title: Pathophysiology of cyclosporine-induced nephrotoxicity in humans: a role for nitric oxide?
abstract: BACKGROUND
  The causes for the nephrotoxicity of cyclosporine A (CsA) have not been fully elucidated. Intrarenal vasoconstriction induced by several different mediators, both in humans and experimental animals, have been proposed.
  
  
  METHODS
  We studied prostaglandin metabolites, endothelin and nitric oxide in kidney transplant patients receiving their first CsA dose. Prostaglandin metabolites in the urine and endothelin and nitric oxide (NO2/NO3 in urine and plasma were measured in 14 patients before and 3 and 6 h after oral ingestion of CsA (10 mg/kg b.w.). Clearances for inulin and p-aminohippuric acid (PAH) were measured before and in two separate 3-hour periods after CsA. Blood pressure, heart rate, and CsA blood levels were also determined.
  
  
  RESULTS
  Clearances of inulin and PAH decreased progressively after CsA dosage while renal vascular resistance increased. Nitric oxide plasma levels decreased in nearly all patients from 21.0 +/- 2.8 to 19.1 +/- 2.6 (p = 0.003) and then rose slightly to 19.5 +/- 2.5 micromol/l (p = 0.1) 3 and 6 h after CsA ingestion, respectively. Urinary excretion of NO2/NO3 decreased nonsignificantly from 269 +/- 38.8 to 259 +/- 27.7 and 254 +/- 41.6 micromol/min (p = 0.5 and 0.5). At the same time, urinary prostaglandin E2 and 6-keto-prostaglandin F(1 alpha) excretion rate declined significantly [from 1,187 +/- 254 to 1,186 +/- 351 and 730 +/- 148 pg/min (p = 0.27 and 0.02) and from 697 +/- 115 to 645 +/- 134 and 508 +/- 58.2 pg/min (p = 0.34 and 0.05)]. Urinary thromboxane B2 and plasma and urinary endothelin first increased and then decreased nonsignificantly. Mean arterial pressure rose from 107 +/- 2.5 to 110 +/- 2.6 and 114 +/- 3.4 mm Hg (p = 0.1 and 0.05).
  
  
  CONCLUSIONS
  The pathophysiology of CsA-induced acute renal vasoconstriction involves several different mechanisms including a decrease of the vasodilating prostaglandins E2 and 6-keto-prostaglandin F(1 alpha) and possibly nitric oxide.
authors: Funktionsbereich Nephrologie, Medizinische Klinik IV, Klinikum der J.W.-Goethe-Universität, Frankfurt am Main, Deutschland.
authors: J
authors: J
authors: Gossmann
authors: A
authors: A
authors: Radounikli
authors: A
authors: A
authors: Bernemann
authors: O
authors: O
authors: Schellinski
authors: H P
authors: HP
authors: Raab
authors: R
authors: R
authors: Bickeböller
authors: E H
authors: EH
authors: Scheuermann
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000502:physiology / Q000652:urine; D000284:Administration, Oral; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D016572:Cyclosporine / Q000009:adverse effects* / Q000494:pharmacology; D015232:Dinoprostone / Q000502:physiology / Q000652:urine; D016232:Endothelins / Q000378:metabolism; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000494:pharmacology; D007444:Inulin / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D016030:Kidney Transplantation; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000502:physiology*; D009573:Nitrites / Q000097:blood; D011453:Prostaglandins / Q000502:physiology*; D012077:Renal Artery / Q000187:drug effects*; D012079:Renal Circulation / Q000187:drug effects; D013929:Thromboxane B2 / Q000652:urine; D014655:Vascular Resistance / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000009:adverse effects* / Q000494:pharmacology; D010130:p-Aminohippuric Acid / Q000378:metabolism
chemical_list: D016232:Endothelins; D007166:Immunosuppressive Agents; D009566:Nitrates; D009573:Nitrites; D011453:Prostaglandins; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D016572:Cyclosporine; D007444:Inulin; D015232:Dinoprostone; D010130:p-Aminohippuric Acid