Feelisch M, Kelm M
Department of Pharmacology, Schwarz Pharma, Monheim, Germany.
Biochem Biophys Res Commun. 1991 Oct 15;180(1):286-93. doi: 10.1016/s0006-291x(05)81290-2.
The vasodilator action of organic nitrates is thought to be mediated by an increase in the level of cGMP following stimulation of the cytosolic enzyme guanylate cyclase in the vascular smooth muscle cell. However, direct evidence for the formation of the putative active metabolite, nitric oxide (NO) within the different compartments of the vascular wall is still missing. We here demonstrate for the first time that cultured vascular smooth muscle cells as well as endothelial cells from different species actively metabolize organic nitrates to NO. We furthermore present evidence for an outward transport of cGMP from both cell types following stimulation of soluble guanylate cyclase. The rate of NO release closely correlated with the rate of cGMP egression. Biotransformation of organic nitrates to NO appeared to comprise at least two different components, a heat-sensitive enzymatic pathway which is short-lived and prone to rapid desensitization and a second non-enzymatic component which is apparently unsaturable and longer lasting. The marked decrease in the release of NO and cGMP upon the repeated administration of organic nitrates suggests that the phenomenon of "nitrate tolerance" is mainly due to an impaired biotransformation. We propose that the metabolism of nitrates to NO may have important implications for the prevention of atherosclerosis and the therapeutic modulation of blood cell function.
有机硝酸盐的血管舒张作用被认为是通过刺激血管平滑肌细胞中的胞质酶鸟苷酸环化酶后，环磷酸鸟苷（cGMP）水平升高来介导的。然而，在血管壁不同区域内形成假定的活性代谢产物一氧化氮（NO）的直接证据仍然缺失。我们在此首次证明，来自不同物种的培养血管平滑肌细胞以及内皮细胞能将有机硝酸盐积极代谢为NO。我们还提供了证据表明，刺激可溶性鸟苷酸环化酶后，两种细胞类型中的cGMP都会向外转运。NO释放速率与cGMP外流速率密切相关。有机硝酸盐向NO的生物转化似乎至少包括两个不同的成分，一个是对热敏感的酶促途径，该途径持续时间短且易于快速脱敏，另一个是第二个非酶促成分，该成分显然不饱和且持续时间更长。反复给予有机硝酸盐后，NO和cGMP释放的显著降低表明，“硝酸盐耐受性”现象主要是由于生物转化受损所致。我们提出，硝酸盐向NO的代谢可能对动脉粥样硬化的预防和血细胞功能的治疗调节具有重要意义。
