title: 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-1 min-1) 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-1 min-1) 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-1 min-1) to levels similar to, or greater than, those observed with the high-dose ANP (300 ng kg-1 min-1). 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.
authors.affiliation: Department of Clinical Pharmacology, Royal Postgraduate Medical School, London.
authors.forename: M R
authors.initials: MR
authors.lastname: Wilkins
authors.forename: S L
authors.initials: SL
authors.lastname: Settle
authors.forename: J E
authors.initials: JE
authors.lastname: Kirk
authors.forename: S A
authors.initials: SA
authors.lastname: Taylor
authors.forename: K P
authors.initials: KP
authors.lastname: Moore
authors.forename: R J
authors.initials: RJ
authors.lastname: Unwin
mesh_terms: D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002303:Cardiac Output, Low / Q000503:physiopathology; D006152:Cyclic GMP / Q000652:urine*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004232:Diuretics / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D008094:Lithium / Q000378:metabolism; D008297:Male; D009318:Natriuresis / Q000187:drug effects*; D015260:Neprilysin / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003509:Cyclohexanecarboxylic Acids; D004232:Diuretics; D010446:Peptide Fragments; C059320:SC 46542; C060942:candoxatrilat; D009320:Atrial Natriuretic Factor; D008094:Lithium; D015260:Neprilysin; D006152:Cyclic GMP