Abstract
The pharmacologic profile of Ib, 5-n-butyl-4-{4-[2-(1H-tetrazole-5-yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2-(2,6-dichloridephenyl)-3H-1,2,4-triazol-3-one, a novel nonpeptide angiotensin AT(1) receptor antagonist, was investigated by receptor-binding studies, functional in vitro assays with rabbit and rat aorta, and in vivo experiments in rats. Ib inhibited [(125)I] angiotensin II binding to AT(1) receptors in rat liver membranes (K(i)=2.5+/-0.5 nM) and did not interact with AT(2) receptors in bovine cerebellar membranes. In functional studies with rat and rabbit aorta, Ib inhibited the contractile response to angiotensin II (pD(2)' value: 7.43 and 7.29, respectively) with a significant reduction in the maximum. In pithed rats, Ib inhibited the angiotensin II induced pressor response in a dose-related manner. After intravenous administration, Ib produced a dose-dependent antihypertensive effects in spontaneously hypertensive rats and renal hypertensive rats. These results suggest that Ib is a potent angiotensin AT(1) selective receptor antagonist with a mode of insurmountable antagonism.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin II / metabolism*
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Angiotensin II Type 1 Receptor Blockers / administration & dosage
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Angiotensin II Type 1 Receptor Blockers / metabolism
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Angiotensin II Type 1 Receptor Blockers / pharmacology*
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Animals
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Antihypertensive Agents / administration & dosage
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Antihypertensive Agents / metabolism
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Antihypertensive Agents / pharmacology*
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Aorta, Thoracic / drug effects
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Aorta, Thoracic / metabolism
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Blood Pressure / drug effects
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Cattle
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Cerebellum / drug effects
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Cerebellum / metabolism
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Hypertension / drug therapy*
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Hypertension / metabolism
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Hypertension / physiopathology
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Injections, Intravenous
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Liver / drug effects
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Liver / metabolism
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Losartan / pharmacology
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Male
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Protein Binding
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Pyrroles / administration & dosage
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Pyrroles / metabolism
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Pyrroles / pharmacology*
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Rabbits
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Rats
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Rats, Inbred SHR
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Rats, Sprague-Dawley
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Receptor, Angiotensin, Type 1 / drug effects*
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Receptor, Angiotensin, Type 1 / metabolism
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Time Factors
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Triazoles / administration & dosage
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Triazoles / metabolism
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Triazoles / pharmacology*
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Vasoconstriction / drug effects
Substances
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5-n-butyl-4-(4-(2-(1H-tetrazole-5-yl)-1H-pyrrol-1-yl)phenylmethyl)-2,4-dihydro-2-(2,6-dichloridephenyl)-3H-1,2,4-triazol-3-one
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Angiotensin II Type 1 Receptor Blockers
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Antihypertensive Agents
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Pyrroles
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Receptor, Angiotensin, Type 1
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Triazoles
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Angiotensin II
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Losartan