Effect of chronic neutral endopeptidase inhibition on cardiac hypertrophy after experimental myocardial infarction.
Candoxatril is an inhibitor of neutral endopeptidase, a membrane-bound enzyme that degrades atrial natriuretic peptide. The effects of candoxatril on hemodynamic parameters and cardiovascular hypertrophy were evaluated in the rat model of myocardial infarction. Myocardial infarction was induced by left coronary artery ligation in rats and they were treated either with candoxatril (10mg/kg per day) or a vehicle for up to 4 weeks. Systolic blood pressure and body weight did not change for up to 4 weeks between the 2 groups. At the end of treatment, hemodynamic parameters were measured, and then plasma, heart, lungs and kidneys were collected. Kidney neutral endopeptidase, as measured by the quantitative autoradiographic method, was significantly inhibited in candoxatril-treated rats compared with that in controls (66.6+/-3.2% of control, p<0.001). On the contrary, there were no significant differences in right atrial pressure, left ventricular end-diastolic pressure, systemic pressure, and plasma level of atrial natriuretic peptide between the 2 groups. There were also no significant differences in cardiac weight and lung weight. These data indicate that inhibition of neutral endopeptidase by candoxatril at a dose of 10 mg/kg per day did not oppose cardiac hypertrophy in the rat model of myocardial infarction in spite of significant neutral endopeptidase inhibition.
Section of Internal Medicine and Disability Prevention, Disability Science, Tohoku University Graduate School of Medicine, Sendai, Japan.
K
K
Yoshida
M
M
Yasujima
D J
DJ
Casley
C I
CI
Johnston
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009320:Atrial Natriuretic Factor / Q000097:blood; D006332:Cardiomegaly / Q000201:enzymology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D006439:Hemodynamics / Q000187:drug effects; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000201:enzymology / Q000473:pathology*; D009206:Myocardium / Q000473:pathology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011422:Propionates / Q000494:pharmacology / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling
D000959:Antihypertensive Agents; D007189:Indans; D011422:Propionates; D011480:Protease Inhibitors; D009320:Atrial Natriuretic Factor; C062766:candoxatril; D015260:Neprilysin