MYOCARDIAL-CONTRACTILITY IS MODULATED BY ANGIOTENSIN-II VIA NITRIC-OXIDE

We hypothesized that in cardiac muscles, angiotensin II partially inhi bits the contractile response to beta-agonists. We studied the contrac tile response of isolated rat left ventricular papillary muscles to is oproterenol and the effect of angiotensin II on this response. We also investigated whether the effect of angiotensin II is mediated by brad ykinin, prostaglandins, nitric oxide, and/or cGMP. Contractility of is olated papillary muscles was recorded with a force transducer, and res t tension, maximal developed tension (DT), maximal rate of rise in dev eloped tension [T-(+)], and maximal velocity of relaxation [T-(-)] wer e measured (1) under basal conditions, (2) after pretreatment with var ious drugs, and (3) after cumulative doses of isoproterenol. Pretreatm ent groups included (1) vehicle (controls); (2) angiotensin II; (3) an giotensin II and N-omega-nitro-L-arginine, an inhibitor of nitric oxid e 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 icati bant (Hoe 140), a bradykinin B-2 antagonist; and (8) angiotensin II an d indomethacin, a cyclooxygenase inhibitor. There were no differences in contractile parameters before and after any of the pretreatments. I soproterenol increased DT, T-(+), and T-(-), and these effects were at tenuated 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 a ngiotensin II. We concluded that angiotensin II partially inhibits the contractile response of cardiac papillary muscles to isoproterenol. T his effect is likely mediated by nitric oxide release, perhaps acting via cGMP. Kinins and prostaglandins do not appear to participate in th e 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-angiot ensin system.