title: Acute reversal of cyclosporine nephrotoxicity by neutral endopeptidase inhibition in stable renal transplant recipients.
abstract: 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 inhibitor candoxatrilat in a double-blind, placebo-controlled cross-over study. Each study day consisted of 2 hr of baseline and 7 hr of postdose evaluation.
  
  
  RESULTS
  After administration of candoxatrilat, plasma atrial 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 pmol/ min; P<0.001), marked natriuresis (207+/-34 micromol/min baseline to 416+/-62 micromol/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 remained elevated above baseline for the remaining 7-hr study period. In 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 vascular resistance from 0.38+/-0.04 to 0.30+/-0.04 mmHg x min x 1.73 m2 x ml(-1) (P=0.02). There was a fall in plasma angiotensin II without a change in plasma renin concentration or plasma aldosterone. Median urinary albumin excretion increased after candoxatrilat administration from 48 (3-131) to 114 (32-641) microg/min (P<0.01).
  
  
  CONCLUSIONS
  Acute neutral endopeptidase inhibition with candoxatrilat appears to reverse the adverse renal hemodynamic and renal excretory effects of cyclosporine in stable renal transplant recipients.
authors.affiliation: Department of Nephrology, St. Bartholomew's Hospital, London, United Kingdom.
authors.forename: G W
authors.initials: GW
authors.lastname: Lipkin
authors.forename: R
authors.initials: R
authors.lastname: Thuraisingham
authors.forename: A B
authors.initials: AB
authors.lastname: Dawnay
authors.forename: S M
authors.initials: SM
authors.lastname: Harwood
authors.forename: A E
authors.initials: AE
authors.lastname: Raine
mesh_terms: D000328:Adult; D000368:Aged; D009320:Atrial Natriuretic Factor / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D006152:Cyclic GMP / Q000097:blood; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use*; D016572:Cyclosporine / Q000009:adverse effects*; D004231:Diuresis / Q000187:drug effects; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology* / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D012039:Regional Blood Flow / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D012964:Sodium / Q000652:urine; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D003509:Cyclohexanecarboxylic Acids; D007166:Immunosuppressive Agents; D011480:Protease Inhibitors; C060942:candoxatrilat; D016572:Cyclosporine; D009320:Atrial Natriuretic Factor; D012964:Sodium; D015260:Neprilysin; D006152:Cyclic GMP