Binding of angiotensin antagonists to rat liver and brain membranes measured ex vivo.

1. The effects of the angiotensin antagonists GR117289, losartan and Sar1Ala8-angiotensin II on the ex vivo binding of [125I]-Sar1Ile8-angiotensin II to rat liver and cortex/hippocampus (Cx/H) membranes have been investigated. 2. GR117289 (0.1-30 mg kg-1, s.c., 2 h pretreatment) caused a dose-dependent reduction in [125I]-Sar1Ile8-angiotensin II binding to both liver and cortex/hippocampus membranes. 3. Administration of a submaximal dose of GR117289 (1 mg kg-1, s.c.) indicated that the peak inhibition of binding in the liver occurred within 0.5 h, whereas the peak inhibition of binding in the Cx/H occurred 2 h after drug treatment. 4. The effect of GR117289 was long lasting. Binding was still reduced in the Cx/H 48 h after drug treatment (10 mg kg-1, s.c.) but had returned to normal 72 h after drug treatment. In the liver binding was still reduced 72 h after treatment with the same dose. 5. Losartan (1-30 mg kg-1, s.c.) was equipotent with GR117289 in its ability to reduce liver binding, but was less effective at inhibiting binding to central receptors. 6. The non-peptide antagonist Sar1Ala8-angiotensin II (3 and 10 mg kg-1) reduced binding in the liver but not in the Cx/H membranes. 7. These results suggest that, unlike the peptide antagonist Sar1Ala8-angiotensin II, the non-peptide angiotensin antagonists, GR117289 and losartan, are able to cross the blood brain barrier and occupy central angiotensin II receptors.