Alteration in endothelin receptor sub-type responsiveness and in the endothelin–TXA 2 mimetic U46619 interaction, in type-2 hypertensive diabetic Zucker rats

Abstract

Background: Type-2 diabetes is characterized by endotheliopathy, which increases target organ damage and mortality. There is excessive endothelin-1 and TXA 2 production, 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 TXA 2 in type-2 diabetes, using Zucker diabetic rats and their lean littermates. Materials and methods: Hemodynamic 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 (25 mg/kg) were constructed after pre-treatment of the rats with either BQ610 1 mg/kg i.v. or BQ788 0.5 mg/kg i.v. The effects of BQ610 and BQ788 on whole blood impedance aggregation were also assessed. Results: BQ788, 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 25 mg/kg or indomethacin 10 mg/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). Conclusion: ET-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 TXA 2 receptor 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 TXA 2 is altered in the type-2 diabetic state. Collectively, these pathophysological changes may contribute to the vicious circle of diabetic endotheliopathy.