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Pharmacological effects of GR138950, a novel angiotensin AT1 receptor antagonist.
J Pharmacol Exp Ther. 1995 Feb; 272(2):750-7.JP

Abstract

The antagonist activity of GR138950 (1-[[3-bromo-2-[2-[[(trifluoromethyl)sulphonyl]amino]phenyl]-5- benzofuranyl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxamide) was investigated at angiotensin AT1 receptors and AT2 receptors in vitro and on blood pressure in conscious rats. GR138950 suppressed and displaced angiotensin II (AII) concentration-effect curves in the rabbit isolated aorta (pKb approximately 9.0-9.7) but had no effect against phenylephrine or serotonin induced-contractions. GR138950 competed with [3H]-AII for angiotensin AT1 receptors in rat liver membranes (pKi = 9.09). GR138950 had no apparent affinity for angiotensin AT2 receptors (bovine cerebellum; pKi < 6.0). GR138950 (1 mg/kg i.a. and p.o.) inhibited pressor responses to AII, but not phenylephrine, in conscious normotensive rats. Parallel displacements in AII dose-response curves occurred without any reduction in the maximum response to AII. The antagonist activity of GR138950 lasted for up to 24 h. GR138950 (> 0.03 mg/kg i.a., > 0.3 mg/kg p.o.) significantly reduced diastolic blood pressure (DBP) in renal artery ligated hypertensive rats. DBP was reduced maximally, 5 to 7 h after administration and the antihypertensive effect of GR138950 lasted for up to 48 h. Daily administration (5 days) of GR138950 to renal artery ligated hypertensive rats produced a sustained reduction in DBP. Acute administration of GR138950 (1 mg/kg i.a.) also significantly reduced DBP in spontaneously hypertensive rats but not in normotensive rats. Heart rate was little changed in renal artery ligated hypertensive rats, normotensive rats and spontaneously hypertensive rats. These experiments demonstrate that GR138950 is a potent, selective and specific angiotensin AT1 receptor antagonist that is orally active and reduces DBP in conscious hypertensive rats.(

ABSTRACT

TRUNCATED AT 250 WORDS)

Authors+Show Affiliations

Department of Medicinal Chemistry, Glaxo Research and Development, Ltd., Ware, Hertfordshire, England.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

7853190

Citation

Hilditch, A, et al. "Pharmacological Effects of GR138950, a Novel Angiotensin AT1 Receptor Antagonist." The Journal of Pharmacology and Experimental Therapeutics, vol. 272, no. 2, 1995, pp. 750-7.
Hilditch A, Hunt AA, Travers A, et al. Pharmacological effects of GR138950, a novel angiotensin AT1 receptor antagonist. J Pharmacol Exp Ther. 1995;272(2):750-7.
Hilditch, A., Hunt, A. A., Travers, A., Polley, J., Drew, G. M., Middlemiss, D., Judd, D. B., Ross, B. C., & Robertson, M. J. (1995). Pharmacological effects of GR138950, a novel angiotensin AT1 receptor antagonist. The Journal of Pharmacology and Experimental Therapeutics, 272(2), 750-7.
Hilditch A, et al. Pharmacological Effects of GR138950, a Novel Angiotensin AT1 Receptor Antagonist. J Pharmacol Exp Ther. 1995;272(2):750-7. PubMed PMID: 7853190.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological effects of GR138950, a novel angiotensin AT1 receptor antagonist. AU - Hilditch,A, AU - Hunt,A A, AU - Travers,A, AU - Polley,J, AU - Drew,G M, AU - Middlemiss,D, AU - Judd,D B, AU - Ross,B C, AU - Robertson,M J, PY - 1995/2/1/pubmed PY - 1995/2/1/medline PY - 1995/2/1/entrez SP - 750 EP - 7 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 272 IS - 2 N2 - The antagonist activity of GR138950 (1-[[3-bromo-2-[2-[[(trifluoromethyl)sulphonyl]amino]phenyl]-5- benzofuranyl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxamide) was investigated at angiotensin AT1 receptors and AT2 receptors in vitro and on blood pressure in conscious rats. GR138950 suppressed and displaced angiotensin II (AII) concentration-effect curves in the rabbit isolated aorta (pKb approximately 9.0-9.7) but had no effect against phenylephrine or serotonin induced-contractions. GR138950 competed with [3H]-AII for angiotensin AT1 receptors in rat liver membranes (pKi = 9.09). GR138950 had no apparent affinity for angiotensin AT2 receptors (bovine cerebellum; pKi < 6.0). GR138950 (1 mg/kg i.a. and p.o.) inhibited pressor responses to AII, but not phenylephrine, in conscious normotensive rats. Parallel displacements in AII dose-response curves occurred without any reduction in the maximum response to AII. The antagonist activity of GR138950 lasted for up to 24 h. GR138950 (> 0.03 mg/kg i.a., > 0.3 mg/kg p.o.) significantly reduced diastolic blood pressure (DBP) in renal artery ligated hypertensive rats. DBP was reduced maximally, 5 to 7 h after administration and the antihypertensive effect of GR138950 lasted for up to 48 h. Daily administration (5 days) of GR138950 to renal artery ligated hypertensive rats produced a sustained reduction in DBP. Acute administration of GR138950 (1 mg/kg i.a.) also significantly reduced DBP in spontaneously hypertensive rats but not in normotensive rats. Heart rate was little changed in renal artery ligated hypertensive rats, normotensive rats and spontaneously hypertensive rats. These experiments demonstrate that GR138950 is a potent, selective and specific angiotensin AT1 receptor antagonist that is orally active and reduces DBP in conscious hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS) SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/7853190/Pharmacological_effects_of_GR138950_a_novel_angiotensin_AT1_receptor_antagonist_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&amp;pmid=7853190 DB - PRIME DP - Unbound Medicine ER -