Beneficial effects of sampatrilat, a novel vasopeptidase inhibitor, on cardiac remodeling and function of rats with chronic heart failure following left coronary artery ligation.

Abstract

Sampatrilat is a novel vasopeptidase inhibitor that may offer a greater benefit than traditional angiotensin-converting enzyme (ACE) inhibitors in the treatment of chronic heart failure (CHF). The present study was undertaken to determine whether sampatrilat improves hemodynamic function and cardiac remodeling through a direct action on the failing heart in rats with CHF following left coronary artery ligation (CAL). Sampatrilat (30 mg/kg a day) was administered orally to the animals from the 1st to 6th week after the operation. Sampatrilat reduced the mortality of the rats with CAL (20 versus 57% for untreated rats). Treatment with sampatrilat for 5 weeks suppressed tissue ACE and neutral endopeptidase (NEP) activities. Sampatrilat did not affect the arterial blood pressure, whereas it attenuated the CAL-induced increases in the left ventricular end-diastolic pressure, heart weight, and collagen content of the viable left ventricle. To assess the direct effects of sampatrilat on collagen synthesis, we measured the incorporation of [(3)H]proline into cultured cardiac fibroblasts. Sampatrilat at concentrations that inhibited NEP activity in vitro augmented the atrial natriuretic peptide-induced decrease in [(3)H]proline incorporation by the cells. In addition, sampatrilat prevented the angiotensin I-induced increase in [(3)H]proline incorporation, whereas captopril did not. The results suggest that long-term treatment with sampatrilat regresses cardiac remodeling in rats with CAL, which is associated with improvement of hemodynamic function. The mechanism by which sampatrilat improved cardiac remodeling may be attributable to the direct inhibition of cardiac fibrosis, possibly acting through the cardiac natriuretic peptide system.

• Authors: Toshiyuki Maki, Yoshihisa Nasa, Kouichi Tanonaka, Masaya Takahashi, Satoshi Takeo
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 305 Issue 1 Pg. 97-105 (Apr 2003) ISSN: 0022-3565 [Print] United States
• PMID: 12649357 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Mesylates
• Tyrosine
• Collagen
• DNA
• Peptide Hydrolases
• Peptidyl-Dipeptidase A
• Neprilysin
• sampatrilat

Topics

• Animals
• Chronic Disease
• Collagen (metabolism)
• DNA (biosynthesis, drug effects)
• Disease Models, Animal
• Enzyme Inhibitors (therapeutic use)
• Fibroblasts (drug effects, metabolism)
• Heart Failure (metabolism, mortality, physiopathology, prevention & control)
• Hemodynamics
• Ligation
• Male
• Mesylates (pharmacology, therapeutic use)
• Myocardial Infarction (etiology, metabolism, mortality, physiopathology)
• Myocardium (metabolism)
• Neprilysin (antagonists & inhibitors, metabolism)
• Organ Size
• Peptide Hydrolases (metabolism)
• Peptidyl-Dipeptidase A (metabolism)
• Rats
• Rats, Wistar
• Tyrosine (analogs & derivatives, pharmacology, therapeutic use)
• Ventricular Remodeling (drug effects)