Effects of angiotensin II on inotropy and intracellular Ca2+ handling in normal and hypertrophied rat myocardium

The direct inotropic effect of angiotensin II on the myocardium is still controversial and little information exists as to its potential modification by heart disorders. Therefore, this study performed simultaneous measurements of isometric force and intracellular Ca2+ concentrations ([Ca2+](i)) in left ventricular papillary muscles from sham-operated and aortic-banded rats at 10 weeks post-surgery, Angiotensin II (10(-6) M) induced a reduction of peak systolic [Ca2+](i) (0.56 +/- 0.03 to 0.48 +/- 0.04 mu M; P<0.05) and a parallel but insignificant diminution of developed tension (10.5 +/- 1.3 to 9.6 +/- 0.8 mN/mm(2)) in normal papillary muscles from sham-operated animals. Hypertrophied papillary muscles from aortic-banded rats demonstrated a significant decline in both peak systolic [Ca2+](i) (0.51 +/- 0.02 to 0.44 +/- 0.01 mu M; P<0.05) and developed tension (8.4 +/- 1.1 to 6.8 +/- 1.7 mN/mm(2): P<0.05) after addition of angiotensin II. The time courses of the mechanical contraction and the intracellular Ca2+ signal were prolonged by angiotension II in both groups. Isoproterenol dose-dependently increased developed tension and peak systolic [Ca2+](i) in papillary muscles from sham-operated rats. In contrast, the positive inotropic response to isoproterenol was markedly reduced in hypertrophied muscles despite a seemingly unimpaired increase in peak systolic [Ca2+](i). Pretreatment with angiotensin II (10(-6) M) resulted in a significant attenuation of the systolic [Ca2+](i) response to isoproterenol stimulation in both normal and hypertrophied papillary muscles. Neither the bradykinin B-2 antagonist icatibent (10(-6) M) nor the nitric oxide (NO) inhibitor L-NMMA (10(-6) M) abolished the depressant effects of angiotension II. Thus, ANG II induces a parallel decline of the mechanical performance and Ca2+ availability in rat myocardium. These effects are more distinct in hypertrophied than in normal muscle and become accentuated during beta-adrenergic stimulation. The underlying mechanism is not associated with the NO pathway but might involve a negative functional coupling between the angiotensin and beta-adrenergic-receptor complex.