title: Pioglitazone attenuates acute cocaine toxicity in rat isolated heart: potential protection by metabolic modulation.
abstract: BACKGROUND
  The authors tested whether cocaine depresses mitochondrial acylcarnitine exchange and if a drug that enhances glucose metabolism could protect against cocaine-induced cardiac dysfunction.
  
  
  METHODS
  Oxygen consumption with and without cocaine was compared in rat cardiac mitochondria using octanoylcarnitine (lipid) or pyruvate (nonlipid) substrates. Isolated hearts from rats with or without a pioglitazone-supplemented diet were exposed to cocaine.
  
  
  RESULTS
  The 0.5 mM cocaine inhibited respiration supported by octanoylcarnitine (82 ± 10.4 and 45.7 ± 4.24 ngatomO min⁻¹ · mg⁻¹ · protein ± SEM, for control and cocaine treatment, respectively; P < 0.02) but not pyruvate-supported respiration (281 ± 12.5 and 267 ± 12.7 ngatomO min⁻¹ · mg⁻¹ · protein ± SEM; P = 0.45). Cocaine altered contractility, lusitropy, coronary resistance, and lactate production in isolated heart. These effects were each blunted in pioglitazone-treated hearts. The pioglitazone diet attenuated the drop in the rate-pressure product (P = 0.002), cocaine-induced diastolic dysfunction (P = 0.04), and myocardial vascular resistance (P = 0.05) compared with that of controls. Lactate production was higher in pretreated hearts (P = 0.008) and in ventricular myocytes cultured with pioglitazone (P = 0.0001).
  
  
  CONCLUSIONS
  Cocaine inhibited octanoylcarnitine-supported mitochondrial respiration. A pioglitazone diet significantly attenuated the effects of cocaine on isolated heart. The authors postulate that inhibition of acylcarnitine exchange could contribute to cocaine-induced cardiac dysfunction and that metabolic modulation warrants additional study.
authors.affiliation: Department of Anesthesiology, University of Illinois, College of Medicine at Chicago, Illinois, USA. guyw@uic.edu
authors.forename: Guy L
authors.initials: GL
authors.lastname: Weinberg
authors.forename: Richard
authors.initials: R
authors.lastname: Ripper
authors.forename: Sarah
authors.initials: S
authors.lastname: Bern
authors.forename: Bocheng
authors.initials: B
authors.lastname: Lin
authors.forename: Lucas
authors.initials: L
authors.lastname: Edelman
authors.forename: Guido
authors.initials: G
authors.lastname: Digregorio
authors.forename: Mariann
authors.initials: M
authors.lastname: Piano
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Feinstein
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D054715:Cardiotoxins / Q000633:toxicity; D002478:Cells, Cultured; D003042:Cocaine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology*; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D054715:Cardiotoxins; D045162:Thiazolidinediones; D003042:Cocaine; D000077205:Pioglitazone