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: E G McMahon, P C Yang, M A Babler, O D Suleymanov, M A Palomo, G M Olins, C S Cook
• Journal: American journal of hypertension (Am J Hypertens) Vol. 10 Issue 6 Pg. 671-7 (Jun 1997) ISSN: 0895-7061 [Print] United States
• PMID: 9194514 (Publication Type: Journal Article)

Chemical References

• Angiotensin Receptor Antagonists
• Antihypertensive Agents
• Pyridines
• Tetrazoles
• forasartan
• Angiotensin II

Topics

• Administration, Oral
• Angiotensin II (pharmacology)
• Angiotensin Receptor Antagonists
• Animals
• Antihypertensive Agents (administration & dosage)
• Blood Pressure (drug effects)
• Dogs
• Hypertension, Renovascular (drug therapy, physiopathology)
• Pyridines (administration & dosage, blood)
• Rabbits
• Rats
• Tetrazoles (administration & dosage, blood)