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.
Marshall
F H
FH
Department of Neuropharmacology, Glaxo Group Research Ltd, Ware, Hertfordshire.
Clark
S A
SA
Michel
A D
AD
Barnes
J C
JC
D015059:1-Sarcosine-8-Isoleucine Angiotensin II / Q000493:pharmacokinetics / Q000494:pharmacology; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001713:Biphenyl Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D019808:Losartan; D008297:Male; D008566:Membranes / Q000187:drug effects; D009539:Nicotinic Acids / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000378:metabolism; D012504:Saralasin / Q000493:pharmacokinetics / Q000494:pharmacology; D013777:Tetrazoles / Q000493:pharmacokinetics / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D007457:Iodine Radioisotopes; D009539:Nicotinic Acids; D011725:Pyridines; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C066253:PD 123177; C078790:GR 117289; D015059:1-Sarcosine-8-Isoleucine Angiotensin II; D012504:Saralasin; D019808:Losartan