Effects of the novel dual inhibitor of neutral endopeptidase and angiotensin-converting enzyme, CGS 30440, on blood pressure and cardiac hypertrophy in spontaneously hypertensive rats.

Abstract

This study examined the long-term effects of CGS 30440 on blood pressure, heart rate, cardiac hypertrophy, and urinary parameters in conscious spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. Initial studies with CGS 30440 produced dose-related reductions in mean arterial pressure, with a dose of 30 mg/kg/day of CGS 30440 producing a maximal sustained response of 40 mm Hg. CGS 30440 significantly inhibited plasma angiotensin-converting enzyme (ACE) activity by 82% in WKY rats. In SHRs, lung ACE and renal neutral endopeptidase (NEP) were inhibited by >60 and >90%, respectively. Urinary cyclic guanosine monophosphate (cGMP) excretion was significantly increased by CGS 30440 in SHRs but was unaltered in WKY rats. One hour after the final dose of an 8-week regimen, blood pressure was 122 +/- 4 and 189 +/- 5 mm Hg in CGS 30440-treated (30 mg/kg/day) and vehicle-treated SHRs, respectively. Heart-rate responses were not different between treatment groups. Left ventricular hypertrophy (LV weight/body weight ratio) was reduced significantly in SHRs to 2.45 +/- 0.08 mg/g at 10 mg/kg/day and 2.26 +/- 0.07 mg/g at 30 mg/kg/day versus 2.91 +/- 0.09 mg/g in rats receiving only vehicle. These results demonstrate that CGS 30440 is a potent, orally active antihypertensive agent with a long duration of action. The cardiac hypertrophy of established hypertension in the SHRs was attenuated by CGS 30440. Thus CGS 30440, an orally active prodrug, has been shown to be a novel antihypertensive agent with dual ACE/NEP inhibitory activity in SHRs.

• Authors: R L Webb, M L Abramson, M E Beil, L M Odorico, R E Chatelain
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 30 Issue 5 Pg. 632-42 (Nov 1997) ISSN: 0160-2446 [Print] United States
• PMID: 9388046 (Publication Type: Journal Article)

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Antihypertensive Agents
• N-((1-((2-(acetylthio)-3-methyl-1-oxobutyl)amino)-1-cyclopentyl)carbonyl)-O-methyl-L-tyrosine ethyl ester
• Tyrosine
• Peptidyl-Dipeptidase A
• Neprilysin
• Cyclic GMP

Topics

• Angiotensin-Converting Enzyme Inhibitors (pharmacology)
• Animals
• Antihypertensive Agents (pharmacology)
• Blood Pressure (drug effects)
• Cardiomegaly (drug therapy, physiopathology)
• Cyclic GMP (urine)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Heart Rate (drug effects)
• Hypertension (drug therapy, physiopathology)
• Kidney (drug effects, enzymology)
• Neprilysin (antagonists & inhibitors, blood)
• Peptidyl-Dipeptidase A (blood)
• Rats
• Rats, Inbred SHR
• Rats, Inbred WKY
• Tyrosine (administration & dosage, analogs & derivatives, pharmacology)
• Urination (drug effects)
• Weight Gain (drug effects)