Myocardial contractility is modulated by angiotensin II via nitric oxide

We hypothesized that in cardiac muscles, angiotensin II partially inhibits the contractile response to beta-agonists. We studied the contractile response of isolated rat left ventricular papillary muscles to isoproterenol and the effect of angiotensin II on this response. We also investigated whether the effect of angiotensin II is mediated by bradykinin, prostaglandins, nitric oxide, and/or cGMP. Contractility of isolated papillary muscles was recorded with a force transducer, and rest tension, maximal developed tension (DT), maximal rate of rise in developed tension [T-(+)], and maximal velocity of relaxation [T-(-)] were measured (1) under basal conditions, (2) after pretreatment with various drugs, and (3) after cumulative doses of isoproterenol. Pretreatment groups included (1) vehicle (controls); (2) angiotensin II; (3) angiotensin II and N-omega-nitro-L-arginine, an inhibitor of nitric oxide release; (4) L-arginine, the substrate for nitric oxide synthase; (5) L-arginine and N-omega-nitro-L-arginine; (6) s-bromo-cGMP, analogous to the second messenger of nitric oxide; (7) angiotensin II and icatibant (Hoe 140), a bradykinin B-2 antagonist; and (8) angiotensin II and indomethacin, a cyclooxygenase inhibitor. There were no differences in contractile parameters before and after any of the pretreatments. Isoproterenol increased DT, T-(+), and T-(-), and these effects were attenuated by angiotensin II, L-arginine, and 8-bromo-cCMP. The effects of angiotensin II and L-arginine were blocked by inhibition of nitric oxide release with N-omega-nitro-L-arginine. Neither the bradykinin B-2 antagonist nor the cyclooxygenase inhibitor altered the effects of angiotensin II. We concluded that angiotensin II partially inhibits the contractile response of cardiac papillary muscles to isoproterenol. This effect is likely mediated by nitric oxide release, perhaps acting via cGMP. Kinins and prostaglandins do not appear to participate in the inhibitory effect of angiotensin II. Attenuation of the contractile effect of isoproterenol by angiotensin II may help explain why cardiac function improves in heart failure after blockade of the renin-angiotensin system.