PHARMACODYNAMICS OF ENDOTHELIUM-DERIVED NITRIC OXIDE

拟议研究的主要目的是阐明 血管生物合成、储存和释放的机制与调控 内皮源性一氧化氮(Endo)来自完整的动、静脉和 分离的内皮细胞。中心假说是NO形成并且 从这些细胞内源性释放，并引发重要的药理作用 和生理动作。该实验室的早期研究表明 真正的一氧化氮能有效而显著地导致短暂的血管畅通 肌肉联系，抑制血小板聚集，增加环状GMP 在这类细胞中的积累，依赖于血红素激活可溶性鸟酸盐 环化酶，均可被亚甲基蓝的血球蛋白拮抗。 这个实验室最近的研究独立地展示了一项 动脉和静脉来源的内皮衍生松弛因子(EDRF)是NO或 自发释放NO的不稳定亚硝基化合物。因此， 拟议的研究旨在进一步表征生物化学和 EDNO的药理作用，以及通过激活 巨噬细胞、中性粒细胞和其他组织。五个具体目标是 建议实现目标：1)通过以下方式阐明机制(S) 合成了哪些内切酶以及影响EDNO生成的因素；2) 确定EDRF是纯NO还是NO加不稳定亚硝基的混合物 前体物；3)表征NO生成的生化途径 L-血管内皮细胞和其他组织中的精氨酸；4)确定 无机亚硝酸盐(NO2)是否为生物转化的主要产物 血管组织的内源性；5)确定血管内皮细胞 环状GMP在内分泌形成和/或调节中发挥任何作用 放手。这些目标和目的代表了一项持续的长期努力 阐明NO的药理作用以及与NO有关的生物学因素 影响和调节血管平滑肌张力。最新消息： 内源性NO的可能来源、形成、释放和作用 有助于更好地了解某些疾病的病因和治疗方法 心血管疾病包括高血压、血管痉挛、 卒中。

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.