Opposite effects of cyclooxygenase-1 and-2 activity on the pressor response to angiotensin II
Opposite effects of cyclooxygenase-1 and-2 activity on the pressor response to angiotensin II
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DOI：
10.1172/jci200214752
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发表时间：
2002-07-01
影响因子：
15.9
通讯作者：
Breyer, MD
中科院分区：
文献类型：
--
作者：
Qi, ZH;Hao, CM;Breyer, MD
治疗性使用环氧化酶抑制（cox -抑制）非甾体抗炎药（NSAIDs）经常并发肾脏副作用，包括高血压和水肿。本研究旨在阐明cox1和COX2在调节血压和肾功能中的作用。COX2抑制剂或基因敲除显著增强血管紧张素II （Ang II）的升压作用。出乎意料的是，在短暂升高后，Ang II的升压作用因COX1缺乏（抑制剂或敲除）而消失。在cox2缺乏的动物中，输注Ang II也减少了髓质血流量，但在对照组或cox1缺乏的动物中没有减少，这表明肾髓质中合成了依赖于cox2的血管扩张剂。与此一致的是，angii不能刺激cox2缺乏动物肾髓质前列腺素E2和前列腺素I-2的产生。正常情况下，输注angii可促进利钠和利尿，但缺乏COX2则阻断了这一作用。因此，COX1和COX2对全身血压和肾功能的作用是相反的。COX2抑制剂可减少肾髓血流量，减少尿流量，增强Ang II的升压作用。相反，抑制COX 1会减弱Ang II的升压作用。这些结果表明，COX 1和COX2的活性在功能上是拮抗的，而不是具有类似的心血管作用。
Therapeutic use of cyclooxygenase-inhibiting (COX-inhibiting) nonsteroidal antiinflammatory drugs (NSAIDs) is often complicated by renal side effects including hypertension and edema. The present studies were undertaken to elucidate the roles of COX 1 and COX2 in regulating blood pressure and renal function. COX2 inhibitors or gene knockout dramatically augment the pressor effect of angiotensin II (Ang II). Unexpectedly, after a brief increase, the pressor effect of Ang II was abolished by COX1 deficiency (either inhibitor or knockout). Ang II infusion also reduced medullary blood flow in COX2-deficient but not in control or COX1-deficient animals, suggesting synthesis of COX2-dependent vasodilators in the renal medulla. Consistent with this, Ang II failed to stimulate renal medullary prostaglandin E2 and prostaglandin I-2 production in COX2-deficient animals. Ang II infusion normally promotes natriuresis and diuresis, but COX2 deficiency blocked this effect. Thus, COX1 and COX2 exert opposite effects on systemic blood pressure and renal function. COX2 inhibitors reduce renal medullary blood flow, decrease urine flow, and enhance the pressor effect of Ang II. In contrast, the pressor effect of Ang II is blunted by COX 1 inhibition. These results suggest that, rather than having similar cardiovascular effects, the activities of COX 1 and COX2 are functionally antagonistic.