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.
Castro-Chaves
Paulo
P
Department of Physiology, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
Roncon-Albuquerque
Roberto
R
Leite-Moreira
Adelino F
AF
D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004727:Endothelium / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009132:Muscles / Q000187:drug effects* / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009842:Oligopeptides / Q000494:pharmacology; D011817:Rabbits; D044022:Receptor, Endothelin A / Q000378:metabolism / Q000502:physiology*; D017466:Receptors, Endothelin / Q000378:metabolism
D009842:Oligopeptides; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D000804:Angiotensin II; C082887:PD 145065; D019808:Losartan