Inhibition of neutral endopeptidase potentiates the effects of atrial natriuretic peptide on acute cyclosporin-induced nephrotoxicity.
BACKGROUND
The use of cyclosporin A (CyA) is limited by its significant nephrotoxicity. Atrial natriuretic peptide (ANP) has been shown to ameliorate the reduction in glomerular filtration rate (GFR) induced by CyA, but its effect is transient. One explanation may be the rapid breakdown of this hormone by neutral endopeptidase (NEP) which is highly active in the kidney. In the present study, we examined the effect of the NEP inhibitor thiorphan on the acute fall in GFR induced by CyA.


METHODS
After a first set of experiments to investigate the renal hemodynamic effects of CyA (20 mg.kg(-1), i.v. bolus), we studied four additional conditions where acute CyA treatment was followed by the administration of: (2) ANP alone (10 microg.kg(-1) i.v. as bolus and a maintenance infusion of 1 microg. kg(-1).min(-1)); (3) thiorphan alone (5 mg.kg(-1) i.v. as bolus and a maintenance infusion of 0.5 mg.kg(-1). min(-1)); (4) ANP plus thiorphan (as in 2 and 3), and (5) an infusion of 0.9% saline, increased from 1.2 to 3 ml.h(-1). The GFR was measured as the clearance of (3)H-methoxyinulin (ml.min(-1).100 g(-1) body weight).


RESULTS
The data show: (1) the GFR fell from 1.06 +/- 0.15 to 0.59 +/- 0.09 ml.min(-1).100 g(-1) (p < 0.01) 60 min after CyA and remained depressed for at least 2 h; (2) ANP caused a marked initial rise in GFR from 0.49 +/- 0.07 to 1.23 +/- 0.18 ml.min(-1).100 g(-1) (p < 0.005 vs. CyA) which declined rapidly to the value seen after CyA injection alone, despite continuing ANP infusion; (3) thiorphan caused a modest, but significant increase in GFR within 15 min from 0.48 +/- 0.04 to 0.69 +/- 0.10 ml.min(-1).100 g(-1) (p < 0.05 vs. CyA) which was sustained during infusion and for at least 30 min after stopping infusion; (4) ANP plus thiorphan produced a marked increase in GFR from 0.58 +/- 0.09 to 1.39 +/- 0.44 ml.min(-1).100 g(-1) (p < 0.05 vs. CyA) which then decreased, but remained above the post-CyA injection value, until infusion of both drugs ended; (5) more than doubling the saline infusion rate per se had no significant effect on the GFR response to CyA. The blood pressure decreased significantly during ANP infusion, but more so when combined with thiorphan.


CONCLUSIONS
These data indicate that the inhibition of NEP by thiorphan is able to ameliorate partially the reduction in GFR induced by CyA and to enhance, and prolong, the vasodilator and diuretic effects of ANP.
Capasso
G
G
Chair of Nephrology, Second University of Naples, Naples, Italy. gcapasso@unina.it
Unwin
R
R
Ciani
F
F
Rizzo
A
A
Russo
F
F
Pica
A
A
De Santo
N G
NG
D000208:Acute Disease; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D016572:Cyclosporine / Q000633:toxicity*; D004357:Drug Synergism; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007275:Injections, Intravenous; D007444:Inulin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012965:Sodium Chloride / Q000494:pharmacology; D015244:Thiorphan / Q000494:pharmacology*; D014316:Tritium
D007166:Immunosuppressive Agents; D011480:Protease Inhibitors; D014316:Tritium; D012965:Sodium Chloride; C036740:methoxyinulin; D016572:Cyclosporine; D009320:Atrial Natriuretic Factor; D007444:Inulin; D015244:Thiorphan; D015260:Neprilysin