PERIPHERAL VASCULAR CONTROL MECHANISMS

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Arachidonic acid serves as the common natural precursor of at least two families of biologically active compounds. Metabolism of arachidonate via the cyclooxygenase pathway gives rise to bisenoic prostaglandins, prostacyclin and thromboxane, whereas derivatives formed via the 5'-lipoxygenase pathway include hydroperoxy acids, hydroxy acids and leukotrienes (LT). It is well-established that vosactivity of arachidonic acid is dependent on conversion to active metabolites. Although cyclooxygenase products have been extensively studied, the leukotriene family of compounds are of more recent discovery, and influences of these products on regional blood flow are not well-established. A long-term goal of these studies is to enhance our knowledge of the relationships of leukotrienes to control of regional hemodynamics. We have previously reported that peptidoleukotrienes, LTC4, LTD4 and LTE4, alter regional blood flow in a divergent manner. Thus, in the anesthetized dog, these substances produced marked intestinal vasoconstriction, but had little to no effect in the kidney. Subsequently, in a preliminary investigation, we observed that LTD4 produced relaxation of isolated superior mesenteric and renal arteries in an apparently endothelial-dependent manner. These observations led to the present proposed research project whose major goal is to comprehensively evaluate these findings and to test the general hypothesis that enhanced levels of peptide leukotrines, whether of local or remote origin, participate in control of distribution of regional blood flow. These studies will focus primarily on the mesentric and renal vascular beds. Experiments described will utilize both in vivo and in vitro models. The in vivo experiments will be conducted in anesthetized dogs under conditions of natural blood flow. Regional flow will be measured with noncannulating electromagnetic flow probes. In vitro studies will be conducted on superior mesenteric and renal arterial segments obtained from dogs. In addition, as studies progress, other blood vessels obtained from dogs as well as other species will be investigated. These studies will comprenhensively define both hemodynamic and vascular smooth muscle influences of leukotrienes as well as relationships of these products to other vasoactive hormonal systems. Overall knowledge gained from these studies will improve our understanding of the potential role of these potent endogenous substances in regulation of the peripheral vascular bed. Enhanced knowledge of peripheral hemodynamic control mechanisms will provide insights into treatment of diseases such as essential hypertension.