ACUTE REVERSAL OF CYCLOSPORINE NEPHROTOXICITY BY NEUTRAL ENDOPEPTIDASE INHIBITION IN STABLE RENAL-TRANSPLANT RECIPIENTS

Background, Atrial natriuretic peptide and cyclosporine have opposing effects on renal hemodynamics and excretory function, Methods. Twelve male stable cyclosporine-treated renal transplant recipients received a single 100-mg i.v. dose of the neutral endopeptidase EC 24.11 inhibi tor candoxatrilat in a double-blind, placebo-controlled cross-over stu dy, Each study day consisted of 2 hr of baseline and 7 hr of postdose evaluation, Results, After administration of candoxatrilat, plasma atr ial natriuretic factor rose from 12.8 +/- 1.6 (mean +/- SEM) to 44.1 /- 6.8 pmol/L (P < 0.001) in association with a threefold increase in urine cGMP excretion (573 +/- 195 pmol/min baseline to 1823 +/- 545 pm ol/ min; P < 0.001), marked natriuresis (207 +/- 34 mu mol/min baselin e to 416 +/- 62 mu mol/min; P < 0.001), fractional sodium excretion (3 .3 +/- 0.5% baseline to 5.6 +/- 0.7%; P < 0.01), and diuresis (3.4 +/- 0.5 ml/min baseline to 7.4 +/- 1 ml/min; P < 0.001), All parameters r emained elevated above baseline for the remaining 7-hr study period. I n response to candoxatrilat, the glomerular filtration rate rose by 19 % (P = 0.01), renal plasma flow by 7% (P = 0.04), renal blood flow by 13% (P = 0.03) in association with an increase in filtration fraction from 24 +/- 2% to 28 +/- 2% (P = 0.002) and small fall in renal vascul ar resistance from 0.38 +/- 0.04 to 0.30 +/- 0.04 mmHg.min.1.73 m(2).m l(-1) (P = 0.02), There was a fall in plasma angiotensin II without a change in plasma renin concentration or plasma aldosterone. Median uri nary albumin excretion increased after candoxatrilat administration fr om 48 (3-131) to 114 (32-641) mu g/min (P < 0.01). Conclusions, Acute neutral endopeptidase inhibition with candoxatrilat appears to reverse the adverse renal hemodynamic and renal excretory effects of cyclospo rine in stable renal transplant recipients.