Response to atrial natriuretic peptide, endopeptidase 24.11 inhibitor and C‐ANP receptor ligand in the rat

Abstract

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.

Renal effects of concurrent E‐24.11 and ACE inhibition in the aorto‐venocaval fistula rat

“…A small proportion of rats fail to compensate for the shunt and die in the first week post-surgery with sodium retention, manifest as pulmonary oedema and _ ascites (Winaver et al, 1988 . Consistent with our previous observations in these anb imals (Wilkins et al, 1992;Kirk & Wilkins, 1993) (Yamamoto et al, 1992;Ward et al, 1995). Third, Time (min) bradykinin is a substrate for both E-24.11 and ACE and coinhibition of these enzymes has been shown to potentiate sy-(a) Urinary sodium excretion (UNaV) in response to nergistically the natriuretic effects of bradykinin in anaes-[at, 3 mgkg-1 (0; n = l1) and sampatrilat, 0.1 mg kg-1 thetized dogs (Seymour et al, 1994).…”

“…A -V fistula rats A -V fistula surgery was performed on male Wistar rats (280-300 g) under Hypnorm (fentanyl/flunasone) anaesthesia as described previously (Wilkins et al, 1992). Briefly, the fistula (1-1.5 mm long) was made through a side to side anastomosis between the aorta and inferior vena cava approximately 10 mm distal to the renal arteries.…”

“…[3H]-inulin levels in urine and plasma were determined by liquid scintillation counting in Insta-gel (Packard) (Wilkins et al, 1992). Urinary cyclic GMP concentrtion was measured by radioimmunoassay on appropriately diluted samples as described previously …”

Effect of endopeptidase‐24.11 inhibition and of atrial natriuretic peptide clearance receptor ligand on the response to rat brain natriuretic peptide in the conscious rat

“…Groups (a) and (b) received 100 il saline in place of candoxatrilat at the appropriate time. Doses of > 3 mg kg-' candoxatrilat represent the top of the dose-response curve for natriuresis in hydrated rats (Shepperson et al, 1991;Wilkins et al, 1992).…”

“…The clearance receptors for ANP are distinct from guanylyl cyclase linked receptors for this peptide in that they have not been clearly linked to any second messenger system but have been shown to internalise ANP in cell culture (Maack, 1992). Inhibition of either pathway alone has been shown to enhance the natriuretic response to ANP (Wilkins et al, 1992) and this observation has therapeutic potential: E-24.11 inhibitors are currently under evaluation as novel agents for treating patients with cardiac failure (Northridge et al, 1989).…”