ROLE OF TYPE-1 AND TYPE-2 ANGIOTENSIN RECEPTORS IN ANGIOTENSIN-II-INDUCED CARDIOMYOCYTE HYPERTROPHY

We compared the ability of angiotensin II (Ang II) to induce hypertrop hy of neonatal rat ventricular myocytes with that of endothelin-1. Ove r 72 hours, Ang II (1 mu mol/L) increased the ratio of protein to DNA by less than 10%, whereas endothelin-1 (100 nmol/L) produced a 28% inc rease. The growth effects of either agonist occurred independently of chronotropic actions. Radioligand binding studies showed that myocytes have nearly 300-fold more receptors for endothelin-1 than Ang II, and type 1 and type 2 Ang II receptor subtypes (AT(1) and AT(2)) are pres ent in near equal proportions. Cotreatment with a 10-fold molar excess of AT(2) antagonists (PD 123177 or CGP 42112) for 72 hours augmented the Ang II-induced increase in the protein-to-DNA ratio to levels near ly as high (23%) as those with endothelin-1 (28%). AT(2) antagonists e nhanced Ang II stimulation of protein synthesis, as indexed by [H-3]le ucine incorporation, whereas an AT(1) antagonist blocked Ang II-induce d incorporation. An ATI antagonist also prevented Ang II-induced prote in degradation. In conclusion, Ang II-induced myocyte growth is temper ed because of low AT(1) levels and an antigrowth effect of AT(2). Thes e findings have potential clinical significance in that regression of hypertension-induced cardiac hypertrophy by ATI antagonists may be in part due to an unopposed antigrowth effect of Ang II mediated via AT(2 ).