In vivo pharmacology of L-159,913, a new highly potent and selective nonpeptide angiotensin II receptor antagonist.

Abstract

The present study was designed to characterize the in vivo pharmacology of L-159,913 (4-[[2'-(N-benzoylsulfamoyl)biphenyl-4-yl]-5butyl-2,4-dihydr o-2- [2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one); a potent All receptor antagonist. In normotensive rats, dogs, rhesus monkeys, and chimpanzees, L-159,913 inhibited All-induced elevations in blood pressure. In conscious rats, the relative potencies (ED50) were 0.51 mg/kg i.v. and 0.72 mg/kg p.o. Duration of action with single i.v. or p.o. doses exceeded 6 hr in rats. L-159,913 was 3 times less potent than losartan in rats and equipotent to losartan in monkeys. All induced elevation of plasma aldosterone in rats was also inhibited by L-159,913. L-159,913 was antihypertensive in high renin hypertensive rats (aortic coarctation). The maximum hypotensive response to an acute dose of L-159,913 (10 mg/kg, po) was equal to that of enalaprilat (0.3 mg/kg, iv) in this renin dependent animal model. In conscious normotensive dogs, L-159,913 had a moderate diuretic, natriuretic and kaliuretic response with no effect on glomerular filtration rate, effective renal plasma flow or filtration fraction, suggesting a tubular site of action. L-159,913 is a selective and potent All receptor antagonist with good oral activity, long duration of action and antihypertensive efficacy.

• Authors: R A Gabel, S D Kivlighn, G J Zingaro, T W Schorn, L W Schaffer, W T Ashton, L L Chang, K Flanagan, W J Greenlee, P K Siegl
• Journal: Clinical and experimental hypertension (New York, N.Y. : 1993) (Clin Exp Hypertens) Vol. 17 Issue 6 Pg. 931-53 (Aug 1995) ISSN: 1064-1963 [Print] England
• PMID: 7581262 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Angiotensin Receptor Antagonists
• Antihypertensive Agents
• Biphenyl Compounds
• Imidazoles
• L 159913
• Receptors, Angiotensin
• Tetrazoles
• Triazoles
• Angiotensin II
• Aldosterone
• Renin
• Losartan
• Potassium

Topics

• Aldosterone (blood)
• Angiotensin II (pharmacology)
• Angiotensin Receptor Antagonists
• Animals
• Antihypertensive Agents (pharmacology)
• Biphenyl Compounds (pharmacology)
• Blood Pressure (drug effects)
• Dogs
• Female
• Hypertension (drug therapy, physiopathology)
• Imidazoles (pharmacology)
• Kidney (drug effects, physiology)
• Losartan
• Macaca mulatta
• Male
• Natriuresis (drug effects)
• Pan troglodytes
• Potassium (urine)
• Rats
• Rats, Sprague-Dawley
• Receptors, Angiotensin (drug effects, physiology)
• Renin (physiology)
• Tetrazoles (pharmacology)
• Triazoles (pharmacology)