Prolonged neutral endopeptidase inhibition in heart failure.
We studied the hormonal, renal and hemodynamic effects of prolonged treatment with SCH 39370, a new neutral endopeptidase (NEP) inhibitor, in experimental congestive heart failure (CHF). Coronary-ligated CHF rats and sham-operated controls received vehicle or SCH 39370 30 mg/kg s.c. twice daily for six days. In rats with heart failure, SCH 39370 elevated the high plasma atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) levels 2-fold both initially and at the end of the experiment. Initially, water balance was more negative in SCH 39370-treated CHF rats than in those treated with vehicle. In all SCH 39370-treated rats, ANP, cGMP and electrolyte excretion and diuresis were pronounced for 6 h after injection but attenuated thereafter. Blood pressure and pulse remained unchanged. On reverse phase high performance liquid chromatography (HPLC), ANP-(99-126) appeared to be the only circulating form of ANP in rats with heart failure. Three forms have been discovered in patients with heart failure. HPLC revealed only intact ANP in plasma of rats with heart failure during SCH 39370 treatment. NEP inhibitors may provide a new tool for treating chronic heart failure.
Helin
K
K
Minerva Institute for Medical Research, Helsinki, Finland.
Tikkanen
I
I
Tikkanen
T
T
Saijonmaa
O
O
Sybertz
E J
EJ
Vemulapalli
S
S
Sariola
H
H
Fyhrquist
F
F
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D006152:Cyclic GMP / Q000097:blood / Q000652:urine; D004151:Dipeptides / Q000627:therapeutic use*; D010450:Endopeptidases / Q000378:metabolism*; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D007677:Kidney Function Tests; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000494:pharmacology*; D011674:Pulse / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012083:Renin / Q000097:blood; D014882:Water-Electrolyte Balance / Q000187:drug effects
D004151:Dipeptides; D011480:Protease Inhibitors; C060631:Sch 39370; D009320:Atrial Natriuretic Factor; D010450:Endopeptidases; D012083:Renin; D008666:Metalloendopeptidases; D006152:Cyclic GMP