Antihypertensive and renal activity of SQ 28,603, an inhibitor of neutral endopeptidase.
SQ 28,603 is a potent and selective inhibitor of neutral endopeptidase 3.4.24.11 (NEP), an enzyme that degrades atrial natriuretic peptide (ANP). In conscious deoxycorticosterone acetate (DOCA)/salt hypertensive rats, 300 mumol/kg, i.v., of SQ 28,603 significantly lowered mean arterial pressure (MAP) from 177 +/- 12 to 154 +/- 8 mm Hg and increased urinary cyclic guanosine monophosphate (GMP) excretion from 204 +/- 70 to 1,068 +/- 326 pmol/kg/min within 2 h. Urinary sodium excretion increased within 20 min from a control 51.2 +/- 17.3 to 102.1 +/- 26.7 muEq/kg/min. Infusion of SQ 28,603 (3.7 mumol/kg/min) for 6 h in a separate group of conscious DOCA/salt hypertensive rats gradually reduced MAP from 180 +/- 7 to 142 +/- 7 mm Hg and increased urinary cyclic GMP excretion from 182 +/- 36 pmol/kg/min to 1,009 +/- 394 pmol/kg/min. Despite the continuous infusion of the inhibitor, the natriuretic response peaked during the first hour of treatment at 128 +/- 18 muEq/kg/min (vehicle = 54 +/- 10 muEq/min). Plasma ANP was significantly greater in the rats infused with SQ 28,603 than in those receiving vehicle (333 +/- 108 and 98 +/- 14 fmol/ml, respectively). SQ 28,603 also significantly reduced NEP activity by 95% in the kidneys (1.28 +/- 0.08 vs. 18.35 +/- 0.61 mumol/min after SQ 28,603 and vehicle respectively) and by 77% in the lungs (0.29 +/- 0.03 vs. 0.92 +/- 0.14 mumol/kg after SQ 28,603 and vehicle, respectively). In conclusion, inhibition of NEP activity by SQ 28,603 significantly decreased MAP and increased plasma ANP concentrations and urinary excretion of cyclic GMP in conscious DOCA/salt hypertensive rats.
Seymour
A A
AA
Department of Pharmacology, Squibb Institute for Medical Research, Princeton, New Jersey 08540.
Norman
J A
JA
Asaad
M M
MM
Fennell
S A
SA
Little
D K
DK
Kratunis
V J
VJ
Rogers
W L
WL
D000409:Alanine / Q000031:analogs & derivatives*; D000818:Animals; D000959:Antihypertensive Agents; D009320:Atrial Natriuretic Factor / Q000097:blood; D006152:Cyclic GMP / Q000652:urine; D003900:Desoxycorticosterone; D004231:Diuresis / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy / Q000209:etiology; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012965:Sodium Chloride
D000959:Antihypertensive Agents; D011480:Protease Inhibitors; C065359:SQ 28603; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D009320:Atrial Natriuretic Factor; D015260:Neprilysin; D006152:Cyclic GMP; D000409:Alanine