Evaluation of the combined toxic effects of cocaine and ethanol on primary myocardial cell cultures

Welder, Allison A.; O'Dell, J.F.; Melchert, Russell B.; Eselin, Julie A.

doi:10.1016/0887-2333(91)90025-9

Cited by 15 publications

(4 citation statements)

References 17 publications

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“…Finally, the determination of the relative stability of cocaine metabolites in intracellular and extracellular compartments may have implications for mechanistic analyses of cocaine-induced target organ toxicity other than the liver, since the optimal degree of reactivity of a metabolite determines the range of interaction with sites critical for viability (Monks and Lau 1988). For example, direct toxic effects of cocaine have been demonstrated in cultured rat cardiomyocytes (Welder et al 1988(Welder et al , 1991, but the significance of cocaine intermediates in the development of cocaine-induced cardiotoxicity has not been studied so far.…”

Section: Discussionmentioning

confidence: 99%

Biomechanisms of cocaine-induced hepatocyte injury mediated by the formation of reactive metabolites

Boelsterli

Göldlin

1991

Arch Toxicol

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Cocaine is an intrinsic hepatotoxin in laboratory animals, and there is growing evidence that high doses of cocaine can precipitate hepatic necrosis in humans. The rodent model of cocaine hepatotoxicity is commensurate with the concept that a multistep mainly cytochrome P-450 dependent N-oxidative pathway is responsible for the expression of hepatocellular injury. Among the possible biomechanisms by which cocaine exerts its cytotoxic effects, direct oxidative damage by reactive oxygen species generated by redox cycling during the metabolic cascade seems most important. The role of the ensuing lipid peroxidation and protein thiol oxidation is less clear. Similarly, the functional role of irreversible (covalent) binding of a not yet defined electrophilic cocaine intermediate to hepatocellular proteins remains enigmatic so long as the critical molecular targets have not been identified. Finally, glutathione plays a pivotal protective role against cocaine-induced hepatic injury. Interactions with ethanol or inducers of the expression of the cytochrome P-450IIB subfamily can potentiate cocaine hepatotoxicity. Thus, the net amount of the ultimate reactive species seems to determine the severity of the hepatic lesions and to be responsible for the marked interspecies, interstrain, and sex differences. Recent advances in culture techniques of hepatocytes and precision-cut liver slices from various species including man have made it possible to correlate cocaine biotransformation with cytotoxicity and to selectively study the putative cellular mechanisms. Clearly, more studies are necessary to further illuminate our understanding of the role of the biochemical and molecular events precipitating hepatic necrosis during cocaine-mediated hepatotoxicity.

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Section: Discussionmentioning

confidence: 99%

Biomechanisms of cocaine-induced hepatocyte injury mediated by the formation of reactive metabolites

Boelsterli

Göldlin

1991

Arch Toxicol

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“…With respect to "street cocaine" fatality victims, autopsy reports from the Office of the Maryland Medical Examiners revealed postmortem blood levels of cocaine that ranged from 0.1 to 24 mg/l (2.9 x 10~7 to 7.06 x 10~5 M) (Virmani et al, 1988), while postmortem reports from the Office of Chief Medical Examiner-Coroner of San Francisco revealed cocaine blood levels of 0-20.8 ¿*g/dl (0-6.12 x 10~7 M) and urine levels of 0-218 /¿g/dl (0-6.42 x 10~6 M) (Tazelaar et al, 1987). As in our earlier studies, we chose to use cocaine concentrations that were slightly lower and higher than the in vivo concentrations to ensure that we would obtain a cardiotoxic profile in vitro Welder, 1990;Welder et al, 1988Welder et al, , 1991. With respect to NE, it has been estimated that the concentration of NE in sympathetic nerve endings is of the order of 1 mg/g of nerve ending (Reichenbach and Benditt, 1970).…”

Section: Discussionmentioning

confidence: 95%

“…After separating the muscle cells from the endothelial cells, they demonstrated that the components of cigarette smoke (nicotine and carbon monoxide) had a deleterious effect on contractile activity, morphology, and enzyme activity. Several years later, Acosta and colleagues employed the postnatal myocardial cell culture model for toxicological testing of many different classes of xenobiotics and demonstrated that the model was useful in delineating factors associated with heart disease and cardiac cell injury (Acosta et al, 1985;Welder and Acosta, in press Welder, 1990;Welder et al, 1988Welder et al, ,1991.…”

Section: Discussionmentioning

confidence: 98%

Effects of cocaine and norepinephrine on primary cultures of neonatal rat myocardial cells

Welder

Eselin

Melchert

et al. 1992

Journal of Toxicology and Environmental Health

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Sudden cardiac death associated with cocaine (Coc) abuse in healthy, physically active individuals became a grave concern in the late 1980s. It is well documented that physical activity increases circulating plasma catecholamine levels. Catecholamines as well as Coc are independently capable of inducing toxic cardiac effects. The purpose of this investigation was to evaluate the synergistic or additive toxic effects of norepinephrine (NE) and Coc in primary myocardial cell cultures obtained from 3- to 5-d-old Sprague-Dawley rats. Alterations in lactate dehydrogenase release (LDH), lysosomal neutral red retention (NR), beating activity, and morphology were evaluated after treatment of the cells for 1-24 h with 1 x 10(-3) M Coc alone, 1 x 10(-5) M Coc alone, 1 x 10(-5) M NE alone, 1 x 10(-3) M Coc with 1 x 10(-5) M NE, or 1 x 10(-5) M Coc with 1 x 10(-5) M NE. LDH release was elevated significantly after 24 h only with those cells exposed to 1 x 10(-3) M Coc alone and 1 x 10(-3) M Coc + 1 x 10(-5) M NE. Using NR retention as a score for lysosomal treatment of the cells with 1 x 10(-5) M Coc and 1 x 10(-3) M Coc alone did not decrease dye retention significantly. However, 1 x 10(-5) M NE combined with 1 x 10(-3) M Coc significantly reduced lysosomal dye retention as early as 1 h after treatment. After 24 h, 1 x 10(-5) M NE alone and 1 x 10(-5) M NE combined with 1 x 10(-5) M Coc significantly increased lysosomal fragility. Beating activity was altered in all treatment groups. Contractile activity was slow and irregular or completely absent with 1 x 10(-5) and 1 x 10(-3) M Coc, respectively. When NE (1 x 10(-5) M) was combined with both concentrations of Coc, there was distinct focalization of sharp, rapid contractions within the cells, which were asynchronous and/or arrhythmic in nature. Those cells exposed to 1 x 10(-5) M NE with 1 x 10(-5) M Coc for 24 h appeared hypercontracted with marked pseudopodia and cytoplasmic granule formation distinctly different from that exhibited by the cells exposed to 1 x 10(-5) M Coc alone. These data demonstrate that NE potentiates the adverse effects of Coc on contractile activity and morphology of spontaneously contracting neonatal myocardial cells maintained in culture.

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“…The combination of ethanol and cocaine tends to produce effects similar to cocaine (Higgins et al, 1993;McCance-Katz et al, 1993). Cocaine-ethanol combinations have been reported to produce a synergistic effect in producing cell damage in cardiac myocytes (Welder et al, 1991). Thus, the co-administration of cocaine and ethanol can lead to greater cardiovascular toxicity than either drug alone.…”

Section: Drug Combinationsmentioning

confidence: 99%

Cocaine and cardiovascular toxicity

Schindler

1996

Addiction Biology

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Over the past 10 years a great deal has been learned about the cardiovascular effects of cocaine. In particular, the acute effects of cocaine have been studied extensively. Upon acute administration cocaine increases blood pressure and heart rate, primarily through an action on the sympathetic nervous system. Cocaine also suppresses the baroreflex response and vagal tone, further contributing to its effects on heart rate. At the same time cocaine is increasing the work-load on the heart it induces coronary artery vasoconstriction, potentially leading to cardiac ischemia. At higher doses cocaine can depress ventricular function and slow electrical conduction in the heart. Both these effects appear to be mediated by cocaine's local anesthetic action. The effects of cocaine mediated by the sympathetic nervous system are greatly reduced in anesthetized animals. Further, when cocaine is administered repeatedly over a short period of time, acute tolerance can develop to the sympathomimetic effects of cocaine. In contrast, the effects of cocaine mediated by its local anesthetic action do not appear blunted by anesthesia or susceptible to acute tolerance. With chronic administration, higher doses appear to induce tolerance while lower doses may induce sensitization to cocaine's sympathomimetic effects. Cocaine also induces a variety of pathological changes in the heart, including myocardial contraction band necrosis and ventricular hypertrophy. These effects of cocaine on the heart can all contribute to potentially lethal cardiovascular events. In addition to the effects of cocaine alone, the metabolites of cocaine may also contribute to cocaine's cardiovascular toxicity, and both licit and illicit drugs used in combination with cocaine might potentially alter its cardiovascular effects.

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Evaluation of the combined toxic effects of cocaine and ethanol on primary myocardial cell cultures

Cited by 15 publications

References 17 publications

Biomechanisms of cocaine-induced hepatocyte injury mediated by the formation of reactive metabolites

Biomechanisms of cocaine-induced hepatocyte injury mediated by the formation of reactive metabolites

Effects of cocaine and norepinephrine on primary cultures of neonatal rat myocardial cells

Cocaine and cardiovascular toxicity

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