title: Membrane sealant Poloxamer P188 protects against isoproterenol induced cardiomyopathy in dystrophin deficient mice.
abstract: BACKGROUND
  Cardiomyopathy in Duchenne muscular dystrophy (DMD) is an increasing cause of death in patients. The absence of dystrophin leads to loss of membrane integrity, cell death and fibrosis in cardiac muscle. Treatment of cardiomyocyte membrane instability could help prevent cardiomyopathy.
  
  
  METHODS
  Three month old female mdx mice were exposed to the β(1) receptor agonist isoproterenol subcutaneously and treated with the non-ionic tri-block copolymer Poloxamer P188 (P188) (460 mg/kg/dose i.p. daily). Cardiac function was assessed using high frequency echocardiography. Tissue was evaluated with Evans Blue Dye (EBD) and picrosirius red staining.
  
  
  RESULTS
  BL10 control mice tolerated 30 mg/kg/day of isoproterenol for 4 weeks while death occurred in mdx mice at 30, 15, 10, 5 and 1 mg/kg/day within 24 hours. Mdx mice tolerated a low dose of 0.5 mg/kg/day. Isoproterenol exposed mdx mice showed significantly increased heart rates (p < 0.02) and cardiac fibrosis (p < 0.01) over 4 weeks compared to unexposed controls. P188 treatment of mdx mice significantly increased heart rate (median 593 vs. 667 bpm; p < 0.001) after 2 weeks and prevented a decrease in cardiac function in isoproterenol exposed mice (Shortening Fraction = 46 ± 6% vs. 35 ± 6%; p = 0.007) after 4 weeks. P188 treated mdx mice did not show significant differences in cardiac fibrosis, but demonstrated significantly increased EBD positive fibers.
  
  
  CONCLUSIONS
  This model suggests that chronic intermittent intraperitoneal P188 treatment can prevent isoproterenol induced cardiomyopathy in dystrophin deficient mdx mice.
authors.affiliation: Children’s National Heart Institute, Division of Cardiology, Children’s National Medical Center, Washington, DC, USA.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Spurney
authors.forename: Alfredo D
authors.initials: AD
authors.lastname: Guerron
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.forename: Arpana
authors.initials: A
authors.lastname: Sali
authors.forename: Jack H
authors.initials: JH
authors.lastname: van der Meulen
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
mesh_terms: D000318:Adrenergic beta-Agonists; D000704:Analysis of Variance; D000818:Animals; D001021:Aortic Valve / Q000187:drug effects / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D009202:Cardiomyopathies / Q000139:chemically induced / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D016189:Dystrophin / Q000172:deficiency* / Q000235:genetics; D005260:Female; D005355:Fibrosis; D006339:Heart Rate / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007545:Isoproterenol; D051379:Mice; D018101:Mice, Inbred mdx; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020442:Poloxamer / Q000008:administration & dosage / Q000494:pharmacology*; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D000318:Adrenergic beta-Agonists; D002317:Cardiovascular Agents; D016189:Dystrophin; D020442:Poloxamer; D003094:Collagen; D007545:Isoproterenol