Cardiovascular disease is a major cause of morbidity and mortality in African-Americans, yet remarkably few mechanistic studies have focussed on this group. We hypothesize that there is enhanced, autonomically-mediated vascular tone in African-Americans; this enhanced tone may play an important role in the pathogenesis of cardiovascular disease. Evidence for interethnic differences includes the demonstration of enhanced pressor responses to psychological stressors, increased sympathetic activity after cold pressor testing, an increased frequency of salt sensitivity, and more recently, our observations 1) that forearm vascular responses to the beta- adrenergic agonist, isoproterenol are attenuated in normotensive African- Americans and 2) that ethnicity and gender both influence the psychological traits associated with adverse cardiovascular outcomes. This project will define the mechanisms for the interethnic differences in the regulation of vascular tone through two specific aims. Our strategy will be (Specific Aim l) to utilize pharmacologic probes, with different receptor and non-receptor modes of action, to localize the sites responsible for the interethnic difference in vasodilation. Thus, the known interethnic differences in cardiovascular responses to stress may reflect differences in autonomic control at multiple levels and based on our preliminary data, we propose that differences in psychological traits may predict autonomically-mediated cardiovascular responses. We will determine (Specific Aim 2) the mechanism(s) of interethnic differences in autonomic reactivity by specifically probing central and peripheral levels of autonomic control, using directly measured muscle sympathetic nerve activity (MSNA) and norepinephrine kinetics to examine interethnic differences in basal awake and asleep sympathetiC activity, in stimulated (physiologic, pharmacologic, psychologic, nociceptive) and inhibited (pharmacologic and baroreflex) sympathetic activity, and in presynaptic receptor sensitivity. By defining the factors contributing to the altered cardiovascular response in African-Americans, physicians will be better able to tailor therapy to this group and reduce their present excessive burden of cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056251-03
Application #
2702325
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1996-06-01
Project End
2001-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Muszkat, Mordechai; Stein, C Michael (2005) Pharmacogenetics and response to beta-adrenergic receptor antagonists in heart failure. Clin Pharmacol Ther 77:123-6
Sofowora, Gbemiga G; Singh, Iqbal; He, Huai B et al. (2005) Effect of acute transdermal estrogen administration on basal, mental stress and cold pressor-induced sympathetic responses in postmenopausal women. Clin Auton Res 15:193-9
Muszkat, Mordechai; Sofowora, Gbenga G; Xie, Hong-Guang et al. (2005) Alpha2B adrenergic receptor 301-303 deletion polymorphism and vascular alpha2 adrenergic receptor response. Pharmacogenet Genomics 15:23-8
Dishy, Victor; Landau, Ruth; Sofowora, Gbenga G et al. (2004) Beta2-adrenoceptor Thr164Ile polymorphism is associated with markedly decreased vasodilator and increased vasoconstrictor sensitivity in vivo. Pharmacogenetics 14:517-22
Landau, Ruth; Xie, Hong-Guang; Dishy, Victor et al. (2004) No association of the Asp298 variant of the endothelial nitric oxide synthase gene with preeclampsia. Am J Hypertens 17:391-4
Sofowora, Gbenga G; Dishy, Victor; Landau, Ruth et al. (2004) Alpha 1A-adrenergic receptor polymorphism and vascular response. Clin Pharmacol Ther 75:539-45
Muszkat, Mordechai; Sofowora, Gbenga G; Wood, Alastair J J et al. (2004) Alpha2-adrenergic receptor-induced vascular constriction in blacks and whites. Hypertension 43:31-5
Dishy, Victor; Sofowora, Gbenga G; Imamura, Hitoshi et al. (2003) Nitric oxide production decreases after salt loading but is not related to blood pressure changes or nitric oxide-mediated vascular responses. J Hypertens 21:153-7
Efrati, Shai; Dishy, Victor; Averbukh, Michael et al. (2003) The effect of N-acetylcysteine on renal function, nitric oxide, and oxidative stress after angiography. Kidney Int 64:2182-7
Sofowora, G G; Dishy, V; Muszkat, M et al. (2003) A common beta1-adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to beta-blockade. Clin Pharmacol Ther 73:366-71

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