RENAL AND DEPRESSOR ACTIVITY OF C-NATRIURETIC PEPTIDE IN CONSCIOUS MONKEYS - EFFECTS OF ENZYME-INHIBITORS

The depressor and renal responses to C-type natriuretic peptide (CNP) were determined in conscious cynomolgus monkeys treated with vehicle o r inhibitors of neutral endopeptidase EC 3.4.24.11 (NEP) and angiotens in-converting enzyme (ACE). The NEP inhibitor SQ 28603 (100 mu mol/kg intravenously, i.v.) significantly (p < 0.05) enhanced the depressor r esponses to 1 and 10 nmol/kg i.v. CNP from -2 +/- 3 to -22 +/- 10 mm H g and from -16 +/- 4 to -66 +/- 4 mm Hg, respectively. SQ 28603 also s ignificantly increased the cyclic GMP responses to I and 10 nmol/kg CN P from 1.4 +/- 1.6 to 11.0 +/- 2.0 nmol/2 h and from 4.2 +/- 0.5 to 53 .3 +/- 12.1 nmol/2 h, respectively. Furthermore, the NEP inhibitor sig nificantly increased the natriuretic activity of I and 10 nmol/kg i.v. CNP from 235 +/- 99 to 760 +/- 60 mu Eq/2 h and from 399 +/- 208 to 1 ,036 +/- 79 mu Eq/2 h, respectively. A positive correlation between th e cumulative natriuretic and cyclic GMP responses suggested a cyclic G MP-mediated mechanism. These data are consistent with the protection o f CNP from degradation by renal NEP. Inhibition of ACE by 100 mu mol/k g i.v. captopril did not significantly alter the depressor or renal ac tivities of I nmol/kg of CNP, neither did it alter the potentiation of CNP activity by SQ 28603. The potentiation of the depressor, cyclic G MP, and natriuretic responses to CNP in nonhuman primates by SQ 28603 suggested that NEP is an important mechanism for in vivo inactivation of natriuretic peptides, including CNP.