Evaluation of SQ 28,603, an inhibitor of neutral endopeptidase, in conscious monkeys.
The potent neutral endopeptidase inhibitor SQ 28,603 (N-(2-(mercaptomethyl)-1-oxo-3-phenylpropyl)-beta-alanine) significantly increased excretion of sodium from 4.9 +/- 2.3 to 14.3 +/- 2.1 muequiv./min and cyclic 3',5'-guanosine monophosphate from 118 +/- 13 to 179 +/- 18 pmol/min after intravenous administration of 300 mumol/kg (approximately 80 mg/kg) in conscious female cynomolgus monkeys. SQ 28,603 did not change blood pressure or plasma atrial natriuretic peptide concentrations in the normal monkeys. In contrast, 1-h infusions of 3, 10, or 30 pmol.kg-1.min-1 of human atrial natriuretic peptide lowered blood pressure by -3 +/- 4, -9 +/- 4, and -27 +/- 3 mmHg (1 mmHg = 133.322 Pa), increased cyclic guanosine monophosphate excretion from 78 +/- 11 to 90 +/- 6, 216 +/- 33, and 531 +/- 41 pmol/min, and raised plasma atrial natriuretic peptide from 7.2 +/- 0.7 to 21 +/- 4, 62 +/- 12, and 192 +/- 35 fmol/mL without affecting sodium excretion. In monkeys receiving 10 pmol.kg-1.min-1 of atrial natriuretic peptide, 300 mumol/kg of SQ 28,603 reduced mean arterial pressure by -13 +/- 5 mmHg and increased sodium excretion from 6.6 +/- 3.2 to 31.3 +/- 6.0 muequiv./min, cyclic guanosine monophosphate excretion from 342 +/- 68 to 1144 +/- 418 pmol/min, and plasma atrial natriuretic peptide from 124 +/- 8 to 262 +/- 52 fmol/mL. In conclusion, SQ 28,603 stimulated renal excretory function in conscious monkeys, presumably by preventing the degradation of atrial natriuretic peptide by neutral endopeptidase.
Seymour
A A
AA
Department of Pharmacology, Squibb Institute for Medical Research, Princeton, NJ 08543-4000.
Abboa-Offei
B
B
Asaad
M M
MM
Rogers
W L
WL
D000409:Alanine / Q000031:analogs & derivatives*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000097:blood / Q000652:urine; D004231:Diuresis / Q000187:drug effects; D004232:Diuretics / Q000494:pharmacology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D008252:Macaca fascicularis; D009318:Natriuresis / Q000187:drug effects; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D012964:Sodium / Q000652:urine
D004232:Diuretics; D010446:Peptide Fragments; C065359:SQ 28603; D009320:Atrial Natriuretic Factor; D012964:Sodium; D015260:Neprilysin; D006152:Cyclic GMP; D000409:Alanine