BLOCKADE BY INTRAVENOUS LOSARTAN OF AT(1) ANGIOTENSIN-II RECEPTORS INRAT-BRAIN, KIDNEY AND ADRENALS DEMONSTRATED BY IN-VITRO AUTORADIOGRAPHY

1. The in vivo inhibition of angiotensin II (AII) receptor binding in the rat brain, kidney and adrenal was investigated after intravenous a dministration of the AT(1)-selective AII receptor antagonist losartan. 2. Male Sprague-Dawley rats were administered intravenously either ve hicle, or losartan at doses of 1, 3 or 10 mg/kg. Plasma samples were c ollected and tissues removed at 1, 2, 8 or 24 h after administration o f the antagonist. The effects of losartan on AII receptor binding were assessed by quantitative in vitro autoradiography. 3. Losartan signif icantly increased plasma renin activity (PRA) by six-fold and nine-fol d at doses of 1 and 10 mg/kg, respectively (P<0.05). Plasma losartan c oncentrations rose from 0.83 mu g/mL at 1 mg/kg to 46.5 mu g/mL at 10 mg/kg 1 h after administration of the drug. Plasma renin activity retu rned to control, whilst losartan was undetectable 24 h after injection of the antagonist. 4. In the brain, losartan produced a dose-dependen t inhibition of AII receptor binding to the brain structures which exp ress exclusively, or predominantly, AT(1) receptors both outside and w ithin the blood brain barrier. By contrast, losartan did not affect bi nding to the nuclei which contain exclusively or predominantly, AT(2) receptors. 5. In the kidney, losartan blocked AII receptor binding to all anatomical sites in a dose-dependent manner. The inhibition peaked at 1 h and persisted beyond 24 h despite the fact that PRA had return ed to control, and losartan was not detectable in the circulation. In the adrenal gland, where AT(1) and AT(2) receptors occur in both the c ortex and medulla, losartan caused partial inhibition at both regions. 6. These results indicate that losartan, administered intravenously a t these doses, and/or its active metabolites, partially penetrate the blood brain barrier to selectively inhibit central AT(1) receptors, an d exert selective and prolonged blockade of AT(1) receptors in periphe ral target tissues.