Overexpression of the human angiotensin II type 1 receptor in the rat heart augments load induced cardiac hypertrophy

Angiotensin II is known to stimulate cardiac hypertrophy and contractility. Most angiotensin II effects are mediated via membrane bound AT(1) receptor s. However, the role of myocardial AT(1) receptors in cardiac hypertrophy a nd contractility is still rarely defined. To address the hypothesis that in creased myocardial AT(1) receptor density causes cardiac hypertrophy apart from high blood pressure we developed a transgenic rat model which expresse s the human AT(1) receptor under the control of the alpha -myosin heavy-cha in promoter specifically in the myocardium. Expression was identified and q uantified by northern blot analysis and radioligand binding assays, demonst rating overexpression of angiotensin II receptors in the transgenic rats up to 46 times the amount seen in nontransgenic rats. Coupling of the human A T(1) receptor to rat G proteins and signal transduction cascade was verifie d by sensitivity to GTP-gamma -S and increased sensitivity of intracellular Ca2+ [Ca2+](i) to angiotensin II in fluo-3 loaded transgenic cardiomyocyte s. Transgenic rats exhibited normal cardiac growth and function under basel ine conditions. Pronounced hypertrophic growth and contractile responses to angiotensin II, however, were noted in transgenic rats challenged by volum e and pressure overload. In summary, we generated a new transgenic rat mode l that exhibits an upregulated myocardial AT(1) receptor density and demons trates augmented cardiac hypertrophy and contractile response to angiotensi n II after volume and pressure overload, but not under baseline conditions.