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 respons e of new protein synthesis and protein kinase C activation in response to a ngiotensin II (Ang II) is altered in left ventricular (LV) hypertrophy comp ared with normal hearts. We have also shown an upregulation of Ang II type 2 (AT(2)) receptors in hypertrophied hearts relative to controls. Activatio n of AT(2) receptors is proposed to counteract growth effects of AT(1) rece ptor in response to Ang II. Thus, we tested the hypothesis that in hypertro phied hearts, the AT(2) receptor mediates inhibitory effects on the new car diac 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 sy nthesis was measured by the rate of [H-3]phenylalanine incorporation into t he LV proteins. In normal hearts, Ang II (n=8) increased the rate of [H-3]p henylalanine incorporation by 74+/-27% (P<0.05 versus no drug). Treatment w ith 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 A ng II alone (P<0.05), AT(2) receptor blockade in Ang II-stimulated hypertro phied hearts was associated with enhanced membrane protein kinase C translo cation and reduced LV cGMP content. Conclusions-These data support the hypothesis that in adult hypertrophied r at hearts, inhibition of cardiac AT(2) receptors, which are upregulated in chronic LV hypertrophy, amplifies the immediate LV growth response to Ang I I, This appears to be related to augmented Ang II-stimulated PKC activation and suppression of cGMP signaling.