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%. EC50 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.