The long-term objectives are to increase our knowledge of the various mechanisms of vasodilation in general, and of endothelium-dependent vasodilation in particular, and to elucidate the physiological significance of endothelium-dependent vasodilation, and to evaluate whether its impairment is of importance in the pathophysiology of various cardiovascular diseases. The first specific aims are to investigate: (1) the chemical identity of the endothelium-derived relaxing factor (EDRF) that mediates endothelium-dependent vasodilation; (2) the mechanisms by which EDRF is produced in and released from vascular endothelial cells; (3) the mechanism by which EDRF activates relaxation of vascular smooth muscle; (4) the mechanisms of inactivation of EDRF by various agents. Because of the striking similarities in the properties of EDRF and nitric oxide (NO) as relaxants, experiments will be conducted to determine whether EDRF is NO. These will be both bioassay experiments for EDRF and NO involving perfusion cascade systems, as well as experiments to quantify chemically or physically NO released from endothelial cells (EC). Cultured EC as well as EC in situ will be used as a source of EDRF. If results identify EDRF as NO, experiments will be conducted on the effects of potential precursors of NO (endogenous compounds containing nitrogen either more reduced or more oxidized than that of NO) on formation of EDRF (determined by bioassay) in intact EC and in broken-cell systems. Selective inhibitors will be used to identify enzyme systems involved in EDRF formation. Experiments will be designed to test whether free calcium levels in smooth muscle cells are reduced when EDRF stimulates increases in cyclic GMP. A study will be made of the reaction whereby O2- rapidly inactivates EDRF (and NO). Additional aims are to determine: (5) whether the acid-activatable inhibitory factor (IF, also a vasodilator) extracted from retractor penis is inorganic nitrite and the acid-activated factor is NO; (6) whether the """"""""neurotransmitter"""""""" relaxing factor released on stimulation of noncholinergic, nonadrenergic nerves in certain smooth muscles is similar to EDRF and NO; (7) whether photorelaxation of smooth muscle is due to release of a photo-induced relaxing factor similar to EDRF. Among the many procedures used in pursuing these aims will be chemical procedures to quantify NO2- and NO (aim 5); transmural electrical stimulation of nerves and perfusion cascade bioassay procedures (aim 6); and UV radiation and perfusion cascade procedures (aim 7).
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