BIBS-222

The effects of four nonpeptide angiotensin receptor antagonists, i.e., losartan (AT1) PD123177 (AT2), and 4'-[(2-n-butyl-6-cyclohexylaminocarbonylamino-benzimidazole-1-yl)- methyl]biphenyl-carboxylic acid (BIBS 39; AT1 and AT2), and 2-n-butyl-1-[4-(6-carboxy-2,5-di-chlorbenzoylamino)-benzyl]-6-N- (methylaminocarbonyl)-n-pentylamino-benzimidazole (BIBS 222; AT1 and AT2) on cardiovascular responses to angiotensin II (AII) were investigated in propranolol-pretreated pithed rats. AII (0.01-10 nmol/kg intravenously, i.v.) induced a dose-dependent increase in diastolic blood pressure (DBP), the rate of increase in left ventricular pressure (LVdP/dtmax), cardiac output (CO), and total peripheral resistance (TPR) without changing LV end-diastolic pressure (LVEDP) or heart rate (HR). Losartan 3 and 10 mg/kg i.v. caused dose-dependent parallel rightward shifts of the dose-response curves (DBP and LVdP/dtmax) without altering the maximal responses to AII. PD123177 (100 mg/kg i.v.) did not influence the dose-response curves for AII significantly. BIBS 39 (1, 3, and 10 mg/kg i.v.) and BIBS 222 (1, 3, and 10 mg/kg, i.v.) shifted the dose-response curves (DBP and LVdP/dtmax) for AII to the right. Although these two compounds (BIBS 39 1, 3, and 10 mg/kg and BIBS 222 1 and 3 mg/kg) did not alter the maximal increase in DBP to angiotensin AII, they decreased the maximal increase in LVdP/dtmax by approximately 35%. BIBS 39 (3 and 10 mg/kg) significantly reduced the increase in CO caused by AII and therefore mean arterial pressure (MAP), whereas the AII-induced increase in TPR remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

BIBS 222, a nonpeptide benzimidazole derivative, displayed insurmountable angiotensin II (Ang II) receptor antagonism in the rabbit aorta (pKB = 7.9), whereas it antagonized Ang II-induced phasic contractions in the rat portal vein in a surmountable manner (pA2 = 8.7, slope = 1.02). The mechanism of the different types of antagonism induced by BIBS 222 in vascular preparations was investigated. Using the slowly dissociating Ang II receptor antagonist sarile, we found that the calculated KA values for Ang II in the rat portal vein and in the rabbit aorta were different (6.0 x 10(-8) M vs. 2.0 x 10(-9) M). The estimated receptor reserve at the maximal response for the effect of Ang II in the rat portal vein amounts to 63%, whereas in rabbit aortic rings it is about 9%. In the presence of the disulfide-reducing agent dithiothreitol (0.5 mM), which led to the inactivation of about 70% of the Ang II receptors in the rat portal vein, BIBS 222 (10(-6) M) shifted the concentration-response curve for Ang II to the right and reduced the maximal response by 24 +/- 4.4% (P < .05). In conclusion, rat portal vein possesses a larger receptor reserve for Ang II than rabbit aortic rings. The surmountable Ang II receptor antagonism induced by BIBS 222 may be caused by the large receptor reserve in this preparation. Alternatively, different KA values for Ang II in these tissues may suggest the existence of two subpopulations of Ang II subtype 1 receptors, accounting for the cross-tissue behavior of BIBS 222.