PHARMACODYNAMICS OF ENDOTHELIUM-DERIVED NITRIC OXIDE

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The principal objective of the proposed research is to elucidate the mechanisms and regulation of biosynthesis, storage, and release of vascular endothelium-derived nitric oxide (ENDO) from intact artery and vein and isolated endothelial cells. The central hypothesis is that NO is formed and released endogenously from such cells and elicits important pharmacological and physiological actions. Earlier studies from this laboratory indicated that authentic NO causes potent and marked but transient vascular smooth muscle relation, inhibition of platelet aggregation, increase cyclic GMP accumulation in such cells, heme-dependent activation of soluble guanylate cyclase, all of which can be antagonized by hemoproteins of methylene blue. Recent studies from this laboratory reveled independently the one endothelium-derived relaxing factor (EDRF) from artery and vein is NO or an unstable nitroso compound that spontaneously liberates NO. Therefore, the proposed studies are designed to characterize further the biochemistry and pharmacology of EDNO, as well as the formation of NO by activated the macrophages, neutrophils, and other tissues. FIVE specific aims are proposed to achieve the objective: 1) to elucidate the mechanism(s) by which ENDO is synthesized and the factors influencing EDNO formation; 2) to ascertain whether EDRF is pure NO or a mixture of NO plus a labile nitroso precursor; 3) to characterize the biochemical pathway of NO formation from L-arginine in vascular endothelial cells and other tissues; 4) to ascertain whether inorganic nitrite (NO2) is the major biotransformation product of ENDO in vascular tissue; 5) to ascertain whether vascular endothelial cell cyclic GMP plays any role in the regulation of ENDO formation and/or release. These objectives and aims represent a continuing long-term effort to elucidate the pharmacology of NO as well as the biological factors that influence and regulate vascular smooth muscle tone. New information on the possible source, formation, release, and actions of endogenous NO should lead to a better understanding of the etiology and therapy of certain cardiovascular disorder including essential hypertension, vasospasm, stroke.