CORONARY VASCULAR EFFECTS OF ENVIRONMENTAL STIMULI

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Environmental stimuli are now recognized as important contributors to cardiovascular disease. However, the mechanisms and sites of action mediating the progression of myocardial ischemia, arrhythmias and sudden cardiac death induced by environmental stimuli such as behavioral stress and high NaCl diet are not understood. (The proposed studies will test the hypothesis that behavioral stress and high NaCl diet can independently, and in combination, impair coronary vasodilation. In conscious normotensive Wistar Kyoto rats (WKY), borderline hypertensive rats (BHR) and spontaneously hypertensive rats (SHR), arterial pressure and heart rate will be monitored during ten days of exposure to air-jet stress, high NaCl diet, or a combination of air-jet stress and high NaCl diet.) At the end of ten days, changes in coronary vascular function will be evaluated by determining altered vascular reactivity of the isolated coronary artery in vitro and by assessing changes in coronary blood flow velocity produced by vasoactive agents in vivo. {Preliminary studies have demonstrated impaired endothelial-dependent relaxation in coronary arteries of BHR and SHR exposed to behavioral stress. Experimental studies in BHR have shown that either behavioral stress or high NaCl diet can produce hypertension which is accompanied by increased plasma catecholamine levels and enhanced sympathetic nervous system activity. In the proposed studies, alpha- and beta-adrenoceptor antagonists, inhibition of neuronal release of norepinephrine, and removal of adrenal medulla will be used in vivo to assess the role of enhanced sympathetic nervous system activity in the altered coronary vascular responses produced by environmental stimuli. Additionally, mechanisms mediating impaired endothelial-dependent coronary relaxation will be determined in vitro. Mechanisms to be tested include: a) a deficiency of L-arginine, b) impaired nitric oxide synthase, c) reduced sensitivity to nitric oxide, d) enhanced inactivation of nitric oxide by superoxide anions, e) reduced sensitivity to cyclic GMP, and f) enhanced inactivation of cyclic GMP by cyclic GMP phosphodiesterase.} These studies will provide new information on the role of environmental stimuli in the development of coronary artery disease and the mechanisms mediating this process. This could lead to more effective prevention of morbidity and mortality from coronary artery disease.