The atriopeptidase inhibitor (+/-) candoxatrilat reduces the clearance of atrial natriuretic factor in both intact and nephrectomized rats: evidence for an extrarenal site of action.
We have demonstrated that in anaesthetized rats. (+/-) candoxatrilat reduces the clearance of both 125IANF and ANF 5-28, and prolongs the elimination half-life. These effects occur independent of glomerular filtration, since they are not attenuated by nephrectomy. Moreover, they cannot be attributed to blockade of ANF-C receptors. Our findings suggest that (+/-)candoxatrilat exerts its activity in vivo by specific inhibition of atriopeptidase at both renal and extra-renal locations.
Barclay
P L
PL
Department of Cardiovascular Biology, Pfizer Central Research Sandwich Kent, U.K.
Bennett
J A
JA
Samuels
G M
GM
Shepperson
N B
NB
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000493:pharmacokinetics*; D002219:Carbamates / Q000494:pharmacology*; D003509:Cyclohexanecarboxylic Acids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006207:Half-Life; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D009392:Nephrectomy; D010446:Peptide Fragments / Q000493:pharmacokinetics; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000378:metabolism
D002219:Carbamates; D003509:Cyclohexanecarboxylic Acids; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011422:Propionates; D011956:Receptors, Cell Surface; C060942:candoxatrilat; D009320:Atrial Natriuretic Factor; C054538:atrial natriuretic factor (5-28)