Ovarian hormones modulate endothelin-1 vascular reactivity and mRNA expression in DOCA-salt hypertensive rats
Ovarian hormones modulate endothelin-1 vascular reactivity and mRNA expression in DOCA-salt hypertensive rats
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DOI：
10.1161/01.hyp.38.3.692
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发表时间：
2001-09-01
期刊：
影响因子：
8.3
通讯作者：
Tostes, RCA
中科院分区：
文献类型：
--
作者：
David, FL;Carvalho, MHC;Tostes, RCA
我们先前在雄性和雌性脱氧皮质酮(DOCA)-盐性高血压大鼠中发现了内皮素-1(ET-1)途径的不同激活，雄性大鼠对ET-1和ETB激动剂Suc-[Glu，(9)Ala(11.15)]-ET-1(8-21)(IRL-1620)的血管和升压反应发生了显著变化。这些性别差异背后的机制尚不清楚，我们假设卵巢激素减弱了雌性DOCA-SALT大鼠的血管ETB反应。将雌性Wistar大鼠随机分为3组：假手术组、去卵巢(OVX)组和去卵巢+激素替代雌二醇组(E组)或雌二醇孕酮(EP组)。两周后，大鼠被随机分为DOCA盐组(皮下注射脱氧皮质酮和含有氯化钠/KCl的饮用水)和正常血压对照组(皮下注射赋形剂和自来水)。血压测定采用直接尾套法和标准尾套法。在活体/原位评价IRL-1620对肠系膜微循环的反应。逆转录-聚合酶链式反应检测肠系膜动脉ET-I和ETA/B受体的mRNA表达，并与GAPDH表达相关。OVX-DOCA大鼠比DOCA大鼠患上更严重的高血压。E或EP治疗使DOCA大鼠的血压恢复到观察到的水平。在肠系膜，IRL-1620对对照组大鼠有明显的血管扩张作用，对DOCA大鼠有轻度的收缩作用，对OVX-DOCA大鼠有明显的收缩作用。在DOCA组，E和EP均能降低IRL-1620引起的血管收缩。在正常血压组，OVX不改变血压或IRL-1620诱导的血管扩张。摘除卵巢可增加DOCA和对照组大鼠动脉中ET-I mRNA的表达，但E或EP处理可逆转这些变化。OVX-DOCA组大鼠血管ETB受体基因表达水平显著升高，而OVX对照组大鼠血管ETB受体mRNA水平无明显变化。激素替代E或EP可恢复DOCA组ETB受体的表达。波生坦(ETA/ETB受体阻滞剂)对OVX-DOCA大鼠有较强的降压作用。OVX加重DOCA雌性大鼠的高血压，以及ETB受体介导的反应改变和波生坦的作用，支持卵巢激素调节DOCA-盐性高血压ET-1/ETB受体血管反应/表达的观点。
We previously demonstrated a differential activation of the endothelin-1 (ET-1) pathway in male and female deoxycorticosterone (DOCA)-salt hypertensive rats, with the male rats exhibiting marked alterations in vascular and pressor responses to ET-1 and Suc-[Glu,(9)Ala(11.15)]-ET-1(8-21) (IRL-1620), an ETB agonist. Mechanisms underlying these gender differences are unclear, and we hypothesized that the ovarian hormones attenuate vascular ETB responses in female DOCA-salt rats. Female Wistar rats were randomized in 3 groups: sham-operated, ovariectomized (OVX), and OVX plus hormone replacement with estradiol (E) or estradiol/progesterone (EP). Two weeks later, rats were uninephrectomized and further randomized in DOCA-salt (subcutaneous injections of desoxycorticosterone and drinking water containing NaCl/KCl) and control normotensive (subcutaneous injections of vehicle and tap water). Blood pressure was evaluated both by direct and standard tail-cuff methods. Responses to IRL-1620 were evaluated in vivo/in situ in the mesenteric microcirculation. mRNA expression of ET-I and ETA/B receptors' was evaluated in mesenteric arteries by reverse transcription-polymerase chain reaction and expressed relative to GAPDH. OVX-DOCA rats developed a more severe form of hypertension than did DOCA rats. Treatment with E or EP restored blood pressure to levels observed in DOCA rats. In the mesentery, IRL-1620 induced vasodilatation in control rats, a mild vasoconstriction in DOCA rats, and marked vasoconstriction in OVX-DOCA rats. Both E and EP decreased IRL-1620-induced vasoconstriction in the DOCA group. In the normotensive group, OVX did not change blood pressure or IRL-1620-induced vasodilation. Removal of the ovaries increased ET- I mRNA in arteries from DOCA and control rats, although treatment with E or EP reversed these changes. Vascular ETB receptor mRNA levels were greatly enhanced in OVX-DOCA but not OVX-control rats. Hormone replacement with E or EP restored ETB receptor expression in the DOCA group. A greater blood pressure-lowering effect of bosentan (ETA/ETB blocker) was observed in OVX-DOCA rats. The observation that OVX worsens hypertension as well as the altered ETB receptor-mediated responses and the effects of bosentan in female DOCA rats supports our suggestion that the ovarian hormones modulate ET-1/ETB receptor vascular responses/expression in DOCA-salt hypertension.