Elevation of plasma atrial natriuretic peptide in rats with chronic heart failure by SCH 39370, a neutral metalloendopeptidase inhibitor.
Hormonal, renal and blood pressure effects of SCH 39370, a selective inhibitor of neutral metalloendopeptidase (endopeptidase 24.11, NEP), were studied in a chronic, congestive heart failure (CHF) model produced by coronary artery ligation in the rat. Sham-operated control rats and rats with CHF were treated either with vehicle or SCH 39370, 30 mg/kg s.c. b.i.d. for 2.5 days. Plasma levels of atrial natriuretic peptide (ANP) and urinary excretion of cyclic GMP (cGMP) were clearly raised in rats with CHF as compared with controls during vehicle treatment. SCH 39370 caused a further increase in plasma ANP in CHF rats but not in control rats. Urinary excretion of immunoreactive ANP and cGMP increased during SCH 39370 treatment both in CHF rats and in controls. SCH 39370 treatment resulted in an initial increase in urine volume in rats with CHF whereas urine sodium excretion did not change significantly. No changes in renal function due to SCH 39370 treatment were seen in control rats. Systolic blood pressure, plasma renin activity and urine excretion of catecholamine metabolites (4-hydroxy-3-methoxyphenyl acetic acid and metanephrines) did not change during SCH 39370 treatment either in controls or in CHF rats. We conclude that the NEP-inhibitory compound SCH 39370 is capable of increasing plasma ANP concentration and urinary excretion of cGMP in rats with chronic CHF. In this severe heart failure model, the possible beneficial effects of additional ANP increments may be blunted, however. NEP inhibitors offer a novel approach to study the significance of ANP elevation in chronic CHF.
Tikkanen
I
I
Minervera Institute for Medical Research, Helsinki, Finland.
Helin
K
K
Tikkanen
T
T
Sybertz
E J
EJ
Vemulapalli
S
S
Sariola
H
H
Näveri
H
H
Fyhrquist
F
F
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood* / Q000652:urine; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000652:urine; D004151:Dipeptides / Q000494:pharmacology*; D006333:Heart Failure / Q000097:blood / Q000378:metabolism*; D006400:Hematocrit; D007279:Injections, Subcutaneous; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009929:Organ Size / Q000187:drug effects; D011188:Potassium / Q000652:urine; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D012083:Renin / Q000097:blood; D012964:Sodium / Q000652:urine
D004151:Dipeptides; C060631:Sch 39370; D009320:Atrial Natriuretic Factor; D012964:Sodium; D003404:Creatinine; D012083:Renin; D008666:Metalloendopeptidases; D011188:Potassium