Alvarez Yolanda, Briones Ana M, Balfagón Gloria, Alonso María J, Salaices Mercedes
Departamento de Farmacología y Terapéutica bDepartamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
J Hypertens. 2005 Apr;23(4):767-77. doi: 10.1097/01.hjh.0000163145.12707.63.
The present study was designed to analyse whether hypertension alters the involvement of cyclooxygenase-2-derived mediators in phenylephrine-induced vasoconstrictor responses.
Vascular reactivity experiments were performed in aortic segments from normotensive, Wistar-Kyoto, and spontaneously hypertensive rats (SHR); protein expression was measured by western blot and/or immunohistochemistry, and prostaglandin F2alpha (PGF2alpha), 8-isoprostane and prostacyclin release were determined by enzyme immunoassay commercial kits.
The protein synthesis inhibitor dexamethasone (1 micromol/l), the non-selective cyclooxygenase inhibitor indomethacin (10 micromol/l), the selective cyclooxygenase-2 inhibitor NS 398 (1 micromol/l), and the thromboxane A2/prostaglandin H2 (TP) receptor antagonist SQ 29,548 (1 micromol/l), reduced the concentration-response curves to phenylephrine more in segments from hypertensive than from normotensive rats; however, the thromboxane A2 (TxA2) synthase inhibitors furegrelate (10 micromol/l) and OKY 046 (1 and 10 micromol/l) had no effect in either strain. Removing endothelium or adding dexamethasone almost abolished the NS 398 effect. Cyclooxygenase-2 protein expression, which was reduced by dexamethasone, was higher in aorta from hypertensive animals. In both strains cyclooxygenase-2 was localized mainly in endothelial cells and adventitial fibroblasts. 13,14-Dihydro-15-keto-PGF2alpha, 6-keto-PGF1alpha and 8-isoprostane levels were greater in the medium from hypertensive than from normotensive rats; NS 398 decreased levels of the three metabolites studied only in the medium from SHR.
PGF2alpha and 8-isoprostane seem to be involved in the response to phenylephrine in rat aorta; this involvement is greater in hypertensive rats, probably due to a higher endothelial induction of cyclooxygenase-2.
本研究旨在分析高血压是否会改变环氧化酶 - 2衍生介质在去氧肾上腺素诱导的血管收缩反应中的作用。
在正常血压的Wistar - Kyoto大鼠和自发性高血压大鼠（SHR）的主动脉段进行血管反应性实验；通过蛋白质印迹和/或免疫组织化学测量蛋白质表达，并使用酶免疫分析商业试剂盒测定前列腺素F2α（PGF2α）、8 - 异前列腺素和前列环素的释放。
蛋白质合成抑制剂地塞米松（1微摩尔/升）、非选择性环氧化酶抑制剂吲哚美辛（10微摩尔/升）、选择性环氧化酶 - 2抑制剂NS 398（1微摩尔/升）和血栓素A2/前列腺素H2（TP）受体拮抗剂SQ 29,548（1微摩尔/升），在高血压大鼠主动脉段比正常血压大鼠主动脉段更能降低对去氧肾上腺素的浓度 - 反应曲线；然而，血栓素A2（TxA2）合酶抑制剂呋咱甲氢龙（10微摩尔/升）和OKY 046（1和10微摩尔/升）对两种品系均无影响。去除内皮或添加地塞米松几乎消除了NS 398的作用。地塞米松降低的环氧化酶 - 2蛋白质表达在高血压动物的主动脉中更高。在两种品系中，环氧化酶 - 2主要定位于内皮细胞和外膜成纤维细胞。高血压大鼠培养基中13,14 - 二氢 - 15 - 酮 - PGF2α、6 - 酮 - PGF1α和8 - 异前列腺素水平高于正常血压大鼠；NS 398仅降低了SHR培养基中所研究的三种代谢物的水平。
PGF2α和8 - 异前列腺素似乎参与大鼠主动脉对去氧肾上腺素的反应；在高血压大鼠中这种参与作用更大，可能是由于内皮中环氧化酶 - 2的诱导更高。
