Effects of systemic treatment with irbesartan and losartan on central responses to angiotensin II in conscious, normotensive rats

Angiotensin AT(1) receptor antagonists represent a novel class of cardiovascular drugs. In conscious, normotensive rats, irbesartan ((2-n-butyl-3-[(2'-( 1H-tetrazol-5-yl)-biphenyl-4-yl) methyl]-1,3-diaza-spiro[4,4]non) and losartan ((2n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl) methyl] imidazol), two specific, high- affinity angiotensin AT(1) receptor antagonists administered intravenously (i.v.) at doses of 0.3, 1, 3 and 10 mg/kg body weight, or orally (p.o.) at doses of 1, 3, 10 and 30 mg/kg body weight, antagonized the presser responses to i.v. angiotensin II (50 ng/kg body weight) in a dose-related manner and with similar potency. In the following sets of experiments, we tested the hypothesis that these angiotensin AT(1) receptor antagonists, when applied systemically, can inhibit the effects of angiotensin AT(1) receptor stimulation in the brain. Irbesartan and losartan were administered i.v. or p.o. at doses of 3, 10, 30 and 100 mg/kg body weight. The responses to 100 ng angiotensin II injected into the lateral brain ventricle (i.c.v.), namely blood pressure increase, vasopressin release into the circulation and drinking, were recorded for up to 3 h. While both angiotensin AT(1) receptor antagonists dose-dependently attenuated the presser responses to central angiotensin AT(1) receptor stimulation to a similar degree (maximal inhibition, irbesartan: 62% i.v., 39% p.o.; losartan: 62% i.v., 46% p.o.; respectively), irbesartan was more effective with respect to the inhibition of vasopressin release (76% i.v., 65% p.o.) and drinking (63% i.v., 79% p.o.) than losartan (58% i.v., 33% p.o and 22% i.v., 56% p.o.: respectively). We conclude that systemically administered angiotensin AT(1) receptor antagonists have access to central angiotensin receptors. The degree of central angiotensin AT(1) receptor blockade following peripheral application may vary between different representatives of this class of drugs. (C) 1999 Elsevier Science B.V. All rights reserved.