Angiotensin II type 2 receptor blockade amplifies the early signals of cardiac growth response to angiotensin II in hypertrophied hearts

Background-We have previously shown that the acute molecular growth response of new protein synthesis and protein kinase C activation in response to angiotensin II (Ang II) is altered in left ventricular (LV) hypertrophy compared with normal hearts. We have also shown an upregulation of Ang II type 2 (AT(2)) receptors in hypertrophied hearts relative to controls. Activation of AT(2) receptors is proposed to counteract growth effects of AT(1) receptor in response to Ang II. Thus, we tested the hypothesis that in hypertrophied hearts, the AT(2) receptor mediates inhibitory effects on the new cardiac protein synthesis in response to acute Ang II stimulation. Methods and Results-Flaccid buffer-perfused adult normal and hypertrophied rat hearts were perfused with Ang II 10(-8) mol/L plus prazosin 10(-7) mol/L or Ang II plus the AT(2) blocker PD 123319 5x10(-7) mol/L, New protein synthesis was measured by the rate of [H-3]phenylalanine incorporation into the LV proteins. In normal hearts, Ang II (n=8) increased the rate of [H-3]phenylalanine incorporation by 74+/-27% (P<0.05 versus no drug). Treatment with PD 123319 (n = 8) did not increase protein synthesis compared with Ang II alone (32+/-11% versus Ang II alone, P=NS). In hypertrophied hearts, Ang II alone (n=6) increased the rate of [H-3]phenylalanine incorporation only by 23+/-13% (P=NS versus no drug). In contrast, treatment with PD123319 (n=7) induced a 76+/-21% increase in new LV protein synthesis compared with Ang II alone (P<0.05), AT(2) receptor blockade in Ang II-stimulated hypertrophied hearts was associated with enhanced membrane protein kinase C translocation and reduced LV cGMP content. Conclusions-These data support the hypothesis that in adult hypertrophied rat hearts, inhibition of cardiac AT(2) receptors, which are upregulated in chronic LV hypertrophy, amplifies the immediate LV growth response to Ang II, This appears to be related to augmented Ang II-stimulated PKC activation and suppression of cGMP signaling.