The role of the endothelium has taken on increasing significance in vascular pharmacology and physiology in the past several years with the discovery that numerous endogenous and exogenous vasodilators exert their action on vascular smooth muscle by releasing from the endothelium a substance termed endothelium- dependent relaxing factor (EDRF). The production of EDRF is calcium dependent; it has a short biologic half-life; and its relaxing action on vascular smooth muscle correlates with an increase in muscle cyclic GMP concentration. Several studies have implicated the importance of oxygen tension in the stability of the relaxation responses induced by EDRF. The proposed research plan will investigate the inhibition of endothelium dependent relaxation by hypoxia. The oxygen sensitivity of these responses could be due to an effect on factor production, to the stability of EDRF once produced, to the reactivity of the vascular smooth muscle where it acts, or to some combination of these events. An experimental system will be used which allows transfer of EDRF from cultured pulmonary artery endothelial cells to one of three bioassays: relaxation of a de-endothelialized vascular ring, increase in cyclic GMP levels in cultured-vascular smooth muscle, or activation of guanylate cyclase. Separate manipulation of the oxygen tensions of the endothelial cells, of EDRF in solution, and of the bioassay preparations will allow us to investigate the sites and mechanisms of oxygen interactions with EDRF. The effects of varying oxygen tensions on the increase in endothelial cell cytoplasmic calcium concentration which normally accompanies EDRF release also will be determined. In addition to providing further insight into the nature of EDRF, these studies will increase our understanding of the potential role of EDRF in the normal and diseased pulmonary circulation including regulation of basal tone, hypoxic pulmonary vasoconstriction, pulmonary hypertension, and adult respiratory distress syndrome.
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