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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL049170-04
Application #
6144001
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1996-09-01
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2001-08-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Washington
Department
Physiology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Tune, J D; Richmond, K N; Gorman, M W et al. (2001) K(ATP)(+) channels, nitric oxide, and adenosine are not required for local metabolic coronary vasodilation. Am J Physiol Heart Circ Physiol 280:H868-75
Tune, J D; Richmond, K N; Gorman, M W et al. (2000) Role of nitric oxide and adenosine in control of coronary blood flow in exercising dogs. Circulation 101:2942-8
Gorman, M W; Tune, J D; Richmond, K N et al. (2000) Quantitative analysis of feedforward sympathetic coronary vasodilation in exercising dogs. J Appl Physiol 89:1903-11
Richmond, K N; Tune, J D; Gorman, M W et al. (2000) Role of K(ATP)(+) channels and adenosine in the control of coronary blood flow during exercise. J Appl Physiol 89:529-36
Gorman, M W; Tune, J D; Richmond, K N et al. (2000) Feedforward sympathetic coronary vasodilation in exercising dogs. J Appl Physiol 89:1892-902
Feigl, E O (1998) Neural control of coronary blood flow. J Vasc Res 35:85-92