Ischemic heart disease represents the most common serious health problem of contemporary western society. An important natural defense mechanism of the diseased heart is the collateral circulation, which increases in structure and function under the influence of myocardial ischemia and hypoxia. However, vasomotor properties of collateral arteries are difficult to evaluate directly using patients and intact experimental models where concomitant non-collateral vascular and myocardial alterations may complicate interpretation of primary collateral responses. Therefore, we have approached this problem using in vitro analyses of vascular smooth muscle (VSM) and endothelium function of collateral arteries isolated from in vivo models of collateral development. The current project is based on the overall hypothesis that intrinsic function or coronary artery smooth muscle and endothelium is altered following progressive coronary occlusion and chronic collateral perfusion; the functional alterations, however, are dependent on vascular site (donor; collateral; recipient) and on artery size (conduit; near-resistance microvessel; resistance arteriole). We also postulate that specific membrane ion transport mechanisms subserving intracellular Ca2+ regulation are subject to alteration in collaterals. Our preliminary studies have provided evidence for impaired vasoconstrictor responses of collaterals to endothelin and PGF2alpha, and altered endothelium-mediated relaxation in collateral and recipient (collateral-dependent arteries.
Specific aims of the current project involve in vitro evaluation of: 1) receptor-mediated (endothelin, PGF2alpha) and selected non-receptor Ca2+-dependent (caffeine, [Ca], phorbol ester, ryanodine) vasomotor interventions in collaterals; 2) VSM membrane ion transport and intracellular Ca2+ concentration ([Ca2+]i) changes associated with altered vasoconstrictor responsiveness of collaterals; 3) endothelium-dependent and-independent relaxation responses and [Ca2+]i in collaterals and collateral-dependent arteries; and 4) smooth muscle and endothelium-dependent responses of coronary and collateral arteries in the presence of hypoxia. End points to be measured include: isometric contraction (conduit and microvessel); microvessel dimensions (video tracking imaging techniques); radioisotope fluxes (42K, 45Ca); and [Ca2+]i (fura-2 microfluorometry). These studies are designed to identify potential pathophysiological mechanisms whereby coronary occlusion and chronic collateral perfusion alter intrinsic contraction and relaxation properties of coronary vasculature. Information gained will aid in the development of pharmacotherapeutic strategies for optimizing collateral blood flow to post-occlusive myocardium and treatment of preinfarction, stenotic coronary artery disease.
