Losartan reduces the increased participation of cyclooxygenase-2-derived products in vascular responses of hypertensive rats
Losartan reduces the increased participation of cyclooxygenase-2-derived products in vascular responses of hypertensive rats
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DOI：
10.1124/jpet.106.115287
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发表时间：
2007-04-01
影响因子：
3.5
通讯作者：
Salaices, Mercedes
中科院分区：
文献类型：
--
作者：
Alvarez, Yolanda;Perez-Giron, Jose V.;Salaices, Mercedes
本研究分析了血管紧张素II（Ang II）通过AT 1受体参与环氧化酶（考克斯）-2衍生的前列腺素类在正常血压大鼠（Wistar京都; WKY）和自发性高血压大鼠（SHR）苯肾上腺素反应中的作用。来自未处理或用氯沙坦（15 mg/kg（.）日）或肼苯哒嗪+氢氯噻嗪（44和9.4 mg/kg（.）d）和来自SHR的血管平滑肌细胞（VSMC）。血管反应性通过等长记录分析;考克斯-2表达通过蛋白质印迹和逆转录聚合酶链反应分析;前列腺素（PG）I-2、PGF（2）α、8-异前列腺素和总抗氧化状态（TAS）通过商业试剂盒分析;超氧阴离子（O-2（.）通过光泽精化学发光法测定血浆丙二醛（MDA）。1 μ M的考克斯-2抑制剂N-[2-（环己氧基）-4-硝基苯基]-甲磺酰胺（NS-398）在SHR中比在WKY大鼠中更能减少苯肾上腺素反应。考克斯-2蛋白和mRNA表达、PGF 2 α、PGI（2）、8-异前列腺素和O-2（（.）结果表明，SHR的TAS水平和MDA水平均高于SHR，但TAS在两个品系中相似。氯沙坦，而不是肼屈嗪-氢氯噻嗪治疗，减少考克斯-2表达和NS-398对苯肾上腺素反应的影响。氯沙坦还增加TAS，降低PGF（2 α）、PGI（2）、8-异前列腺素和O-2（。在SHR中的MDA水平。Ang Ⅱ（0.1 μ M）诱导SHR VSMC中考克斯-2的表达，30 μ M夹竹桃苷和100 μ M别嘌呤醇、NADPH氧化酶和黄嘌呤氧化酶抑制剂可分别抑制该表达。结论：Ang Ⅱ激活AT（1）受体，可能通过调节考克斯-2表达，增加考克斯-2源性收缩性前列腺素类物质参与苯肾上腺素引起的高血压血管收缩。氧化应激的增加似乎是其中一个机制。
This study analyzes the role of angiotensin II (Ang II), via AT 1 receptors, in the involvement of cyclooxygenase (COX)-2-derived prostanoids in phenylephrine responses in normotensive rats (Wistar Kyoto; WKY) and spontaneously hypertensive rats (SHR). Aorta from rats untreated or treated for 12 weeks with losartan (15 mg/kg (.) day) or hydralazine plus hydrochlorothiazide (44 and 9.4 mg/kg (.) day, respectively) and vascular smooth muscle cells (VSMC) from SHR were used. Vascular reactivity was analyzed by isometric recording; COX-2 expression by Western blot and reverse transcription-polymerase chain reaction; prostaglandin (PG)I-2, PGF(2)alpha, 8-isoprostane, and total antioxidant status (TAS) by commercial kits; superoxide anion (O-2((.) over bar)) by lucigenin chemiluminescence; and plasmatic malondialdehyde (MDA) by thiobarbituric acid assay. The COX-2 inhibitor N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398) at 1 mu M reduced phenylephrine responses more in SHR than in WKY rats. COX-2 protein and mRNA expressions, PGF2 alpha, PGI(2), 8-isoprostane, and O-2((.) over bar) production, and MDA levels were higher in SHR, but TAS was similar in both strains. Losartan, but not hydralazine-hydrochlorothiazide treatment, reduced COX-2 expression and the effect of NS-398 on phenylephrine responses in SHR. Losartan also increased TAS and reduced PGF(2 alpha), PGI(2), 8-isoprostane, and O-2((.) over bar) production and MDA levels in SHR. Ang II (0.1 mu M) induced COX-2 expression in VSMC from SHR that was reduced by 30 mu M apocynin and 100 mu M allopurinol, NADPH oxidase, and xanthine oxidase inhibitors, respectively. In conclusion, AT(1) receptor activation by Ang II could be involved in the increased participation of COX-2-derived contractile prostanoids in vasoconstriction to phenylephrine with hypertension, probably through COX-2 expression regulation. The increased oxidative stress seems to be one of the mechanisms involved.