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Pharmacology of a potent long-acting imidazole-5-acrylic acid angiotensin AT1 receptor antagonist



Pharmacology of a potent long-acting imidazole-5-acrylic acid angiotensin AT1 receptor antagonist



European Journal Of Pharmacology. 283(1-3): 63-72



The angiotensin II antagonistic activity of SB 203220, (E-alpha-((2-butyl-1-(4-carboxy-1-naphthalenyl)methyl)-1H-imidazol-5-yl)methylene)-2-thiophene-propanic acid), was examined in several in vitro and in vivo assays. SB 203220 displaced (125I)angiotensin II binding from a variety of tissues including the cloned human AT-1 receptor (IC-50 5-15 nM). SB 203220 (10 mu-M) did not interact with AT-2 endothelin (ET-A and ET-B) or calcitonin gene-related peptide receptors. (3H)SB 203220 bound with high affinity to the AT-1 receptor (K-d = 4.9 nM), but dissociated from the receptor at a much slower rate when compared to (3H)SK&F 108566. SB 203220 antagonized intracellular Ca-2+ mobilization induced by angiotensin II in rat vascular smooth muscle cells and exhibited a selective and partially insurmountable antagonism of angiotensin II-induced contraction in isolated rabbit aorta. In the aorta, SB 203220 produced a concentration-dependent parallel shift in the concentration-response curve to angiotensin II (EC-30 = 5.94 +- 1.6 10-11 M) and depressed the maximal contractile response to angiotensin II by approximately 35%. The antagonistic effect of SB 203220 in rabbit aorta was slowly reversible compared to SK and F 108566. SB 203220 displayed no agonist activity and had no effect on the contractile responses to KCl, endothelin-1 or norepinephrine. In rats, SB 203220 at 10 mg/kg i.v. inhibited angiotensin II-induced aldosterone release. Intraduodenal or oral administration of SB 203220 (1-10 mg/kg) to conscious rats and dogs inhibited the pressor responses to exogenous angiotensin II. SB 203220 (3-10 mg/kg) also produced a long-lasting ( gtoreq 12 h) antihypertensive response in renin-dependent hypertensive rats and dogs. These data demonstrate that SB 203220 is a potent and highly selective AT-1 receptor antagonist having good oral activity and duration of action in hypertensive models.

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Accession: 009182578

Download citation: RISBibTeXText

PMID: 7498322

DOI: 10.1016/0014-2999(95)00287-u


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