title: Pharmacology of a potent long-acting imidazole-5-acrylic acid angiotensin AT1 receptor antagonist.
abstract: 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 AT1 receptor (IC(50)5-15 nM). SB 203220 (10 microM) did not interact with AT2, endothelin (ETA and ETB) or calcitonin gene-related peptide receptors. [3H]SB 203220 bound with high affinity to the AT1 receptor (Kd = 4.9 nM), but dissociated from the receptor at a much slower rate when compared to [3H]SK&F 108566. SB 203220 antagonized intracellular Ca2+ 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 [EC30 = 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&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.(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009281:Naphthalenes / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013876:Thiophenes / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D009281:Naphthalenes; D013876:Thiophenes; D000804:Angiotensin II; C095799:SB 203220; D002118:Calcium