Regulation of vascular prostaglandin synthesis by metabolites of arachidonic acid in perfused rabbit aorta.
Regulation of vascular prostaglandin synthesis by metabolites of arachidonic acid in perfused rabbit aorta.
复制标题
灌注兔主动脉中花生四烯酸代谢物对血管前列腺素合成的调节。
DOI：
10.1172/jci110993
复制
发表时间：
1983
期刊：
影响因子：
--
通讯作者：
Whorton,AR
中科院分区：
文献类型：
--
作者：
Kent,RS;Diedrich,SL;Whorton,AR
为了解决花生四烯酸代谢物是完整血管组织中前列腺素 (PG) 合成的重要调节剂这一假设，我们研究了连续输注 10 微克/毫升花生四烯酸时兔主动脉中花生四烯酸的代谢。前列环素（PGI2；以 6-酮基-PGF1 α 测量）产生速率在前 2 分钟内加速，在 2 分钟时达到峰值速度，然后逐渐减慢。 PGI2 产生的速度曲线与先前报道的体外测定的环氧合酶全酶的速度曲线相似，并且与导致 PGI2 合成的酶的逐渐失活一致。我们通过测量 PGI2 和 PGE2 生产率以及注入环状内过氧化物来确定环加氧酶和前列环素合成酶的特异性抑制作用。我们的结果表明，在花生四烯酸代谢过程中，环氧合酶优先失活，这很可能是由于环氧合酶衍生的氧化中间体所致。这是一种剂量依赖性反应，导致 6-酮-PGF1 α/PGE2 比率逐渐下降。另一方面，外源添加的15-氢过氧二十碳四烯酸实际上在低剂量下刺激了环氧合酶活性，同时显着抑制前列环素合成酶。这一发现以及花生四烯酸代谢的加速性质与“过氧化物调”作为该系统中环氧合酶活性介质的概念是一致的。这些结果表明花生四烯酸代谢物调节完整血管中的 PG 合成。花生四烯酸代谢固有的渐进酶抑制可能是在脂质过氧化增强状态下发生类似变化的模型。这些代谢改变可能会极大地影响已知涉及花生四烯酸代谢的众多血管功能。
To address the hypothesis that metabolites of arachidonic acid are important regulators of prostaglandin (PG) synthesis in intact vascular tissue, we studied arachidonate metabolism in rabbit aortas in response to a continuous infusion of arachidonic acid, 10 micrograms/ml. Prostacyclin (PGI2; measured as 6-keto-PGF1 alpha) production rate accelerated during the first 2 min, reached peak velocity at 2 min, and then progressively decelerated. The velocity profile of PGI2 production was similar to that previously reported for cyclooxygenase holoenzyme assayed in vitro, and was consistent with progressive inactivation of the enzymes leading to PGI2 synthesis. We determined the specific inhibition of cyclooxygenase and prostacyclin synthetase by measuring PGI2 and PGE2 production rates and by infusing cyclic endoperoxides. Our results indicate preferential inactivation of cyclooxygenase during arachidonate metabolism, most likely due to cyclooxygenase-derived oxidative intermediates. This was a dose-dependent response and resulted in a progressive decrease in the 6-keto-PGF1 alpha/PGE2 ratio. Exogenously added 15-hydroperoxy eicosatetraenoic acid, on the other hand, actually stimulated cyclooxygenase activity at low doses, while markedly inhibiting prostacyclin synthetase. This finding, along with the accelerating nature of arachidonate metabolism, is consistent with the concept of "peroxide tone" as a mediator of cyclooxygenase activity in this system. These results demonstrate that arachidonate metabolites regulate PG synthesis in intact blood vessels. The progressive enzymatic inhibition intrinsic to arachidonate metabolism may be a model for similar changes occurring in states of enhanced lipid peroxidation. These metabolic alterations might greatly influence the numerous vascular functions known to involve arachidonic acid metabolism.