Comparative vasoconstrictor effects of angiotensin II, III, and IV in human isolated saphenous vein.
Elevated levels of angiotensin (Ang II) and its degradation products angiotensin III (Ang III) and angiotensin IV (Ang IV) may contribute to the regulation of vascular tone under various clinical circumstances. We investigated the contractile effects of Ang III and Ang IV in endothelium-denuded human saphenous vein (SV) preparations and compared them with those of Ang II. The veins were suspended in organ chambers, and changes in isometric force were recorded. Ang II (0.1-100 nM), Ang III (1 nM-3 microM), and Ang IV (0.3 microM-0.1 mM) caused concentration-dependent contractions with comparable maximal responses (Emax). Ang III was 16 times less active than Ang II, whereas Ang IV was approximately 2,700-fold less potent than Ang II. In the presence of the aminopeptidase-A and -M inhibitor amastatin (10 microM), the potencies of Ang III and Ang IV were increased by approximately 16 and 12 times, respectively, although no changes of Ang II potency were observed. The AT1-selective Ang II receptor antagonist losartan (10 and 100 nM) but not the AT2-selective antagonist PD123177 (1 microM), shifted the concentration-response curves (CRC) for the angiotensin peptides to the right in a parallel manner. Preincubation with indomethacin (10 microM), a cyclooxygenase inhibitor, did not influence the CRCs for any of the angiotensin peptides studied. Tachyphylaxis was investigated by constructing a second series of CRCs for the angiotensin peptides after an interval of 60 min. Ang II showed strong tachyphylaxis (the Emax value of the second Ang II CRC was approximately 50% of the first), whereas Ang III and Ang IV did not. Our results indicate that in endothelium-denuded human SV, both Ang III and Ang IV are less potent but similarly efficacious vasoconstrictor agents compared with Ang II. Endogenous aminopeptidase activity may counteract the effects of the angiotensin peptides. The contractile responses to all three peptides are mediated via AT1-receptors but not AT2-receptors.
Li
Q
Q
Department of Pharmacotherapy, University of Amsterdam, The Netherlands.
Feenstra
M
M
Pfaffendorf
M
M
Eijsman
L
L
van Zwieten
P A
PA
D000368:Aged; D000369:Aged, 80 and over; D000626:Aminopeptidases / Q000494:pharmacology; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000805:Angiotensin III / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D043384:Glutamyl Aminopeptidase; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan; D008297:Male; D008666:Metalloendopeptidases / Q000494:pharmacology; D063208:Methionyl Aminopeptidases; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010455:Peptides; D011480:Protease Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012501:Saphenous Vein / Q000187:drug effects*; D013618:Tachyphylaxis; D013777:Tetrazoles / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000900:Anti-Bacterial Agents; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D010455:Peptides; D011480:Protease Inhibitors; D011725:Pyridines; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C066253:PD 123177; D000805:Angiotensin III; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; C016977:amastatin; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases; D043384:Glutamyl Aminopeptidase; D008666:Metalloendopeptidases; D019808:Losartan