliation(s)
- X P Li
- Departments of Cardiology, Second Affiliated Hospital, Human Medical University, 410011, Changsha, PR China
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Eichstädt HW, Abletshauser CB, Störk T, Weidinger G. Beneficial effects of fluvastatin on myocardial blood flow at two time-points in hypercholesterolemic patients with coronary artery disease. J Cardiovasc Pharmacol 2000; 35:735-40. [PMID: 10813375 DOI: 10.1097/00005344-200005000-00009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Hypercholesterolemia is a major risk factor initiating and accelerating atherosclerosis and leading to severe stages of coronary artery disease (CAD) with a high risk of cardiovascular events. We investigated the impact of lipid lowering in patients with hypercholesterolemia and evident CAD on clinically relevant parameters like myocardial perfusion. Myocardial imaging was performed with thallium-201 single photon-emission computed tomography at rest and after maximal bicycle exercise in 22 patients after a 4-week lead-in period, and after 12 and 24 weeks of therapy with fluvastatin. Perfusion defects occurred in all patients, indicating stress-induced myocardial ischemia. After 12 weeks of therapy, the perfusion of the ischemic segments increased by 26% (277+/-99 to 349+/-96 cpm; p < 0.001), whereas the value of the normal segments was augmented only by 4% (478+/-44 to 497+/-28 cpm; p < 0.05). The results slightly improved further after 24 weeks. Moreover, a subgroup analysis elucidated a more pronounced effect in patients without lipid-lowering premedication. This nonpretreated group (n = 11) revealed an improvement of ischemic segments at stress by 42% at week 24. In contrast, pretreated patients had an increase of only 18% (between groups, p < 0.05), indicating a carryover effect of premedication. In conclusion, short-term therapy with fluvastatin acts beneficially on impaired vascular function in hypercholesterolemic patients with CAD.
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Affiliation(s)
- H W Eichstädt
- Department of Imaging Cardiology and Nuclear Medicine, Humboldt-University, Berlin, Germany
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Kingwell BA. Nitric oxide as a metabolic regulator during exercise: effects of training in health and disease. Clin Exp Pharmacol Physiol 2000; 27:239-50. [PMID: 10779120 DOI: 10.1046/j.1440-1681.2000.03232.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
1. Accumulating animal and human data suggest that nitric oxide (NO) is important for both coronary and peripheral haemodynamic control and metabolic regulation during performance of exercise. 2. While still controversial, NO of endothelial origin is thought to potentiate exercise-induced hyperaemia, both in the peripheral and coronary circulations. The mechanism of release may include both acetylcholine derived from the neuromuscular junction and vascular shear stress. 3. A splice variant of neuronal nitric oxide synthase (NOS), nNOSmicro, incorporating an extra 34 amino acids, is expressed in human skeletal muscle. In addition to being a potential modulator of blood flow, skeletal muscle-derived NO is an important regulator of muscle contraction and metabolism. In particular, recent human data indicate that NO modulates muscle glucose uptake during exercise, independently of blood flow. 4. Exercise training in healthy individuals promotes adaptations in the various NO systems, which can increase NO bioavailability through a variety of mechanisms, including increased NOS enzyme expression and activity. Such adaptations likely contribute to increased exercise capacity and protection from cardiovascular events. 5. Cardiovascular risk factors, including hypercholesterolaemia, hypertension, diabetes and smoking, as well as established disease, are associated with impairment of the various NO systems. Given that NO is an important signalling mechanism during exercise, such impairment may contribute to limitations in exercise capacity through inadequate coronary or peripheral blood delivery and via metabolic effects. 6. Exercise training in individuals with elevated cardiovascular risk or established disease can increase NO bioavailability and may represent an important mechanism by which exercise training provides benefit in the setting of secondary prevention.
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Affiliation(s)
- B A Kingwell
- Alfred and Baker Medical Unit, Baker Medical Research Institute, Prahran, Victoria, Australia.
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John S, Schmieder RE. Impaired endothelial function in arterial hypertension and hypercholesterolemia: potential mechanisms and differences. J Hypertens 2000; 18:363-74. [PMID: 10779084 DOI: 10.1097/00004872-200018040-00002] [Citation(s) in RCA: 126] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
This review focuses on the role of impaired endothelial function for the development of atherosclerosis in human arterial hypertension and hypercholesterolemia in vivo. Potential mechanisms underlying impaired endothelial function and decreased bioavailability of nitric oxide under these clinical conditions are discussed and potential differences in these mechanisms between arterial hypertension and hypercholesterolemia are outlined. It further addresses therapeutic strategies aiming to improve the bioavailability of nitric oxide in these patients. The overall conclusion is that the bioavailability of nitric oxide is probably impaired not by a single defect, but by various mechanisms affecting nitric oxide synthesis as well as nitric oxide breakdown. In both diseases, increased superoxide anion production and oxidative stress represents a major mechanism. However, potential differences in the underlying mechanisms of superoxide production or nitric oxide synthesis are evident between arterial hypertension and hypercholesterolemia. Decreased bioavailability of nitric oxide does not only impair endothelium-dependent vasodilation, but also activates other mechanisms that play an important role in the pathogenesis of atherosclerosis. Thus, therapeutic strategies should aim to restore bioavailability of nitric oxide, which has been demonstrated for lipid-lowering therapy in hypercholesterolemia. The mechanisms by which nitric oxide bioavailability can be improved by any drug therapy remain to be elucidated and may provide further insights into the mechanisms that are involved in impaired endothelial function and atherogenesis.
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Affiliation(s)
- S John
- Department of Medicine IV, University of Erlangen-Nürnberg, Klinikum Nürnberg-Süd, Nürnberg, Germany
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47
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Cortella A, Zambon S, Sartore G, Piarulli F, Calabrò A, Manzato E, Crepaldi G. Calf and forearm blood flow in hypercholesterolemic patients. Angiology 2000; 51:309-18. [PMID: 10779001 DOI: 10.1177/000331970005100406] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Patients with hypercholesterolemia without vascular disease have an impaired endothelium-dependent (nitric oxide-mediated) vasodilation in coronary and peripheral vascular beds. This study was designed to establish whether hypercholesterolemia (and its reduction) affects also the microcirculation vasomotion during postischemic hyperemia in both calf and forearm. Thirteen male patients, aged 36.2+/-8.5 years, mean +/-SD, with heterozygous familial hypercholesterolemia and 10 male control subjects, aged 32.2+/-3.6 years free from vascular lesions were studied. Plasma lipids, hematologic parameters, and limb vasoreactivity were evaluated while the patients were treated only with diet and during therapy with simvastatin. Calf and forearm blood flows were determined by venous occlusion strain gauge plethysmography at rest, during reactive hyperemia, and after sublingual isosorbide dinitrate administration. Calf resting flow rate of the hypercholesterolemic patients during and without treatment was similar to that of the controls. Calf resting vascular resistance was greater in the untreated hypercholesterolemic subjects than in the normal controls, but during treatment this difference was abolished. Peak flow during reactive hyperemia and flow debt repayment were lower in the untreated hypercholesterolemic subjects as compared to the controls, but they were normalized following hypocholesterolemic therapy. No differences were observed in forearm blood flow measurements between hypercholesterolemic subjects (without and during therapy) and control subjects. The blood flow and vascular resistance after isosorbide dinitrate were modified in a similar manner in the hypercholesterolemic (without and during therapy) and control subjects at both calf and forearm. Hypercholesterolemia does not affect vasodilation in the forearm as determined by postocclusive reactive hyperemia, while in the calf hypercholesterolemia is associated with higher resting vascular resistance, lower peak flow during reactive hyperemia, and lower flow debt repayment. These abnormalities are corrected by the hypocholesterolemic treatment.
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Affiliation(s)
- A Cortella
- Department of Internal Medicine, University of Padova, Italy
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Peterson LR, Courtois M, Peterson LF, Peterson MR, Dávila-Román VG, Spina RJ, Barzilai B. Estrogen increases hyperemic microvascular blood flow velocity in postmenopausal women. J Gerontol A Biol Sci Med Sci 2000; 55:M174-9. [PMID: 10795732 DOI: 10.1093/gerona/55.3.m174] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Epidemiologic studies suggest that estrogen replacement therapy (ERT) is protective against vascular disease. ERT confers this benefit by lowering lipid levels and improving arterial function. However, its effect on the microvasculature in vivo is unknown. Thus the purposes of this study were to evaluate effect of estrogen status on the hyperemic response of the microvasculature in vivo in postmenopausal women and to compare the hyperemic response of the microvasculature in postmenopausal women taking ERT with that of premenopausal women. METHODS We measured forearm microvasculature flow velocity by using a laser Doppler in a cross section of 64 healthy premenopausal and postmenopausal women 23 to 72 years old. Microvasculature blood flow velocity was measured at baseline. throughout 2 minutes of ischemia, and immediately after the ischemic period was terminated (i.e., during the peak hyperemic response). RESULTS The peak of the hyperemic flow velocity (PHFV) in the postmenopausal women who were taking long-term ERT at usual doses was greater than that of postmenopausal women who were not currently taking ERT (p < .0001). Moreover, the PHFV of postmenopausal women taking ERT was similar to that of premenopausal women. Multivariate regression analysis showed estrogen status and baseline flow velocity to be independent predictors of PHFV. CONCLUSIONS Current, long-term ERT at usual replacement doses is associated with improved microvascular responses in postmenopausal women, which may explain some of its beneficial vascular effects.
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Affiliation(s)
- L R Peterson
- Division of Geriatrics and Gerontology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
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Hort W, Schwartzkopff B. Anatomie und Pathologie der Koronararterien. PATHOLOGIE DES ENDOKARD, DER KRANZARTERIEN UND DES MYOKARD 2000. [DOI: 10.1007/978-3-642-56944-9_3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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