Different types of antagonism by losartan and irbesartan on the effects ofangiotensin II and its degradation products in rabbit arteries

A previous study by our group has demonstrated that the selective AT(1)-rec eptor endothelium, antagonist losartan behaves as a noncompetitive antagoni st in rabbit isolated renal artery (RA), In the present investigation, the influence of losartan and irbesartan on the contractile effects of angioten sin II (AII) and its degradation products angiotensin III (AIII) and angiot ensin 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 f orce were recorded, In both rabbit isolated RA and FA preparations, AII, AI II and AIV elicited significant contractile responses with a similar effica cy. These effects were impaired by the presence of functional endothelium i n RA preparations but not in FA preparations. In both preparations studied, the effects of ALI, AIII and AIV were influenced neither by the aminopepti dase-A and -M inhibitor amastatin (10 muM), nor by the aminopeptidase-B and -M inhibitor bestatin (10 muM). In endothelium-denuded FA preparations, pr eincubation with losartan (3-300 nM) antagonized AII-, AIII- and AIV-induce d contractions in a competitive manner, However, in endothelium-denuded RA preparations, losartan depressed the maximal contractile responses induced by ALI but not those induced by AIII and AIV, fn the same preparations, pre incubation of another selective AT(1)-receptor antagonist irbesartan (3-30 nM) concentration-dependently shifted ALI and AIII curves to the right in a n insurmountable manner. The reduction of the maximal response of AII is mo re 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 selectiv e AT(2)-receptor antagonist PD123177 (1 muM) did not influence the response s to all three peptides in both RA and FA preparations. These heterogeneous antagonistic effects of the two AT(1)-receptor antagonists studied with re spect to the contractile actions of Ail, AIII and AIV suggest the possible existence of multiple, functionally relevant AT(1)-receptor subtypes in rab bit RA preparations.