Interaction of ANP and bradykinin during endopeptidase 24.11 inhibition: renal effects.
Experiments were performed on anesthetized rats to determine whether inhibition of endopeptidase 24.11 (EP) potentiates the biological activity of atrial natriuretic peptide, ANP-(99-126), and to examine the mechanisms that underlie this effect. Thiorphan (30 mg/kg iv), an inhibitor of EP, produced a modest increase in urinary sodium excretion when administered alone but did not affect urine flow, mean arterial pressure (MAP), or the endogenous level of plasma ANP. The infusion of ANP-(99-126) alone (67 ng.kg-1.min-1 iv) produced a modest natriuresis and decrease in MAP while increasing plasma ANP levels fivefold. When thiorphan (30 mg/kg iv) was administered during the ANP infusion, urine flow and urinary sodium excretion increased markedly but no further decrease in MAP or increase in plasma ANP levels was observed. This potentiation of the renal actions of ANP was not mediated by inhibition of angiotensin-converting enzyme, an increase in glomerular filtration rate, or an increase in renal blood flow but was completely abolished by a specific antagonist of the bradykinin receptor [( DArg0, Hyp3, Thi5, DPhe7, Thi8]bradykinin, 30 micrograms.kg-1.min-1 iv). These data suggest that inhibitors of EP can potentiate the renal activity of ANP by a mechanism which is independent of altered ANP catabolism and which may involve the accumulation of bradykinin, another substrate for EP, within the kidney.
Smits
G J
GJ
Searle Research and Development, Chesterfield, Missouri 63198.
McGraw
D E
DE
Trapani
A J
AJ
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D001920:Bradykinin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002216:Captopril / Q000494:pharmacology; D004232:Diuretics / Q000494:pharmacology; D004357:Drug Synergism; D007668:Kidney / Q000187:drug effects*; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D015244:Thiorphan / Q000494:pharmacology
D004232:Diuretics; D010446:Peptide Fragments; C053748:B 4162; D009320:Atrial Natriuretic Factor; D002216:Captopril; D015244:Thiorphan; D015260:Neprilysin; D001920:Bradykinin