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.
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.
Webb
R L
RL
Metabolic and Cardiovascular Diseases, Novartis Pharmaceuticals Corp, Summit, New Jersey 07901, U.S.A.
Abramson
M L
ML
Beil
M E
ME
Odorico
L M
LM
Chatelain
R E
RE
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D006332:Cardiomegaly / Q000188:drug therapy* / Q000503:physiopathology; D006152:Cyclic GMP / Q000652:urine; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000097:blood; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014443:Tyrosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D014554:Urination / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; C100918:N-((1-((2-(acetylthio)-3-methyl-1-oxobutyl)amino)-1-cyclopentyl)carbonyl)-O-methyl-L-tyrosine ethyl ester; D014443:Tyrosine; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin; D006152:Cyclic GMP