Vasomotor Reaction to Cyclooxygenase-1-Mediated Prostacyclin Synthesis in Carotid Arteries from Two-Kidney-One-Clip Hypertensive Mice.
Vasomotor Reaction to Cyclooxygenase-1-Mediated Prostacyclin Synthesis in Carotid Arteries from Two-Kidney-One-Clip Hypertensive Mice.
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DOI：
10.1371/journal.pone.0136738
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Zhou Y
中科院分区：
文献类型：
--
作者：
Liu B;Li Z;Zhang Y;Luo W;Zhang J;Li H;Zhou Y
本研究验证了一种假设，即在高血压动脉中，环氧合酶-1(COX-1)仍然是主要的形式，介导前列腺素I2(Prostaglandin I2，PGI2)的合成，在功能性血管扩张剂PGI2(IP)受体存在的情况下，可能引发血管收缩反应。用野生型(WT)小鼠和/或COX-1缺陷(COX-1-/-)小鼠诱导两肾一夹(2K1C)高血压。4周后分离颈动脉进行分析。结果表明，与正常血压小鼠一样，毒扁豆碱受体激动剂ACh可引起前列腺素I2代谢产物6-酮-前列腺素F1α的产生和内皮依赖性的血管收缩反应，这两种反应均可被COX-1抑制而取消。同时，引起高血压血管收缩的前列环素(PGI2)在血栓素-前列腺素(TP)受体拮抗后引起松弛，从而取消ACh引起的收缩。拮抗IP受体可增强对COX底物花生四烯酸(AA)的收缩。此外，COX-1-/-小鼠被发现患有高血压；然而，他们的血压和/或心脏质量的增加没有达到WT小鼠的水平。此外，我们发现，在COX-1-/-高血压小鼠中，ACh引起的收缩或AA引起的收缩都被取消。这些结果表明，与正常血压条件下一样，COX-1是2K1C高血压颈动脉合成PGI2的主要贡献者，它分别通过IP和TP受体的相反的扩张剂和血管收缩活性而导致血管收缩反应。此外，我们的数据表明，COX-1-/-可以减轻小鼠2K1C高血压的发展，反映了病理条件下COX-1介导的所有活动产生的净不利作用。
This study tested the hypothesis that in hypertensive arteries cyclooxygenase-1 (COX-1) remains as a major form, mediating prostacyclin (prostaglandin I2; PGI2) synthesis that may evoke a vasoconstrictor response in the presence of functional vasodilator PGI2 (IP) receptors. Two-kidney-one-clip (2K1C) hypertension was induced in wild-type (WT) mice and/or those with COX-1 deficiency (COX-1-/-). Carotid arteries were isolated for analyses 4 weeks after. Results showed that as in normotensive mice, the muscarinic receptor agonist ACh evoked a production of the PGI2 metabolite 6-keto-PGF1α and an endothelium-dependent vasoconstrictor response; both of them were abolished by COX-1 inhibition. At the same time, PGI2, which evokes contraction of hypertensive vessels, caused relaxation after thromboxane-prostanoid (TP) receptor antagonism that abolished the contraction evoked by ACh. Antagonizing IP receptors enhanced the contraction to the COX substrate arachidonic acid (AA). Also, COX-1-/- mice was noted to develop hypertension; however, their increase of blood pressure and/or heart mass was not to a level achieved with WT mice. In addition, we found that either the contraction in response to ACh or that evoked by AA was abolished in COX-1-/- hypertensive mice. These results demonstrate that as in normotensive conditions, COX-1 is a major contributor of PGI2 synthesis in 2K1C hypertensive carotid arteries, which leads to a vasoconstrictor response resulting from opposing dilator and vasoconstrictor activities of IP and TP receptors, respectively. Also, our data suggest that COX-1-/- attenuates the development of 2K1C hypertension in mice, reflecting a net adverse role yielded from all COX-1-mediated activities under the pathological condition.