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Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes
Published on: September 18, 2017
Metabolites of MDMA induce oxidative stress and contractile dysfunction in adult rat left ventricular myocytes
Sylvia K Shenouda1, Kurt J Varner, Felix Carvalho
1Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido Street, New Orleans, LA 70112, USA.
Abstract:
Repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy) produces eccentric left ventricular (LV) dilation and diastolic dysfunction. While the mechanism(s) underlying this toxicity are unknown, oxidative stress plays an important role. MDMA is metabolized into redox cycling metabolites that produce superoxide. In this study, we demonstrated that metabolites of MDMA induce oxidative stress and contractile dysfunction in adult rat left ventricular myocytes. Metabolites of MDMA used in this study included alpha-methyl dopamine, N-methyl alpha-methyl dopamine and 2,5-bis(glutathion-S-yl)-alpha-MeDA. Dihydroethidium was used to detect drug-induced increases in reactive oxygen species (ROS) production in ventricular myocytes. Contractile function and changes in intracellular calcium transients were measured in paced (1 Hz), Fura-2 AM loaded, myocytes using the IonOptix system. Production of ROS in ventricular myocytes treated with MDMA was not different from control. In contrast, all three metabolites of MDMA exhibited time- and concentration-dependent increases in ROS that were prevented by N-acetyl-cysteine (NAC). The metabolites of MDMA, but not MDMA alone, significantly decreased contractility and impaired relaxation in myocytes stimulated at 1 Hz. These effects were prevented by NAC. Together, these data suggest that MDMA-induced oxidative stress in the left ventricle can be due, at least in part, to the metabolism of MDMA to redox active metabolites.
Insights
3,4-methylenedioxymethamphetamine (MDMA) metabolites, not MDMA itself, cause oxidative stress and impair heart cell function. N-acetyl-cysteine (NAC) protected against these harmful effects, suggesting a metabolic pathway for MDMA cardiotoxicity.
Area of Science:
- Cardiology
- Toxicology
- Biochemistry
Background:
- Repeated 3,4-methylenedioxymethamphetamine (MDMA) use leads to left ventricular dilation and diastolic dysfunction.
- The precise mechanisms behind MDMA cardiotoxicity remain unclear, but oxidative stress is implicated.
- MDMA metabolism generates reactive intermediates contributing to oxidative stress.
Purpose of the Study:
- To investigate whether MDMA metabolites induce oxidative stress and contractile dysfunction in adult rat ventricular myocytes.
- To identify specific MDMA metabolites responsible for cardiac toxicity.
- To evaluate the protective effects of N-acetyl-cysteine (NAC) against MDMA metabolite-induced damage.
Main Methods:
- Isolated adult rat left ventricular myocytes were treated with MDMA and its metabolites.
- Reactive oxygen species (ROS) production was measured using dihydroethidium.
- Myocyte contractility and intracellular calcium transients were assessed using the IonOptix system.
- The effects of N-acetyl-cysteine (NAC) were evaluated.
Main Results:
- MDMA treatment alone did not increase ROS production in myocytes.
- Three specific MDMA metabolites (alpha-methyl dopamine, N-methyl alpha-methyl dopamine, and 2,5-bis(glutathion-S-yl)-alpha-MeDA) induced time- and concentration-dependent increases in ROS.
- These metabolites, but not MDMA, significantly impaired myocyte contractility and relaxation.
- NAC administration prevented both the ROS production and the contractile dysfunction induced by the metabolites.
Conclusions:
- MDMA-induced oxidative stress and cardiotoxicity in the left ventricle are, at least partly, mediated by its redox-active metabolites.
- Targeting these metabolic pathways may offer therapeutic strategies for mitigating MDMA-related cardiac damage.
- The findings highlight the importance of understanding drug metabolism in predicting and preventing toxicity.
