Competitive antagonism of pressor responses to angiotensin II and angiotensin III by the angiotensin II-1 receptor ligand losartan

Abstract

Losartan (DuP 753) and PD123177 are nonpeptide angiotensin (ANG) receptor ligands for subtypes of ANG II receptors ANG II-1 and ANG II-2, respectively. We examined the effects of losartan and PD123177 on dose – mean arterial pressure (MAP) response curves for ANG II and ANG III in eight groups (n = 6 each) of conscious rats. Saline (0.9% NaCl), losartan (1 × 10−6 and 9 × 10−6 mol/kg), and PD123177 (2 × 10−5 mol/kg) were i.v. bolus injected 15 min before the construction of ANG II dose–response curves in groups I, II, III, and IV, respectively. Groups V–VIII were treated similarly to I–IV except that ANG III was given in place of ANG II. Losartan dose dependently shifted the dose–response curves of ANG II and ANG III to the right with similar dissociation constants (−log KI of 6.6 ± 0.7 and 6.6 ± 0.1 mol/kg, respectively) and no change in the maxima. PD123177 affected neither maximum MAP nor ED50 values for ANG II or ANG III. Our results show that losartan but not PD123177 is a competitive antagonist of the MAP effects of ANG II and ANG III.Key words: nonpeptide angiotensin receptor antagonist, angiotensin II, angiotensin III, blood pressure, losartan.