Different types of antagonism by losartan and irbesartan on the effects of angiotensin II and its degradation products in rabbit arteries.
A previous study by our group has demonstrated that the selective AT1-receptor antagonist losartan behaves as a noncompetitive antagonist in rabbit isolated renal artery (RA). In the present investigation, the influence of losartan and irbesartan on the contractile effects of angiotensin II (AII) and its degradation products angiotensin III (AIII) and angiotensin IV (AIV) was determined in the rabbit isolated RA and femoral artery (FA). The arteries were set up in organ chambers and changes in isometric force were recorded. In both rabbit isolated RA and FA preparations, AII, AIII and AIV elicited significant contractile responses with a similar efficacy. These effects were impaired by the presence of functional endothelium in RA preparations but not in FA preparations. In both preparations studied, the effects of AII, AIII and AIV were influenced neither by the aminopeptidase-A and -M inhibitor amastatin (10 microM), nor by the aminopeptidase-B and -M inhibitor bestatin (10 microM). In endothelium-denuded FA preparations, preincubation with losartan (3-300 nM) antagonized AII-, AIII- and AIV-induced contractions in a competitive manner. However, in endothelium-denuded RA preparations, losartan depressed the maximal contractile responses induced by AII but not those induced by AIII and AIV. In the same preparations, preincubation of another selective AT1-receptor antagonist irbesartan (3-30 nM) concentration-dependently shifted AII and AIII curves to the right in an insurmountable manner. The reduction of the maximal response of AII is more potent when compared to that of AIII (47.7 +/- 1.51% vs. 66.7 +/- 1.88%, percentage of the initial maximal response; P < 0.05; n=5). The selective AT2-receptor antagonist PD123177 (1 microM) did not influence the responses to all three peptides in both RA and FA preparations. These heterogeneous antagonistic effects of the two AT1-receptor antagonists studied with respect to the contractile actions of AII, AIII and AIV suggest the possible existence of multiple, functionally relevant AT1-receptor subtypes in rabbit RA preparations.
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Department of Pharmacotherapy, AMC, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, the Netherlands.
Pfaffendorf
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van Zwieten
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D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D000805:Angiotensin III / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D004730:Endothelium, Vascular; D005263:Femoral Artery / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D000077405:Irbesartan; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D010455:Peptides; D011480:Protease Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1; D012077:Renal Artery / Q000187:drug effects*; 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; D044140:Receptor, Angiotensin, Type 1; 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; D007930:Leucine; C012211:ubenimex; D000077405:Irbesartan; D019808:Losartan