FUNCTIONAL EVIDENCE FOR THE ABILITY OF ANGIOTENSIN AT(1) RECEPTOR ANTAGONISTS TO CROSS THE BLOOD-BRAIN-BARRIER IN RATS

The angiotensin AT(1) receptor antagonists, losartan 2'(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]imidazole potassium salt), EXP3174 l-5-yl)biph enyl-4-yl)methyl]imidazole-5-carboxylic acid), GR117289 methyl]-2-buty l-4-chloro-1H-imidazole-5-carboxylic acid) and LR-B/081 iphenyl]-4-yl] methyl]-1(6H)-pyrimidinyl]methyl]-3- thiophenecarboxylate), given by i ntraperitoneal (i.p.) injection 15 min before intracerebroventricular administration of angiotensin II, inhibited drinking with the followin g order of potency: EXP3174 > GR117289 > losartan > LR-B/081. When 20 mu mol/kg of each antagonist was i.p. injected 15 min, 4, 12 or 24 h b efore angiotensin II, EXP3174 and GR117289 inhibited water intake at e ach observation time, losartan at 4, 12 and 24 h, LR-B/081 only at 4 a nd 12 fi. After per os administration of the same dose 4 or 12 h befor e angiotensin II, losartan reduced drinking at 4, but not at 12 h; LR- B/081 did not inhibit drinking either at 4 or 12 h. The present result s suggest that EXP3174 and GR117289 cross the barrier readily. The eff ect of i.p. losartan on central angiotensin mechanisms is not prompt, suggesting that it may require conversion to EXP3174. LR-B/081 apparen tly crosses the barrier less readily than the other antagonists follow ing both i.p. and per os administration.