title: In vitro and in vivo effects of the phosphodiesterase-III inhibitor enoximone on malignant hyperthermia-susceptible swine.
abstract: BACKGROUND
  In human skeletal muscles, the phosphodiesterase-III inhibitor enoximone induces in vitro contracture development, and it has been suggested that enoximone could trigger malignant hyperthermia (MH). In this study, the in vitro and in vivo effects of enoximone in MH-normal (MHN) and MH-susceptible (MHS) swine were investigated.
  
  
  METHODS
  Malignant hyperthermia trigger-free general anesthesia was performed in MHS and MHN swine. Skeletal muscle specimens were excised for an in vitro contracture test with 0.6 mm enoximone. Thereafter, MHS and MHN swine were exposed to cumulative administration of 0.5, 1, 2, 4, 8, 16, and 32 mg/kg enoximone intravenously. Clinical occurrence of MH was defined by a Pco(2) greater than 70 mmHg, a pH less than 7.20, and an increase in body temperature of more than 2.0 degrees C.
  
  
  RESULTS
  Enoximone induced marked contractures in all MHS muscle specimens in vitro. In contrast, only small or no contracture development was observed in MHN muscle specimens, without an overlap in contractures between MHS and MHN muscles. However, in vivo, no clinical differences were found between MHS and MHN swine following cumulative enoximone doses. According to the defined criteria, none of the swine developed MH during the experiment. Furthermore, high enoximone doses induced progressive circulatory insufficiency, and after receiving 32 mg/kg enoximone, all animals died of cardiovascular failure.
  
  
  CONCLUSIONS
  The cumulative enoximone doses used in this study were 30- to 50-fold higher than therapeutic doses in humans. Enoximone does not trigger MH in genetically determined swine. However, enoximone might be useful for in vitro diagnosis of MH.
authors.affiliation: Department of Anesthesiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany. fiege@uke.uni-hamburg.de
authors.forename: Marko
authors.initials: M
authors.lastname: Fiege
authors.forename: Frank
authors.initials: F
authors.lastname: Wappler
authors.forename: Ralf
authors.initials: R
authors.lastname: Weisshorn
authors.forename: Mark U
authors.initials: MU
authors.lastname: Gerbershagen
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kolodzie
authors.forename: Jochen
authors.initials: J
authors.lastname: Schulte Am Esch
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002245:Carbon Dioxide / Q000097:blood; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004305:Dose-Response Relationship, Drug; D017335:Enoximone / Q000494:pharmacology*; D005260:Female; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000097:blood; D008297:Male; D008305:Malignant Hyperthermia / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D013552:Swine
chemical_list: D010726:Phosphodiesterase Inhibitors; D002245:Carbon Dioxide; D019344:Lactic Acid; D017335:Enoximone; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3