LOAD-INDUCED GROWTH-RESPONSES IN ISOLATED ADULT-RAT HEARTS - ROLE OF THE AT(1) RECEPTOR

Background Stimulation of the angiotensin II type 1 (AT(1)) receptor b y angiotensin II appears to be mandatory for the acute load-induced hy pertrophic response of cultured neonatal rat cardiocytes, but its role in the adult heart is controversial. We tested the hypothesis that AT (1) receptor blockade will inhibit the acute induction of proto-oncoge nes and protein synthesis by the elevation of systolic wall stress in isolated beating adult rat hearts. Methods and Results Using the estab lished isovolumic perfused heart preparation under constant coronary f low, we found that an increment in left ventricular balloon volume gen erated an increase in systolic wall stress. The induction of left vent ricular c-fos and c-myc mRNA (Northern blotting) was assessed in heart s subjected to increased systolic load without AT(1) blockade (No AT(1 ), n = 11) and with AT(1) blockade (AT(1), n = 11, losartan 40 mg.kg(- 1).d(-1) x 5 days followed by 10(-5) mol/L infusion during perfusion). Flaccid hearts (no left ventricular balloon) served as controls (C, n = 9). The stimulation of new protein synthesis in response to increas ed systolic load was measured by incorporation of [H-3]phenylalanine i nto cardiac proteins. Elevation of systolic load was associated with a twofold (P < .05) increase in c-fos and c-myc mRNA levels that was no t blocked by losartan. The rate of [H-3]phenylalanine incorporation in to cardiac proteins was increased 2.7-fold (P < .01) in hearts subject ed to increased systolic load compared with control hearts. However, A T(1) receptor blockade with losartan did not prevent the stimulation o f [H-3]phenylalanine incorporation (881 +/- 97 versus 923 +/- 82 nmol. g.protein(-1).h(-1) P = NS). Conclusions In contrast with immature myo cytes subjected to stretch, the acute growth responses induced by syst olic pressure overload in adult rat hearts do not depend on AT(1) rece ptor activation.