title: Asymmetric dimethylarginine in response to recombinant tissue-type plasminogen activator and erythropoietin in acute stroke.
abstract: OBJECTIVE
  In the German Multicenter Erythropoietin (EPO) Stroke Trial, patients not receiving thrombolysis most likely benefited from EPO on clinical recovery, whereas a combination of rtPA and EPO was associated with increased mortality. We investigated whether the combination of rtPA and EPO increased release of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA), and thereby potentially deteriorated ischemic stroke outcome, as suggested from experimental data.
  
  
  METHODS
  ADMA was determined in serum samples from 90 patients of the German Multicenter EPO Stroke Trial taken at days 1 (within 6 hours after symptom onset), 2, 3, 4, and 7 after stroke using high-performance liquid chromatography-tandem mass spectrometry. ADMA was analyzed for the different treatment groups (EPO, n=25; placebo, n=30; rtPA+placebo, n=18; EPO+rtPA, n=17). Clinical outcome was expressed as difference between National Institutes of Health Stroke Scale at baseline and 90 days.
  
  
  RESULTS
  ADMA levels significantly increased during the observation time in EPO, EPO+rtPA, and placebo groups (P<0.05). A treatment effect on ADMA levels was revealed by repeated measures ANOVA only in the rtPA+placebo group (P=0.027). Here, ADMA levels were decreased compared with the placebo group (P<0.05). Both the EPO and the rtPA+placebo groups in the Hannover subgroup of the EPO trial had better outcome than the placebo group (P<0.05).
  
  
  CONCLUSIONS
  Our data underscore the potential benefit of EPO in ischemic stroke. The hypothesis from experimental data, that EPO treatment increases ADMA in stroke patients, was disproved. Further studies are needed to clarify whether decreased ADMA might contribute to therapeutic rtPA effects.
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Worthmann
authors.forename: Jens
authors.initials: J
authors.lastname: Martens-Lobenhoffer
authors.forename: Majed
authors.initials: M
authors.lastname: Joumaah
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Ralf
authors.initials: R
authors.lastname: Lichtinghagen
authors.forename: Hartmut
authors.initials: H
authors.lastname: Hecker
authors.forename: Jan T
authors.initials: JT
authors.lastname: Kielstein
authors.forename: Hannelore
authors.initials: H
authors.lastname: Ehrenreich
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Bode-Böger
authors.forename: Karin
authors.initials: K
authors.lastname: Weissenborn
mesh_terms: D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000009:adverse effects*; D004921:Erythropoietin / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D015912:Thrombolytic Therapy / Q000009:adverse effects / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D004921:Erythropoietin; C018524:N,N-dimethylarginine; D001120:Arginine; D010959:Tissue Plasminogen Activator
keywords: asymmetric dimethylarginine; clinical trial; erythropoietin; ischemic stroke; rtPA