Constriction of large coronary arteries (coronary vasospasm) leads to acute restriction of coronary blood flow. Although many factors (e.g. aggregating platelets, cardiac glycosides, catecholamines, 5-hydroxytryptamine, prostaglandins, hypoxia) are able to trigger contraction of coronary vascular smooth muscle, the exact etiology of coronary vasospasm is unknown. The prime purpose of the proposed study is to determine the cellular mechanisms underlying contraction of coronary smooth muscle caused by acute hypoxia. The experiments will be performed on isolated coronary arteries taken from dogs and pigs to determine whether or not the phenomena observed are species-specific. Responses of vascular smooth muscle will be measured as changes in isometric force. Preparations with and without endothelium will be compared to assess the role of the endothelial cells. Responses of the adrenergic nerves will be determined by measuring the overflow of labeled norepinephrine and by comparing control preparations with tissue denervated chemically with 6-hydroxydopamine. Particular attention will be paid to the effect of hypoxia under resting conditions and during contractions evoked by other potential mediators of coronary vasospasm, in particular cardiac glycosides, catecholamines, 5-hydroxytryptamine, thromboxane A2 and potassium ions. Studies to examine the possible mechanisms underlying the hypoxic vasoconstriction will require examination of the metabolism of arachidonic acid. It is expected that the knowledge gained will help provide new information on the cellular mechanism(s) underlying spasm of coronary arteries.
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