title: Effects of SC-52458, an angiotensin AT1 receptor antagonist, in the dog.
abstract: We have previously reported on the basic pharmacologic properties of SC-52458 (5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl) methyl]-2-[2-(1H-tetrazol-5-ylphenyl)]pyridine), a novel angiotensin (AII) receptor antagonist that binds potently to AT1 receptors in rat adrenal cortex and blocks AII-mediated contraction in isolated rabbit aorta. In the present study, the ability of SC-52458 to block AII pressor responses in conscious dogs was measured. In addition, we determined whether SC-52458 lowered mean arterial pressure in dogs with 2 kidney/1 clip renal hypertension when given daily for 4 days. In conscious, normotensive dogs, SC-52458 at 30 mg/kg orally, blocked the pressor response to AII (50 ng/kg, intravenously) with maximal inhibition (91%) observed 2 h after dosing. Plasma concentrations of SC-52458 measured by HPLC also were highest at the 2-h time point. After 24 h, the AII pressor response remained inhibited (by 35%) and SC-52458 was still measurable in plasma from treated dogs. In dogs made hypertensive by constriction of the left renal artery, SC-52458 lowered mean arterial pressure compared to vehicle treatment although heart rate was not different in the two groups. The maximal blood pressure lowering achieved with SC-52458 was similar to the maximal effect observed with the angiotensin converting enzyme inhibitor lisinopril. We conclude that SC-52458 blocks AII mediated pressor responses in normotensive, conscious dogs and SC-52458 is an efficacious antihypertensive agent in dogs with 2 kidney/1 clip renal hypertension.
authors.affiliation: G.D. Searle & Co, St. Louis, Missouri 63167, USA.
authors.forename: E G
authors.initials: EG
authors.lastname: McMahon
authors.forename: P C
authors.initials: PC
authors.lastname: Yang
authors.forename: M A
authors.initials: MA
authors.lastname: Babler
authors.forename: O D
authors.initials: OD
authors.lastname: Suleymanov
authors.forename: M A
authors.initials: MA
authors.lastname: Palomo
authors.forename: G M
authors.initials: GM
authors.lastname: Olins
authors.forename: C S
authors.initials: CS
authors.lastname: Cook
mesh_terms: D000284:Administration, Oral; D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects*; D004285:Dogs; D006978:Hypertension, Renovascular / Q000188:drug therapy* / Q000503:physiopathology; D011725:Pyridines / Q000008:administration & dosage* / Q000097:blood; D011817:Rabbits; D051381:Rats; D013777:Tetrazoles / Q000008:administration & dosage* / Q000097:blood
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D011725:Pyridines; D013777:Tetrazoles; C084927:forasartan; D000804:Angiotensin II