Abuse of cocaine, a local anesthetic, is associated with widespread and costly adverse public health effects. It is used regularly by more than a million Americans and can cause immediate and long-term medical problems, including severely elevated blood pressure, dangerous irregularities in heart rhythm, heart attack, heart failure and possibly atherosclerosis. Unfortunately, no specific therapy exists to treat either the acute or chronic adverse cardiac effects of cocaine abuse. Clinically used local anesthetics, such as lidocaine, impair function of mitochondria, the intracellular organelles that synthesize adenosine triphosphate (ATP), the molecule that serves cells' energy needs. This effect includes reduction of the mitochondrial proton-motive force, which may contribute to local anesthetic toxicity. Interestingly, the cytotoxicity of lidocaine is reduced by coincubating cells with members of the thiazolidinedione (TZD) class of Peroxisome Proliferator Activated Receptor-gamma (PPARg) agonists, drugs commonly used to treat adult-onset diabetes. We have found that TZDs also increase cellular glucose uptake and lactate production and increase the mitochondrial proton-motive force. In preliminary studies, we find that TZDs protect against cocaine-induced cell death and cardiac diastolic dysfunction. These novel observations suggest that improved metabolism could be considered for treatment of acute cocaine toxicity. The major goal of this proposal is to test the hypothesis that TZD-induced improvements in cellular energy state will rescue cells from metabolic inhibition by cocaine. This research will define the dynamics, biochemistry and mechanisms of TZD salvage from cocaine-induced toxicity, looking specifically at the time course and type of cell death caused by cocaine, and whether altered nitric oxide levels or activation of programmed cell death (apoptosis) play a role. We will also establish an isolated heart model to study the potential for clinical application of TZDs to treat acute cocaine cardiac toxicity. ? ?
