Comparative effects of angiotensin II and its degradation products angiotensin III and angiotensin IV in rat aorta.
1. In the present study, the contractile effects of angiotensin III (AIII) and angiotensin IV (AIV) compared with those of angiotensin II (AII) were determined in rat aortic ring preparations. 2. All three peptides caused concentration-dependent contractions with similar maximal responses. AIII proved approximately 4 times less potent than AII, whereas AIV was about 1000 times less active than AII. 3. The selective AT1-receptor antagonist, losartan (10-300 nM) caused parallel rightward shifts of the concentration-response curves (CRC) for all three peptides. The Schild plot slopes for the effect of losartan on AIII curves were significantly lower than unity (P < 0.05). The selective AT2-receptor antagonist, PD123177 did not influence the CRCs for AII and AIV. However, the AIII curves were moderately shifted leftward in the presence of PD123177 (0.1 and 1 microM). 4. Destruction of the endothelium or incubation with the NO-synthesis inhibitor NG-monomethyl-L-arginine acetate (L-NMMA) (0.1 mM) significantly enhanced the contractile responses to all three peptides. 5. Tachyphylaxis was investigated by constructing a second CRC for all three peptides, after an interval of 1 h. The presence of endothelium significantly enhanced the development of tachyphylaxis to all three peptides. However, in endothelium-denuded preparations, the Emax value of the second curve elicited by AII was about 50%, compared with the first one, whereas for AIII and AIV Emax values were as high as 90% and 100%, respectively. 6. Our results indicate that both AIII and AIV are less potent but similarly efficacious vasoconstrictor agents compared with AII. Their contractile effects are also mediated by AT1-receptors and probably modulated by endothelium. Tachyphylaxis induced by AIII and AIV proved weaker than that for AII. Tachyphylaxis appears to be enhanced by the presence of an intact endothelium.
Li
Q
Q
Department of Pharmacotherapy, University of Amsterdam, The Netherlands.
Zhang
L
L
Pfaffendorf
M
M
van Zwieten
P A
PA
D000804:Angiotensin II / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000805:Angiotensin III / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004730:Endothelium, Vascular; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D013618:Tachyphylaxis / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D019323:omega-N-Methylarginine
D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000805:Angiotensin III; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D019323:omega-N-Methylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase