1 The present studies compared the renal and hypotensive response to (a) exogenous atrial natriuretic peptide (ANP) (99-126), (b) an endopeptidase-24.11 inhibitor (candoxatrilat) and (c) an antagonist of ANP clearance receptors (SC 46542) in conscious rats. 2 Infusion of low-dose-ANP (100 ng kg-' min-') produced a gradual increase in urinary sodium and guanosine 3':5'-cyclic monophosphate (cyclic GMP) excretion without significant change in glomerular filtration rate (GFR) or fractional lithium clearance (FeLi). There was a significant fall in blood pressure.3 Infusion of high-dose ANP (300 ng kg-' min-') produced a brisk, 3 fold increase in urinary sodium and cyclic GMP excretion along with a rise in GFR, but had no significant effect on FeLi compared to the control group. The renal response was accompanied by a pronounced fall in blood pressure. 4 Candoxatrilat or SC 46542, alone, had no significant effect on sodium excretion compared to control animals. Both compounds enhanced the natriuretic and cyclic GMP responses to a low-dose ANP infusion (100 ng kg-' min-') to levels similar to, or greater than, those observed with the high-dose ANP (300 ng kg-' min-). However, unlike high-dose ANP, these renal effects were not accompanied by a significant change in GFR and neither compound potentiated the hypotensive effect of the low-dose ANP infusion. Only candoxatrilat when given with ANP produced a marked rise in FeLi. 5 Similarly, combined administration of candoxatrilat and SC 46542 (without exogenous ANP) induced an increase in sodium and cyclic GMP excretion comparable to high-dose ANP but did so without a significant increase in GFR and with a significantly smaller fall in blood pressure. Interestingly, there was no increase in FeLi with the combination of the two compounds, suggesting that the major contribution to sodium excretion came from SC 46542. 6 Both candoxatrilat and SC 46542 increased sodium and cyclic GMP excretion in the rat A-V fistula model of heart failure, a model hyporesponsive to infusions of ANP, without significant change in blood pressure.7 These data show that candoxatrilat and SC 46542 do not simply reproduce the effects of an ANP infusion but preferentially enhance the natriuretic response to ANP. Inhibition of E-24.11 may potentiate a tubule action of ANP while the renal mechanism of action of the C-ANP receptor ligand needs further study. Both manipulations are of potential value in the management of heart failure.

1 The present studies compare the early renal response to (a) an endopeptidase-24.11 (E-24.11) inhibitor (candoxatrilat) (b) an angiotensin-converting enzyme (ACE) inhibitor (lisinopril) and (c) the combination of endopeptidase-24.11 and ACE inhibition in the rat A-V fistula model of chronic volume overload. 2 Candoxatrilat (3 and 10 mg kg-') i.v. produced a prompt 3 fold increase in urinary sodium and cyclic GMP excretion without affecting significantly blood pressure or glomerular filtration rate (GFR).3 Lisinopril (0.03 mg kg-') alone inhibited the pressor response to angiotensin I but had no significant effect on urinary sodium excretion or blood pressure.4 Lisinopril (0.03 mg kg-') attenuated significantly the early natriuretic response to candoxatrilat (3 mg kg-1) and the associated rise in urinary cyclic GMP, but sodium excretion eventually reached levels associated with acute E-24.11 inhibition. 5 Doses of the dual E-24. 11/ACE inhibitor, sampatrilat, that inhibited the pressor response to angiotensin I reduced mean arterial blood pressure and produced a delayed natriuresis and rise in urinary cyclic GMP excretion when compared to candoxatrilat alone. 6 Concurrent administration of an ACE inhibitor reduces the early renal response to E-24.11 inhibition in the A-V fistula rat, an effect attributable to the hypotensive action of this combination.

1 The present studies examined the effect of (a) a specific endopeptidase-24.11 (E-24.11) inhibitor (candoxatrilat) and (b) a ligand for the atrial natriuretic peptide (ANP) clearance receptor (SC 46542) on the renal and blood pressure response to brain natriuretic peptide (BNP) in conscious rats.2 Infusion of BNP 200 ng kg-' min-' for 60 min produced a small rise in urinary sodium and guanosine 3':5'-cyclic monophosphate (cyclic GMP) excretion with a non-significant fall in mean arterial blood pressure. 3 Candoxatrilat (3 mg kg-') alone had no significant effect on sodium excretion or blood pressure but markedly potentiated the natriuretic response to BNP.4 Similarly SC 46542 ( 68 fig kg-'; 6.8 fig kg-' min-') which produced no significant effect on its own, potentiated the natriuresis-induced by BNP, although the effect was of shorter duration compared to that of candoxatrilat. 5 The data indicate two approaches to the potentiation of the renal activity of BNP and suggest that BNP may mediate some of the activity of E-24.11 inhibitors reported in cardiac failure.