BLOCKADE BY INTRAVENOUS LOSARTAN OF AT(1) ANGIOTENSIN-II RECEPTORS IN RAT-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 administration of the AT(1)-selective AII receptor antagonist losartan. 2. Male Sprague-Dawley rats were administered intravenously either vehicle, or losartan at doses of 1, 3 or 10 mg/kg. Plasma samples were collected and tissues removed at 1, 2, 8 or 24 h after administration of the antagonist. The effects of losartan on AII receptor binding were assessed by quantitative in vitro autoradiography. 3. Losartan significantly increased plasma renin activity (PRA) by six-fold and nine-fold at doses of 1 and 10 mg/kg, respectively (P<0.05). Plasma losartan concentrations 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 returned to control, whilst losartan was undetectable 24 h after injection of the antagonist. 4. In the brain, losartan produced a dose-dependent inhibition of AII receptor binding to the brain structures which express exclusively, or predominantly, AT(1) receptors both outside and within the blood brain barrier. By contrast, losartan did not affect binding 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 returned 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 cortex and medulla, losartan caused partial inhibition at both regions. 6. These results indicate that losartan, administered intravenously at these doses, and/or its active metabolites, partially penetrate the blood brain barrier to selectively inhibit central AT(1) receptors, and exert selective and prolonged blockade of AT(1) receptors in peripheral target tissues.