The blood pressure and renal responses to SCH 34826, a neutral metalloendopeptidase inhibitor, and C-ANF (4-23) in Doca-salt hypertensive rats.
C-ANF (4-23) and neutral metalloendopeptidase (NEP) inhibitors have been shown to prevent ANF metabolism and lower blood pressure presumably by the accumulation of ANF in the circulation. In the present study, we examined the interaction between C-ANF (4-23) and SCH 34826, an inhibitor of NEP, and ensuing effects on blood pressure, excretion of urine and sodium, and cGMP in the plasma and urine in conscious DOCA-salt hypertensive rats. C-ANF (100 micrograms/kg, iv bolus plus 10 micrograms/kg/min X 30) or SCH 34826 (90 mg/kg, sc) alone caused significant reductions in blood pressure and increases in plasma and urinary excretion of cGMP, a biochemical marker of endogenous ANF activity, at one hour post-drug. C-ANF (4-23) alone elicited a significant diuresis and natriuresis. SCH 34826 also enhanced sodium excretion and tended to increase urine volume. In comparison, the combination of C-ANF (4-23) and SCH 34826 produced a greater reduction in blood pressure and increases in plasma and urinary excretion of cGMP than either agent alone. The combination also caused significant diuresis and natriuresis. It is suggested that the greater blood pressure and renal responses to a combination of SCH 34826 and C-ANF than either agent alone reflect greater accumulation of endogenous ANF due to concomitant inhibition of both receptor-mediated clearance and NEP.
Vemulapalli
S
S
Department of Pharmacology, Schering-Plough Research, Bloomfield, New Jersey 07003.
Chiu
P J
PJ
Brown
A
A
Griscti
K
K
Sybertz
E J
EJ
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D006152:Cyclic GMP / Q000097:blood / Q000652:urine; D003900:Desoxycorticosterone; D004148:Dioxolanes / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology*; D006973:Hypertension / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects*; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats
D004148:Dioxolanes; D004151:Dipeptides; D010446:Peptide Fragments; C056319:Sch 34826; C065367:atrial natriuretic factor (4-23)NH2, de-Gln(18)-de-Ser(19)-de-Gly(20,22)-de-Leu(21)-; D003900:Desoxycorticosterone; D009320:Atrial Natriuretic Factor; D015260:Neprilysin; D006152:Cyclic GMP