title: Cardioprotective effect of ritonavir, an antiviral drug, in isoproterenol induced myocardial necrosis: a new therapeutic implication.
abstract: BACKGROUND
  Ritonavir is a HIV protease inhibitor. In addition to its antiviral effect, Ritonavir directly inhibits the insulin-regulated glucose transporter GLUT4 and blocks glucose entry into fat and muscle cells. However, the effect of Ritonavir on cardiac GLUT4 inhibition during myocardial necrosis is not investigated. In the present study, we evaluated the role of Ritonavir in isoproterenol-induced myocardial necrosis in vivo and compared the effect with Phlorizin, a nonslective SGLTs inhibitor.
  
  
  METHODS
  Isoproterenol (ISO) (150 mg/kg/day, i.p for 2 consecutive days) was administered to mice to cause myocardial necrosis. Phlorizin (400 mg/kg/day i.p twice daily for 2 days) and Ritonavir (10 mg/kg/day i.p twice daily for 2 days) were administered in two different groups of mice before isoproterenol administration.
  
  
  CONCLUSIONS
  Isoproterenol (ISO) (150 mg/kg/day, i.p for 2 consecutive days) administration caused significant (p < 0.05) increase in heart/body weight ratio, and myocardial necrosis as evident by significant (p < 0.05) increase in serum markers i.e. SGOT and CK; and cardiac histopathological changes. Significant (p < 0.05) reduction in myocardial SOD and catalase activities, and GSH level along with a significant (p < 0.05) rise in myocardial TBARS and nitric oxide levels were observed after ISO administration. However, administration of phlorizin, a SGLT1 inhibitor has been found to exhibit partial protection in ISO induced myocardial necrosis, as observed by significant decrease in heart/body weight ratio and myocardial nitric oxide level; significant increase in myocardial SOD and catalase activities along with no histopathological alterations. On the other hand, administration of ritonavir, a nonspecific GLUT inhibitor has been found to exhibit complete protection as observed by normalisation of heart/body weight ratio, serum markers, antioxidant enzymes activities and histopathological alterations. In vitro study with heart homogenate confirmed no antioxidant effect of ritonavir and phlorizin in the absence and presence of isoproterenol.
  
  
  CONCLUSIONS
  Our study concluded that ritonavir, a nonspecific GLUT inhibitors showed complete protection in catecholamine induced myocardial necrosis.
authors.affiliation: Division of Medicinal Chemistry and Pharmacology, Indian Institute of Chemical Technology (IICT), Hyderabad, India.
authors.forename: Prachi
authors.initials: P
authors.lastname: Gupta
authors.forename: Abhinav
authors.initials: A
authors.lastname: Kanwal
authors.forename: Uday Kumar
authors.initials: UK
authors.lastname: Putcha
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Bulani
authors.forename: Bhavesh
authors.initials: B
authors.lastname: Sojitra
authors.forename: Tarak Nath
authors.initials: TN
authors.lastname: Khatua
authors.forename: Madhusudana
authors.initials: M
authors.lastname: Kuncha
authors.forename: Sanjay Kumar
authors.initials: SK
authors.lastname: Banerjee
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D001835:Body Weight; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000188:drug therapy*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007545:Isoproterenol / Q000009:adverse effects*; D008297:Male; D051379:Mice; D009336:Necrosis / Q000139:chemically induced* / Q000188:drug therapy*; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D010695:Phlorhizin / Q000494:pharmacology; D019438:Ritonavir / Q000627:therapeutic use*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D000975:Antioxidants; D002316:Cardiotonic Agents; D051275:Glucose Transporter Type 4; C495693:Slc2a4 protein, mouse; D017392:Thiobarbituric Acid Reactive Substances; D009569:Nitric Oxide; D010695:Phlorhizin; D007545:Isoproterenol; D019438:Ritonavir