Concurrent neutral endopeptidase and ACE inhibition in experimental heart failure: renal and hormonal effects.
Neutral endopeptidase (NEP) inhibitors have been shown to strengthen the effects of endogenous atrial natriuretic peptide (ANP). It has been well documented that angiotensin I-converting enzyme (ACE) inhibitors act beneficially in chronic congestive heart failure (CHF). In the present study, renal and hormonal effects of SCH 34826, an orally active NEP inhibitor, were studied in a coronary-ligation model of experimental CHF in the rat. The effects were compared to those of captopril. The drugs were also administered in combination. In anaesthetized rats with CHF, SCH 34826 (90 mg kg-1 sc) elevated plasma ANP from 382 +/- 85 to 658 +/- 120 ng l-1 compared with vehicle (p = 0.002). In sham-operated control rats, plasma ANP also increased slightly from 52 +/- 6 to 70 +/- 9 ng l-1 (p = 0.05). Plasma renin activity did not change in either group. When given orally for 36 h (90 mg kg-1 b.i.d.), SCH 34826 enhanced natriuresis in controls but not in rats with CHF. Captopril (0.2 mg ml-1 in drinking water) enhanced natriuresis in CHF rats and both natriuresis and kaliuresis in controls. When SCH 34826 and captopril were combined, natriuresis was potentiated in control rats as compared with captopril alone; in rats with CHF, however, a brisk kaliuresis was seen. The excretion of cyclic guanosine monophosphate was enhanced in CHF rats by 52% during treatment with SCH 34826 but not with captopril or combination of the two drugs. Moreover, captopril suppressed aldosterone excretion both in CHF rats and controls when administered alone but not when combined with SCH 34826.(ABSTRACT TRUNCATED AT 250 WORDS)
Helin
K
K
Minerva Institute for Medical Research, Helsinki, Finland.
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D002908:Chronic Disease; D006152:Cyclic GMP / Q000097:blood; D004148:Dioxolanes / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D004151:Dipeptides / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D007668:Kidney / Q000503:physiopathology; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar
D000806:Angiotensin-Converting Enzyme Inhibitors; D004148:Dioxolanes; D004151:Dipeptides; C056319:Sch 34826; D009320:Atrial Natriuretic Factor; D015260:Neprilysin; D006152:Cyclic GMP