EFFECT OF VARIOUS ANGIOTENSIN RECEPTOR ANTAGONISTS ON CARDIOVASCULAR-RESPONSES TO ANGIOTENSIN-II IN PITHED RATS

The effects of four nonpeptide angiotensin receptor antagonists, i.e., losartan (AT(1)) PD123177 (AT(2)), and 4'-[(2-n-butyl-6-cyclohexylami nocarbonylamino- benzimidazole-1-yl)-methyl]biphenyl-carboxylic acid ( BIBS 39; AT(1) and AT(2)), and 6-carboxy-2,5-di-chlorbenzoylamino)-ben zyl]-6-N-(m nocarbonyl)-n-pentylamino-benzimidazole (BIBS 222; AT(1) a nd AT(2)) on cardiovascular responses to angiotensin II (AII) were inv estigated in propranolol-pretreated pithed rats. AII (0.01-10 nmol/kg intravenously, i.v.) induced a dose-dependent increase in diastolic bl ood pressure (DBP), the rate of increase in left ventricular pressure (LV dP/dt(max)), 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 rig htward shifts of the dose-response curves (DBP and LV dP/ dt(max)) wit hout 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 LV dP/dt(max)) for AII to th e 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 a ngiotensin AII, they decreased the maximal increase in LV dP/dt(max) b y similar to 35%. BIBS 39 (3 and 10 mg/kg) significantly reduced the i ncrease in CO caused by AII and therefore mean arterial pressure (MAP) , whereas the AII-induced increase in TPR remained unchanged. BIBS 222 (3 and 10 mg/kg) significantly decreased maximal increments in MAP an d TPR to AII, but the maximum increase in CO decreased slightly. These results indicate that in pithed rats various AII-induced cardiovascul ar responses are mediated by AT(1)- but not by AT(2)-receptors. BIBS 3 9 and BIBS 222, two less selective AII receptor antagonists, are also potent antagonists of the hemodynamic responses to AII. However, these compounds antagonize the cardiac and vascular responses to AII in a m anner different from that of a selective AT(1)-receptor antagonist, su ggesting the existence of a mechanism in addition to mere AT(1)- recep tor blockade by the two compounds.