CARDIAC-SPECIFIC OVEREXPRESSION OF ANGIOTENSIN-II AT2 RECEPTOR CAUSESATTENUATED RESPONSE TO AT1 RECEPTOR-MEDIATED PRESSOR AND CHRONOTROPICEFFECTS

Angiotensin (Ang) II has two major receptor isoforms, AT1 and AT2. Cur rently, AT1 antagonists are undergoing clinical trials in patients wit h cardiovascular diseases. Treatment with AT1 antagonists causes eleva tion of plasma Ang II which selectively binds to AT2 and exerts as yet undefined effects. Cardiac AT2 level is low in adult hearts, whereas its distribution ratio is increased during cardiac remodeling and its action is enhanced by application of AT1 antagonists. Although in AT2 knock-out mice sensitivity to the presser action of Ang II was increas ed, underlying mechanisms remain undefined. Here, we report the unexpe cted finding that cardiac-specific overexpression of the AT2 gene usin g a-myosin heavy chain promoter resulted in decreased sensitivity to A T1-mediated presser and chronotropic actions, AT2 protein undetectable in the hearts of wildtype mice was overexpressed in atria and ventric les of the AT2 transgenic (TG) mice and the proportions of AT2 relativ e to AT1 were 41% in atria and 45% in ventricles, No obvious morpholog ical change was observed in the myocardium and there was no significan t difference in cardiac development or heart to body weight ratio betw een wildtype and TG mice. Infusion of Ang II to AT2 TG mice caused a s ignificantly attenuated increase in blood pressure response and the ch ange was completely blocked by pretreatment with AT2 antagonist. This decreased sensitivity to Ang II-induced presser action was mainly due to the AT2-mediated strong negative chronotropic effect and exerted by circulating Ang II in a physiological range that did not stimulate ca techolamine release, Isolated hearts of AT2 transgenic mice perfused u sing a Langendorff apparatus also showed decreased chronotropic respon ses to Ang II with no effects on left ventricular dp/dt max values, an d Ang II-induced activity of mitogen-activated protein kinase was inhi bited in left ventricles in the transgenic mice. Although transient ou tward K+ current recorded in cardiomyocytes from AT2 TG mice was not i nfluenced by AT2 activation, this study suggested that overexpression of AT2 decreases the sensitivity of pacemaker cells to Ang II. Our res ults demonstrate that stimulation of cardia AT2 exerts a novel antipre ssor action by inhibiting AT1-mediated chronotropic effects, and that application of AT1 antagonists to patients with cardiovascular disease s has beneficial pharmacotherapeutic effects of stimulating cardiac AT 2.