Abstract 5508: Angiotensin Type-2 Receptor-mediated Coronary Arteriolar Dilation is Enhanced in Rats With Type-2 Diabetes Mellitus: A Role of Enhanced Nitric Oxide Mechansim via the Overexpression of Bradykinin B 2 Receptor

Abstract

Angiotensin type-2 (AT 2 ) receptor is said to function as a counterregulator against angiotensin type-1 (AT 1 ) receptor, and its expression was shown to be increased in various pathological states. However, the role of AT 2 receptor in type-2 diabetes mellitus (DM) is unclear. We examined AT 2 receptor-mediated coronary arteriolar dilation comparatively in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a type-2 DM model, and control Long-Evans Tokushima Otsuka (LETO) rats. At the age of 40 weeks, the coronary arterioles were isolated, cannulated, pressurized with 60 mmHg, and preconstricted with 40 mM potassium chloride. In the presence of valsartan (10 −4 M), each of angiotensin II (10 −11 to 10 −6 M) and a selective AT 2 receptor agonist CGP-42112A (CGP, 10 −11 to 10 −6 M) dilated the coronary arterioles in a dose-dependent manner, and the dilator responses were greater in OLETF than in LETO rats (both p<0.05). An AT 2 receptor antagonist PD 123319 (10 −4 M) and N G -nitro-L-arginine methyl ester (10 −4 M) completely abolished the dilator effects of angiotensin II and CGP. Bradykinin B 2 receptor antagonist HOE-140 significantly attenuated the vasodilator effects of CGP and bradykinin, but did not alter the effect of acetylcholine. Reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that AT 1 receptor mRNA level in the coronary arterioles was upregulated by 1.44±0.14 times in OLETF compared with that in LETO (p<0.05). In contrast, AT 2 receptor mRNA level did not differ between LETO and OLETF. Bradykinin B 2 receptor mRNA level was upregulated by 2.56±0.38 times in OLETF compared with that in LETO (p<0.05). In conclusion, in the presence of AT 1 receptor blocker, angiotensin II causes vasodilation in the rat coronary arterioles by a nitric oxide mechanism. This AT 2 receptor-mediated vasodilation is enhanced in rats with type-2 DM, which can be explained, at least in part, by the overexpression of bradykinin B 2 receptor in DM rats.