PHARMACODYNAMICS OF ENDOTHELIUM-DERIVED NITRIC OXIDE

拟议研究的主要目标是阐明 血管生成、储存和释放的机制和调控 来自完整动脉和静脉的内皮源性一氧化氮（ENDO）， 分离的内皮细胞。核心假设是NO的形成， 从这些细胞内源性释放，并具有重要的药理学作用， 和生理行为。该实验室的早期研究表明， 真正的NO会导致有效的和显著的，但短暂的血管平滑， 肌肉联系，抑制血小板聚集，增加环鸟苷酸 积累在这样的细胞，血红素依赖性激活可溶性鸟苷酸 环化酶，所有这些都可以被亚甲蓝血红素蛋白拮抗。 该实验室最近的研究独立地揭示了 来自动脉和静脉的内皮源性舒张因子（EDRF）是NO或 不稳定的亚硝基化合物，自发释放NO。因此， 拟议的研究旨在进一步表征生物化学和 EDNO的药理学，以及通过激活 巨噬细胞、嗜中性粒细胞和其他组织。 五个具体目标是 建议达到的目的：1）阐明机制， 研究了ENDO的合成方法及影响EDNO生成的因素; 2） 确定EDRF是纯NO还是NO和不稳定亚硝基的混合物 前体; 3）表征NO形成的生化途径， 血管内皮细胞和其他组织中的L-精氨酸; 4）确定 无机亚硝酸盐（NO2）是否是主要的生物转化产物， ENDO在血管组织中的作用; 5）确定血管内皮细胞是否 环GMP在调节ENDO形成和/或 release. 这些目标和宗旨是一项持续的长期努力 阐明NO的药理学以及 影响和调节血管平滑肌张力。 的新信息 内源性NO的可能来源、形成、释放和作用应 导致更好地了解某些疾病的病因和治疗 心血管疾病，包括原发性高血压，血管痉挛， 中风

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.