The overall objective of our research is the delineation of the determinants of nitrovasodilator action and tolerance. Several nitrovasodilators (e.g. nitroglycerin, isosorbide dinitrate, sodium nitroprusside) are important therapeutic agents for the treatment of cardiovascular disease. These agents are safe and effective, but many members of its class (viz: the organic nitrates) produce rapid pharmacologic tolerance. The mechanisms of nitrate tolerance are not completely understood, but may involve a reduction in the ability of the vascular smooth muscle cells to produced nitric oxide (NO). This putative intracellular messenger has also been identified as the endothelium-derived relaxing factor (EDRF), which plays a critical physiological role in regulating vasodilation. Because of the common link of NO generation, mechanisms that govern nitrovasodilator tolerance might overlap with processes that control the endogenous release and action of EDRF. In this application, we propose a series of integrated and fundamental mechanistic studies to define both the biochemical and pharmacokinetic determinants of nitrovasodilator action and tolerance. These studies are important for advancing our knowledge on nitrovasodilators so that their use in cardiovascular therapy may be further improved. Our studies may also shed light on the potential interactions between EDRF and nitrovasodilators, thus enhancing our understanding fo the complex factors that govern the physiology and pharmacology of vasodilatation.
Our specific aims are (1) to develop a sensitive analytical method for NO assay in biological samples using a commercially available chemiluminescence detector, (2) to indentify the subcellular site (s) and conditions which govern the metabolic activation of organic nitrates in vascular smooth muscle cells, (3) to re- examine the """"""""sulfhydryl depletion"""""""" hypothesis of nitrate tolerance in detail, (4) to examine the mechanism(s) of action of sodium nitroprusside and its cross-tolerance properities with orther nitrovasodilators, (5) to examine the effects and mechanism(s) of intermittent drug delivery on the tolerance characteristics of nitrovasodilators, and (6) to determine the relationships between the systemic kinetics of several isomeric organic mononitrates and their pharmacologic properties of hypotension and tolerance (e.g. the rates of tolerance development, persistence and reversal). Isolated blood vessel preparations and intact animals (rats) will be used in these studies.
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