Alteration in endothelin receptor sub-type responsiveness and in the endothelin-TXA(2) mimetic U46619 interaction, in type-2 hypertensive diabetic Zucker rats.
Alteration in endothelin receptor sub-type responsiveness and in the endothelin-TXA(2) mimetic U46619 interaction, in type-2 hypertensive diabetic Zucker rats.
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DOI：
10.1016/j.diabres.2003.09.011
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发表时间：
2004-03
影响因子：
5.1
通讯作者：
A. Ajayi;G. O. Ogungbade;H. Hercule;A. Oyekan;L. Mutembei
中科院分区：
文献类型：
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作者：
A. Ajayi;G. O. Ogungbade;H. Hercule;A. Oyekan;L. Mutembei
背景2型糖尿病以内皮病变为特征，内皮病变可增加靶器官损害和死亡率。在Zucker糖尿病大鼠中，内皮素-1和TXA 2的产生过量，血管对内皮素-1的反应异常，表现为反常的扩张作用，而在瘦大鼠中则没有。我们研究的假设，有一个改变ET-A/ET-B受体亚型的敏感性，和/或ET-1和TXA 2在2型糖尿病之间的相互作用或串扰，使用Zucker糖尿病大鼠和他们的瘦littermates.Materials and MethodsHemodynamic studies进行了瘦和Zucker脂肪糖尿病大鼠的性别。采用激光多普勒血流仪测量肾皮质（RCF）和髓质血流（MBF）反应。分别静脉注射BQ 610 1 mg/kg和BQ 788 0.5mg/kg，建立大鼠对ET-1、U46619、乙酰胆碱和L-NAME（25 mg/kg）的平均动脉压（MAP）、MBF和RCF的剂量反应曲线，并观察BQ 610和BQ 788对全血阻抗聚集的影响。BQ 610可明显抑制Zucker糖尿病大鼠血浆ET-1的反常性升高（n=7，P<0.001），但不能抑制MBF的剂量依赖性升高（P<0.001）。BQ 788而不是BQ 610消除了瘦和糖尿病Zucker大鼠之间对ET-1反应的差异。U46619对雄性Zucker大鼠有明显的肥胖作用，可被i. v. l-NAME 25 mg/kg或消炎痛10 mg/kg所消除。U46619与BQ 788对瘦大鼠和糖尿病Zucker大鼠MAP和MBF的相互作用有显著性差异（P<0.03）。BQ 788而不是BQ 610减弱了对乙酰胆碱或l-NAME的MAP和MBF反应（P<0.02 ANOVA）。结论ET-B受体拮抗剂可明显抑制瘦型糖尿病大鼠的血管反应性，并使其MBF反应性恢复到正常瘦型糖尿病大鼠的水平。ET-1受体阻断可影响TXA 2受体激活的反应。在体循环和肾循环中，这种相互作用似乎主要是ET-B受体介导的，而在血小板中，ET-A受体的作用可能是主要的。2型糖尿病状态下ET-1与TXA 2的相互作用或串扰发生改变。总的来说，这些病理生理变化可能导致糖尿病内皮病变的恶性循环。
BackgroundType-2 diabetes is characterized by endotheliopathy, which increases target organ damage and mortality. There is excessive endothelin-1 and TXA2production, and abnormal vascular reactivity to endothelin-1, manifested as a paradoxical hypotensive action in Zucker diabetic, but not lean rats. We examined the hypothesis that there is an alteration in the ET-A/ET-B receptor subtype sensitivity, and/or the interaction or cross-talk between ET-1 and TXA2in type-2 diabetes, using Zucker diabetic rats and their lean littermates.Materials and methodsHemodynamic studies were performed in lean and Zucker fatty diabetic rats of both sexes. Laser doppler flowmetry was used to measure renal cortical (RCF) and medullary blood flow (MBF) responses. Dose response curves for mean arterial blood pressure (MAP), MBF and RCF in response to ET-1, U46619, acetylcholine, and l-NAME (25mg/kg) were constructed after pre-treatment of the rats with either BQ610 1mg/kg i.v. or BQ788 0.5mg/kg i.v. The effects of BQ610 and BQ788 on whole blood impedance aggregation were also assessed.ResultsBQ788, but not BQ610 abolished both the paradoxical hypotensive action of ET-1 in Zucker diabetic rats (n=7 each, P<0.001 ANOVA) as well as the dose-dependent rise in MBF (P<0.001 ANOVA). BQ788, but not BQ610 abolished the difference in response to ET-1 between lean and diabetic Zucker rats. U46619 caused a hypotensive action in male Zucker rats which was abolished by l-NAME 25mg/kg or indomethacin 10mg/kg i.v. The U46619 interaction with BQ788 on both MAP and MBF was significantly (P<0.03 ANOVA) different between lean and diabetic Zucker rats. BQ788, but not BQ610 attenuated both the MAP and MBF responses to acetylcholine or l-NAME P<0.02 ANOVA). However, BQ610 dose-dependently attenuated the slope of platelet aggregation in both lean and Zucker diabetic rats (P<0.02 ANOVA).ConclusionET-B receptor antagonism abolished the abnormal vascular reactivity and MBF responses to ET-1, and also normalized the vasoactive responses to the level seen in healthy lean Zucker rats. ET-1 receptor blockade influences the responses to TXA2receptor activation. In the systemic and renal circulation, this interaction appears to be mostly ET-B receptor mediated, whilst in platelets, ET-A receptor role may be predominant. The interaction or cross-talk between ET-1 and TXA2is altered in the type-2 diabetic state. Collectively, these pathophysological changes may contribute to the vicious circle of diabetic endotheliopathy.