Evaluation of the ability of irbesartan to cross the blood-brain barrier following acute intragastric treatment.
The present study evaluated in functional tests the ability of the angiotensin AT1 receptor antagonist irbesartan, 2-n-butyl-3-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-1,3-d iaza-spiro[4,4]non-1-en-4-one, in comparison to losartan, 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'(1H-tetrazol-5-yl) bi-phenyl-4-yl)methyl]imidazole, to cross the blood-brain barrier following acute intragastric administration. Two tests were used: the dipsogenic response to intracerebroventricular injection of angiotensin II, and Na+ intake in response to adrenalectomy. In normotensive rats, irbesartan reduced the dipsogenic response to angiotensin II, 10 pmol per rat, at the dose of 90 mg/kg, but not at lower doses. Losartan significantly reduced angiotensin II-induced drinking at 30 mg/kg, but not at a lower dose. In spontaneously hypertensive rats, irbesartan reduced the response to angiotensin II at 50 mg/kg, but not at lower doses, while losartan significantly inhibited angiotensin II-induced drinking even at 10 mg/kg. In adrenalectomized rats, the intake of 2% NaCl was inhibited by the intragastric administration of losartan 30 or 50 mg/kg, while irbesartan did not reduce it in doses up to 50 mg/kg. The results of the present study consistently indicate that after acute intragastric administration, the ability of irbesartan to cross the blood-brain barrier is lower than that of losartan.
Polidori
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C
Department of Pharmacological Sciences and Experimental Medicine, University of Camerino, Italy. polidori@cambio.unicam.it
Ciccocioppo
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R
Nisato
D
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Cazaubon
C
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Massi
M
M
D000315:Adrenalectomy; D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier; D002217:Carbachol / Q000008:administration & dosage / Q000494:pharmacology; D004341:Drug Evaluation; D007276:Injections, Intraventricular; D000077405:Irbesartan; D019808:Losartan / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013270:Stomach; D013777:Tetrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000804:Angiotensin II; D002217:Carbachol; D000077405:Irbesartan; D019808:Losartan