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 B2 Receptor
Angiotensin type-2 (AT2) receptor is said to function as a counterregulator against angiotensin type-1 (AT1) receptor, and its expression was shown to be increased in various pathological states. However, the role of AT2 receptor in type-2 diabetes mellitus (DM) is unclear. We examined AT2 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 (10−4M), each of angiotensin II (10−11 to 10−6M) and a selective AT2 receptor agonist CGP-42112A (CGP, 10−11 to 10−6M) 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 AT2 receptor antagonist PD 123319 (10−4M) and NG-nitro-L-arginine methyl ester (10−4M) completely abolished the dilator effects of angiotensin II and CGP. Bradykinin B2 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 AT1 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, AT2 receptor mRNA level did not differ between LETO and OLETF. Bradykinin B2 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 AT1 receptor blocker, angiotensin II causes vasodilation in the rat coronary arterioles by a nitric oxide mechanism. This AT2 receptor-mediated vasodilation is enhanced in rats with type-2 DM, which can be explained, at least in part, by the overexpression of bradykinin B2 receptor in DM rats.