PERIPHERAL VASCULAR CONTROL MECHANISMS

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Leukotrienes (LT) C4 and D4 are the principal Components of slow reacting substance of anaphylaxis (SRS-A). Results of previous studies have shown that these substances have the capacity to produce endothelium dependent vasomotor relaxation, which, in arteries, is dependent on the release of an endothelium derived relaxing factor (EDRF). The factor released by LTD4 from arteries could not be distinguished by pharmacological criteria from the classical EDRF, considered to be nitric oxide (NO) or an unstable nitroso compound that releases NO. In contrast to these observations, it was found that LTD4 induced endothelium-dependent relaxation of the renal vein in a more potent and efficacious manner, but the vasorelaxant activity was due to a mechanism or mediator other than cyclooxygenase-derived products of arachidonic acid, the classic EDRF/NO, or vascular smooth muscle hyperpolarization consequent to ATP-sensitive K+ channel activation. More recent observations suggest that multiple signal transduction pathways and perhaps different LT receptors may account for the diverse activity of these substances in arteries and veins. Additionally, both LTC4 and LTD4 evoke marked endothelium- dependent relaxation of visceral capacitance veins. These latter observations appear to be consistent with the known hemodynamic changes which occur during anaphylactic shock, including hypotension and a fall in cardiac output associated with a reduction in venous return to the heart secondary to vasodilation of splanchnic venous capacitance vasculature. It was these aforementioned observations that led to the formulated working hypotheses: a) endothelium dependent relaxation evoked in veins by LTs is consequent to a mechanism/mediator that differs from EDRF/NO and b) receptors for LTs localized on venous and arterial endothelium differ. In order to evaluate these hypotheses, studies are proposed to: comprehensively characterize evoked changes in vasomotor tone in isolated vascular ring preparations; identify and characterize, via bioassay, vasomotor mediators derived from vascular segments or primary endothelial cell cultures; and define receptor binding characteristics of LTs on endothelial cell membranes. Overall knowledge gained from these studies will help to improve our understanding of the role of these potent endogenous substances in the regulation of vasomotor tone and peripheral hemodynamics.