Li D Y, Hardy P, Abran D, Martinez-Bermudez A K, Guerguerian A M, Bhattacharya M, Almazan G, Menezes R, Peri K G, Varma D R, Chemtob S
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Am J Physiol. 1997 Oct;273(4):R1283-90. doi: 10.1152/ajpregu.1997.273.4.R1283.
Ibuprofen, a cyclooxygenase (COX) inhibitor nonselective for either COX-1 or COX-2 isoform, upregulates cerebrovascular prostaglandin E2 (PGE2) and PGF2alpha receptors in newborn pigs. COX-2 was shown to be the predominant form of COX and the main catalyst of prostaglandin synthesis in the newborn brain. We proceeded to establish direct evidence that COX-2-generated prostaglandins govern PGE2 and PGF2alpha receptor density and function in the cerebral vasculature of the newborn. Hence, we determined PGE2 and PGF2alpha receptor density and functions in brain vasculature by using newborn pigs treated with saline, ibuprofen, COX-1 inhibitor (valerylsalicylate), or COX-2 inhibitors (DUP-697 and NS-398). Newborn brain PGE2 and PGF2alpha concentrations were significantly reduced by ibuprofen, DUP-697, and NS-398 but not by valerylsalicylate. In newborn pigs treated with DUP-697, NS-398, and ibuprofen, PGE2 and PGF2alpha receptor densities in brain microvessels were increased to adult levels; there was also a significant increase in inositol 1,4,5-trisphosphate (IP3) production and cerebral vasoconstrictor effects of 17-phenyl trinor PGE2 (EP1 receptor agonist), M&B-28767 (EP3 receptor agonist), PGF2alpha, and fenprostalene (PGF2alpha analog). Treatment with ibuprofen or DUP-697 also increased the upper blood pressure limit of cerebral cortex and periventricular blood flow autoregulation from 85 to > or = 125 mmHg (uppermost blood pressure studied). However, valerylsalicylate treatment did not affect cerebrovascular PGE2 and PGF2alpha receptors, IP3 production, or vasoconstrictor effects in newborn animals. These in vivo and in vitro observations indicate that COX-2 is mainly responsible for the regulation of PGE2 and PGF2alpha receptors and their functions in the newborn cerebral vasculature.
布洛芬是一种对COX - 1或COX - 2同工酶均无选择性的环氧化酶（COX）抑制剂，它可上调新生猪脑血管中的前列腺素E2（PGE2）和前列腺素F2α（PGF2α）受体。COX - 2被证明是COX在新生脑内的主要形式以及前列腺素合成的主要催化剂。我们着手建立直接证据，证明COX - 2生成的前列腺素在新生脑的脑血管中调控PGE2和PGF2α受体的密度及功能。因此，我们通过使用生理盐水、布洛芬、COX - 1抑制剂（戊酰水杨酸）或COX - 2抑制剂（DUP - 697和NS - 398）处理新生猪，来测定脑微血管中PGE2和PGF2α受体的密度及功能。布洛芬、DUP - 697和NS - 398可显著降低新生脑内PGE2和PGF2α的浓度，但戊酰水杨酸则无此作用。在用DUP - 697、NS - 398和布洛芬处理的新生猪中，脑微血管中PGE2和PGF2α受体密度增加至成年水平；1,4,5 - 三磷酸肌醇（IP3）的生成以及17 - 苯基三降PGE2（EP1受体激动剂）、M&B - 28767（EP3受体激动剂）、PGF2α和芬前列林（PGF2α类似物）的脑血管收缩效应也显著增加。用布洛芬或DUP - 697处理还使大脑皮质和脑室周围血流自动调节的血压上限从85 mmHg提高到≥125 mmHg（研究的最高血压）。然而，戊酰水杨酸处理对新生动物的脑血管PGE2和PGF2α受体、IP3生成或血管收缩效应无影响。这些体内和体外观察结果表明，COX - 2主要负责调控新生脑的脑血管中PGE2和PGF2α受体及其功能。
