In vivo pharmacological characterization of UP 269-6, a novel nonpeptide angiotensin II receptor antagonist.
UP 269-6, 5-methyl-7-propyl-8(-)[2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl]-1,2,4-triazolo]1,5-c]pyrimidin-2(3H)-one is a novel nonpeptide angiotensin II receptor antagonist. In vivo studies were performed to evaluate UP 269-6 for its angiotensin II antagonistic action. In pithed rats, i.v. administration of UP 269-6 (0.03-1 mg/kg) shifted dose dependently to the right the dose-pressor response curve for angiotensin II and decreased the maximum response. The angiotensin II antagonistic effect of UP 269-6 was as potent as that of L-158,809 (5,7-dimethyl-2-ethyl-3(-)[[2'- (1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-imidazo[4,5-b]pyridine) and 10 times more potent than that of losartan. UP 269-6 antagonized the angiotensin II sympathetic-mediated tachycardiac response. UP 269-6 inhibited dose dependently the pressor response to angiotensin II with an ID50 of 4.5 micrograms/kg, i.v. in conscious normotensive dogs. Oral administration of UP 269-6 (0.1 to 30 mg/kg) resulted in a dose-dependent and long-lasting inhibition of the angiotensin II-induced pressor response in conscious normotensive rats and dogs. Compared to losartan, UP 269-6 presented a more rapid onset of action. UP 269-6 caused similar angiotensin II antagonistic effects in rats and dogs but the duration of the effect was greater in dogs than in rats. UP 269-6 did not alter the tachycardiac response to isoproterenol and the pressor response to vasopressin. UP 269-6 was demonstrated to be devoid of agonistic properties in rats and dogs. Furthermore, UP 269-6 did not induce hypotension and did not cause alteration in heart rate and ECG waveforms in dogs even at a dose 1000 times higher than the angiotensin II antagonistic effective dose. These results demonstrate that UP 269-6 is a potent and specific angiotensin II receptor antagonist and dose not possess agonistic properties.
Laboratories UPSA, Rueil-Malmaison, France.
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Cazes
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Provost
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Versigny
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Cloarec
D000284:Administration, Oral; D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000805:Angiotensin III / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003655:Decerebrate State / Q000503:physiopathology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D007275:Injections, Intravenous; D019808:Losartan; D008297:Male; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D011743:Pyrimidines; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000805:Angiotensin III; C088791:UP 269-6; C070967:L 158809; D019808:Losartan