Ischemic heart disease (IHD) remains the most common serious health problem of contemporary western society. However, patients with IHD enrolled in exercise-based rehabilitation programs experience lower mortality rates, and exercise training appears to be the key ingredient. Mechanisms involved in the beneficial effects of training are not fully understood. This proposal will focus on coronary effects of exercise training in an experimental model of chronic coronary artery occlusion and collateral perfusion. In vitro analyses of vascular smooth muscle (VSM) and endothelium function will be compared in normal coronary arteries and in arteries isolated distal to the coronary occlusion (collateral-dependent myocardial region). Our preliminary studies suggest that alpha-adrenergic vasoconstrictor responses are enhanced and endothelium-mediated coronary relaxation is impaired in collateral- dependent vasculature. On the other hand, exercise training decreases alpha-adrenergic vasoconstriction and enhances endothelium-mediated coronary vasorelaxation. Our overall hypothesis is that exercise training of animals exposed to chronic coronary artery occlusion produces beneficial adaptive responses of coronary VSM and endothelium function; functional alterations are dependent upon vascular site (normal vs. collateral-dependent myocardium) and on artery size (conduit, near- resistance, resistance arteries).
Specific aims of the current project involve in vitro evaluation of 1) agonist (norepinephrine, vasopressin, endothelin)-mediated VSM contractile mechanisms and intracellular Ca2+ ([Ca]i) regulation; 2) endothelium-dependent (bradykinin, ADP, substance P, flow) and endothelium-independent (nitroprusside, adenosine) relaxation responses; 3) mechanisms of altered endothelium-dependent relaxation including synthesis/release of EDRF/nitric oxide and vasoactive prostanoids; 4) vasomotor responsiveness in the presence of reduced perfusate oxygen tension; and 5) blood flow responses of collateral-dependent myocardium in vivo. In vitro end points to be measured include: isometric contraction and relaxation; vessel luminal diameter (videotracking imaging techniques); radioisotope fluxes (42K) and [Ca]i (fura-2 microfluorometry). We anticipate that exercise training will have a beneficial effect upon intrinsic function of VSM and endothelium in coronary-occluded hearts, shifting the balance of vasoconstrictor/vasodilator influence toward increased vasorelaxation and optimization of myocardial blood flow to collateral dependent myocardium.
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