FEEDFORWARD CONTROL OF CORONARY BLOOD FLOW

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DESCRIPTION: (Adapted from the Investigator's Abstract) This is an application that is intended to address the hypothesis that activation of sympathetic fibers to the heart as well as elevations in circulating catecholamine levels activate beta-receptors that simultaneously result in tachycardia, increases in myocardial contractility and beta-adrenergic vasodilation of the coronary circulation. The applicant postulates that beta-mediated coronary vasodilation is a form of feedforward or parallel control that helps to match coronary blood flow to myocardial metabolism preventing myocardial ischemia during physiological adjustments to flow that occur during adrenergic activation. The central focus of the application is that feedforward beta-dilation combines with the previously demonstrated feedback control mechanisms that, to a large extent, are sensitive to regional myocardial oxygen tension. Under normal circumstances, major increases in myocardial metabolism are secondary to adrenergic beta-receptor-mediated increases in the determinants of oxygen consumption. It is likely that beta-receptor-mediated coronary vasodilation is a significant part of the physiological response to sympathetic activation. The experiments propose to address three Specific Aims. The first will test the hypothesis that there is beta-receptor-mediated coronary vasodilation when oxygen consumption is augmented by epinephrine infusion and determine the dose-response relation for arterial epinephrine that causes coronary beta-vasodilation. These will extend the previous observations of the applicant during the intracoronary norepinephrine infusion. The second Specific Aim will be to test the hypothesis that beta-receptor-mediated coronary vasodilation is an important part of the carotid sinus baro reflex and determine what component of this vasodilation is related to circulating catecholamines released by the adrenal gland as opposed to direct activation of sympathetic nerves and the local release of norepinephrine. The third Specific Aim will be to test the hypothesis that beta-receptor-mediated coronary vasodilation is important in matching flow to myocardial metabolism during graded levels of exercise and define what fraction of this is due to circulating epinephrine as opposed to direct sympathetic activation. Abnormalities in myocardial blood flow in patients with coronary artery disease are a major health problem. The proposed research will investigate the basic physiological mechanisms that control coronary blood flow with beta-receptor-mediated feedforward control. Beta-receptor blocking agents are frequently used to treat patients with angina pectoris with the rationale that limiting adrenergically-mediated increases in heart rate and myocardial contractility restricts oxygen consumption so that the oxygen supply demand ratio will be in better balance. However, not all patients benefit from beta-receptor blockade and the proposed research may clarify this problem since beta-receptor-mediated coronary vasodilation may have a beneficial effect on the oxygen supply-demand ratio that will be prevented by beta-receptor blockade. Furthermore, characterizing the beta-receptor-mediated coronary vasodilation may be the first step to developing agents that selectively inhibit cardiac beta-receptor activation without blocking the vascular beta-receptor dilation.