SODIUM LOADS ENHANCE THE NATRIURETIC RESPONSES TO ATRIAL-NATRIURETIC-PEPTIDE AND NEUTRAL ENDOPEPTIDASE INHIBITORS IN CONSCIOUS CYNOMOLGUS MONKEYS

1. The effects of sodium supplements on the renal responses to human a trial natriuretic peptide (hANP 99-126) and to the selective inhibitor s of neutral endopeptidase 3.4.24.11 (NEP) SQ 28 603 and candoxatrilat were determined in conscious monkeys. 2. When the monkeys' diet was c hanged from 0.55% sodium to 1.1% sodium, the natriuretic response to 1 00 mu mol/kg intravenous of SQ 28 603 increased from 665 +/- 64 to 101 5 +/- 224 mu Eq/3 h. An acute oral load of 25 mEq sodium significantly increased the natriuresis stimulated by 300 mu mol/kg, p.o., of SQ 28 603 from 700 +/- 332 mu Eq/3 h in normal monkeys to 2437 +/- 841 mu E q/3 h. Therefore, the non-human primate model was appropriate for inve stigating the effects of sodium loads on the urinary ANP and cGMP resp onses to exogenous ANP in the presence and absence of NEP inhibitors. 3. Graded intravenous infusions of saline increased basal urine volume and excretion of sodium and ANP. Salt supplements enhanced the diuret ic, natriuretic and ANP responses to 0.3 nmol/kg intravenous of hANP 9 9-126 in monkeys treated with vehicle or 10 mu mol/kg intravenous of c andoxatrilat. The sodium and ANP excretions stimulated by hANP 99-126 were positively correlated with each other and with the calculated int ravenous sodium load in the presence or absence of candoxatrilat. 4. S Q 28 603 and candoxatrilat (0.3 to 10 mu mol/kg intravenous) each prod uced significant, dose-related potentiation of the natriuretic, cGMP a nd ANP responses to 0.3 nmol/kg intravenous of hANP 99-126 in monkeys receiving 5 mL/kg + 0.2 mL/min saline. In addition, the highest dose o f SQ 28 603 produced significant depressor activity. 5. In conclusion, the increased natriuretic activity of hANP 99-126 in sodium loaded mo nkeys was mediated, in part, by increased ANP delivery to the guanylat e cyclase linked ANP receptors in the distal renal tubules.