Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 20, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn129
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Ecstasy produces left ventricular dysfunction and oxidative stress in rats
1 Department of Pharmacology and Experimental Therapeutics, the Cardiovascular Center, Louisiana State University Health Sciences Center, New Orleans, LA. 70112
2 Department of Cardiopulmonary Science, School of Allied Health Professions, Louisiana State University Health Sciences Center, New Orleans, LA. 70112
Corresponding Author: Kurt J. Varner, Ph.D. Professor and Interim Head Department of Pharmacology and Experimental Therapeutics LSU Health Sciences 1901 Perdido Street P7-1 New Orleans, LA 70112 Tel: (504) 568-4742 Fax: (504) 568-2361 E mail: kvarne{at}lsuhsc.edu
Aim: Our aim was to determine whether the repeated, binge administration of 3, 4-methylenedioxymethamphetamine (ecstasy; MDMA) produces structural and/or functional changes in the myocardium that are associated with oxidative stress.
Methods: Echocardiography and pressure-volume conductance catheters were used to assess left ventricular structure and function in rats subjected to 4 ecstasy binges (9 mg/kg i.v. for 4 d, separated by a 10 d drug-free period). Hearts from treated and control rats were used for either biochemical and proteomic analysis or the isolation of adult left ventricular myocytes.
Results: After the 4th binge, treated hearts showed eccentric left ventricular dilation and diastolic dysfunction. Systolic function was not altered in vivo; however, the magnitude of the contractile responses to electrical stimulation was significantly smaller in myocytes from rats treated in vivo with ecstasy compared to myocytes from control rats. The magnitude of the peak increase in intracellular calcium (measured by Fura-2) was also significantly smaller in myocytes from ecstasy-treated vs. control rats. The relaxation kinetics of the intracellular calcium transients were significantly longer in myocytes from ecstasy-treated rats. Ecstasy significantly increased nitrotyrosine content in the left ventricle. Proteomic analysis revealed increased nitration of contractile proteins (troponin-T, tropomyosin alpha-1 chain, myosin light polypeptide, and myosin regulatory light chain), mitochondrial proteins (Ub-cytochrome-c reductase and ATP synthase) and sarcoplasmic reticulum calcium ATPase.
Conclusion: The repeated, binge administration of ecstasy produces eccentric left ventricular dilation and dysfunction that is accompanied by oxidative stress. These functional responses may result from the redox modification of proteins involved in excitation-contraction coupling and/or mitochondrial energy production. Together, these results indicate that ecstasy has the potential to produce serious cardiac toxicity and ventricular dysfunction.
Time for primary review: 23 days