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-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole potassium salt), EXP3174 (2-n-butyl-4-chloro-1-[(2'(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid), GR117289 (1-[[3-bromo-2-[2-(1H-tetrazol-5-yl)phenyl]5-benzofuranyl]methyl]-2-butyl-4-chloro-1H-imidazole-5-carboxylic acid) and LR-B/081 (methyl-2-[[4-butyl-2-methyl-6-oxo-5-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1(6H)-pyrimidinyl]methyl]-3- thiophenecarboxylate), given by intraperitoneal (i.p.) injection 15 min before intracerebroventricular administration of angiotensin II, inhibited drinking with the following 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 before angiotensin II, EXP3174 and GR117289 inhibited water intake at each observation time, losartan at 4, 12 and 24 h, LR-B/081 only at 4 and 12 fi. After per os administration of the same dose 4 or 12 h before 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 results suggest that EXP3174 and GR117289 cross the barrier readily. The effect of i.p. losartan on central angiotensin mechanisms is not prompt, suggesting that it may require conversion to EXP3174. LR-B/081 apparently crosses the barrier less readily than the other antagonists following both i.p. and per os administration.