EFFECTS OF SC-52458, AN ANGIOTENSIN AT(1) RECEPTOR ANTAGONIST, IN THEDOG

We have previously reported on the basic pharmacologic properties of S C-52458 yl)methyl]-2-[2-(1H-tetrazol-5-ylphenyl]pyridine), a novel ang iotensin (All) receptor antagonist that binds potently to AT(1) recept ors in rat adrenal cortex and blocks AII-mediated contraction in isola ted rabbit aorta. In the present study, the ability of SC-52458 to blo ck AII presser 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, I n conscious, normotensive dogs, SC-52458 at 30 mg/kg orally, blocked t he presser response to AII (50 ng/kg, intravenously) with maximal inhi bition (91%) observed 2 h after dosing, Plasma concentrations of SC-52 458 measured by HPLC also were highest at the 2-h time point. After 24 h, the AII presser response remained inhibited (by 35%) and SC-52458 was still measurable in plasma from treated dogs. In dogs made hyperte nsive by constriction of the left renal artery, SC-52458 lowered mean arterial pressure compared to vehicle treatment although heart rate wa s not different in the two groups. The maximal blood pressure lowering achieved with SC-52458 was similar to the maximal effect observed wit h the angiotensin converting enzyme inhibitor lisinopril. We conclude that SC-52458 blocks AII mediated presser responses in normotensive, c onscious dogs and SC-52458 is an efficacious antihypertensive agent in dogs with 2 kidney/1 clip renal hypertension. (C) 1997 American Journ al of Hypertension, Ltd.