Endothelin ETA receptors and endothelium partially mediate the positive inotropic and lusitropic effects of angiotensin II.

We analyzed the influence of endothelin-1 and endocardial endothelium on the myocardial effects of angiotensin-II. Angiotensin-II (10(-9)-10(-5) M) was tested in rabbit right papillary muscles in absence (Protocol-A) or presence of PD-145065 (10(-7) M; Protocol-B), BQ-123 (10(-7) M; Protocol-C) or losartan (10(-6) M; Protocol-E), as well as, after removing the endocardial endothelium with Triton X-100 0.5% (Protocol-D). In Protocol-F increasing concentrations of endothelin-1 (10(-10)-10(-8) M) were added in presence of angiotensin-II (10(-7) M) after selective removal of the endocardial endothelium. In Protocol-A, angiotensin-II had dose-dependent positive inotropic and lusitropic effects, maximal at 10(-6) M increasing 122+/-13% active tension, 117+/-16% dT/dtmax and 86+/-9% dT/dtmin. In Protocols B, C and D the inotropic and lusitropic effects of angiotensin-II were significantly attenuated. The same concentration (10(-6) M) of angiotensin-II increased respectively 48+/-11%, 59+/-27% and 72+/-16% active tension; 54+/-14%, 54+/-20% and 32+/-9% dT/dtmax; and 39+/-8%, 48+/-19% and 59+/-11% dT/dtmin; and 40+/-10%. EC(50) for active tension significantly increased from -7.8+/-0.1 logM in Protocol A to -7.1+/-0.3, -6.7+/-0.4 and -6.8+/-0.3 logM in Protocols B, C and D respectively, while Emax decreased from 106+/-14% in Protocol A to 50+/-14 and 51+/-19% in Protocols B and C respectively, but did not significantly change in Protocol D (114+/-25%). Losartan completely blocked the inotropic and lusitropic effects of angiotensin-II, while the attenuation of these effects after the selective removal of the endocardial endothelium was blunted by concomitant administration of endothelin-1 (Protocol F). In conclusion, angiotensin-II has a dose-dependent positive inotropic effect that depends, to a great extent, on endothelin ETA receptor activation and intact endocardial endothelium.