Tostes R C, David F L, Carvalho M H, Nigro D, Scivoletto R, Fortes Z B
University of Sao Paulo, Institute of Biomedical Science, Department of Pharmacology, SP, Brazil.
J Cardiovasc Pharmacol. 2000 Nov;36(5 Suppl 1):S99-101. doi: 10.1097/00005344-200036051-00032.
In experimental models of hypertension, blood pressure reaches a higher level in male than in female rats. Because endothelin-1 (ET-1) seems to play a role in blood pressure elevation in deoxycorticosterone acetate (DOCA)-salt hypertension, we hypothesized that male DOCA-salt rats would display a greater vascular responsiveness to ET-1 than female DOCA-salt rats. Male and female Wistar rats were uninephrectomized, received DOCA injections (50 mg/kg/week) and water plus 1.0% NaCl/0.2% KCl. Control rats received vehicle and tap water. Responses to ET-1, norepinephrine (NE), serotonin (5-HT), IRL-1620, a selective endothelin-B- (ET(B)) receptor agonist, and acetylcholine (ACh) were evaluated in isolated aortic rings and also in vivo in the mesenteric microcirculation. Endothelium-intact aortas from male and female DOCA rats displayed increased sensitivity (p < 0.05) to NE and 5-HT, but decreased relaxation to ACh in comparison to aortas from respective control male and female rats. Endothelium-denuded, but not endothelium-intact, arteries from male DOCA rats displayed increased sensitivity (-log EC20) to ET-1, but no changes in ET-1 sensitivity were observed in female DOCA aortas. IRL-1620 induced contraction in male DOCA aortas, but not in female DOCA or control endothelium-denuded aortas. In the microcirculation, IRL-1620 induced vasodilation in male and female control rats, but marked vasoconstriction in male DOCA and minimal changes in vessels diameter in female DOCA rats. Bosentan, an ET(A)/ET(B)-receptor antagonist, induced a greater decrease in mean arterial blood pressure in male than in female DOCA-salt hypertensive rats. These data support the hypothesis that DOCA-salt rats exhibit gender differences in ET-1 vascular reactivity, which probably result from functional changes in ET(B)-receptors. The increased ET(B) responses in male DOCA-salt hypertensive rats may play a role in their higher blood pressure levels.
在高血压实验模型中，雄性大鼠的血压比雌性大鼠达到更高水平。由于内皮素 -1（ET-1）似乎在醋酸脱氧皮质酮（DOCA）-盐性高血压的血压升高中起作用，我们推测雄性DOCA-盐大鼠对ET-1的血管反应性会比雌性DOCA-盐大鼠更强。将雄性和雌性Wistar大鼠进行单侧肾切除，给予DOCA注射（50mg/kg/周）以及含1.0%NaCl/0.2%KCl的水。对照大鼠给予溶剂和自来水。在离体主动脉环以及肠系膜微循环中对ET-1、去甲肾上腺素（NE）、5-羟色胺（5-HT）、IRL-1620（一种选择性内皮素B（ET(B)）受体激动剂）和乙酰胆碱（ACh）的反应进行了评估。与各自的对照雄性和雌性大鼠的主动脉相比，雄性和雌性DOCA大鼠的内皮完整主动脉对NE和5-HT的敏感性增加（p<0.05），但对ACh的舒张反应降低。雄性DOCA大鼠的去内皮动脉（而非内皮完整动脉）对ET-1的敏感性增加（-log EC20），但在雌性DOCA主动脉中未观察到ET-1敏感性的变化。IRL-1620在雄性DOCA主动脉中诱导收缩，但在雌性DOCA或对照去内皮主动脉中未诱导收缩。在微循环中，IRL-1620在雄性和雌性对照大鼠中诱导血管舒张，但在雄性DOCA大鼠中诱导明显血管收缩，在雌性DOCA大鼠中血管直径变化极小。波生坦，一种ET(A)/ET(B)受体拮抗剂，在雄性DOCA-盐性高血压大鼠中比雌性大鼠引起更大的平均动脉血压下降。这些数据支持了以下假设：DOCA-盐大鼠在ET-1血管反应性方面表现出性别差异，这可能是由ET(B)受体的功能变化导致的。雄性DOCA-盐性高血压大鼠中ET(B)反应的增加可能在其较高的血压水平中起作用。
