Spasm of medium-sized arteries is recognized as the pathogenetic mechanism underlying Prinzmetal's variant angina, as well as contributing to coronary ischemia of angina pectoris and myocardial infarction; it also accounts for Raynaud's phenomenon. Despite the documentation that spasm occurs clinically in otherwise normal vessels, the factors which cause an artery to constrict and to close its lumen are not understood. Since maximal contraction of the smooth muscle of perfused coronary arteries does not result in vessel closure, factors other than smooth muscle contractility must play a role in clinical spasm. The hypothesis of this proposal is that physical conditions acting on the blood vessel wall must cooperate with smooth muscle contraction to facilitate spasm. The goal of the study is to analyze systematically the response of isolated canine and human coronary and peripheral arteries to local physical, humoral, and nervous influences to which they might be exposed in normal and abnormal circumstances, to determine if separately, or in combination, vasospasm can be documented in vitro. Since blood vessels are normally exposed to substances from inside and outside the vessel, the isolated arteries will be perfused in an organ bath so that they may be exposed to intraluminal or extraluminal agents. Hemodynamic factors of perfusion pressure, flow, lumen size, and blood viscosity will be varied to determine those physical conditions which most favor spasm. The arterial smooth muscle will be stimulated under pathologic conditions known, or suspected, to initiate vasospasm: aggregating platelets, stimulation of adrenergic nerves, anoxia, cooling, and vibration. Since the endothelium plays and important role in modulating the responses to vaso-active agents, studies will be conducted before, and after removal of, the endothelium. Since closure of the vessel lumen implies that smooth muscle contraction has overcome the hymodynamic forces maintaining the vessel patent, a direct measurement of vascular transmural pressure, the closing pressure, will be used to determine how each condition or stimulus affects the blood vessel to close.
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