Cocaine and lidocaine interfere with epinephrine-induced changes in intracellular calcium concentration and glucose efflux from rat hepatocytes.
The mechanism of cocaine-induced hepatotoxicity is not clearly understood. Recent studies show that fluctuations in intracellular Ca2+ ([Ca2+]i) and/or cyclic-AMP ([cAMP]) concentration play a major role in hormone action, and sustained elevations in [Ca2+]i may be involved in the initiation of hepatocellular damage. To evaluate the possible involvement of intracellular Ca2+ and/or cAMP, we investigated effects of cocaine and lidocaine on basal, epinephrine and dibutyryl cyclic-AMP (DBcAMP)-induced changes in [Ca2+]i and glucose efflux from isolated rat hepatocytes. [Ca2+]i was monitored continuously using a Ca2(+)-selective fluorescence indicator, Quin-2, and was calculated after correcting for autofluorescence. Neither cocaine nor lidocaine (0.1-5 mmol/l) affected basal [Ca2+]i, yet both agents decreased epinephrine (10 mumol/l) and DBcAMP (100 mumol/l)-induced increases in [Ca2+]i in a dose-dependent fashion. Half-maximal inhibition occurred at 0.75 mmol/l cocaine and 1.7 mmol/l lidocaine. Cocaine and lidocaine also decreased epinephrine and DBcAMP-induced glucose efflux. The dose-dependent effect on epinephrine-induced glucose efflux was similar to that of both anesthetics on epinephrine-induced increases in [Ca2+]i. However, 5 mmol/l cocaine or lidocaine decreased DBcAMP-induced glucose efflux by less than 50%, and [Ca2+]i by more than 80%. Taken together, these results indicate that cocaine and lidocaine decrease the ability of epinephrine to stimulate glucose efflux by interfering with the Ca2(+)-mediated, and not the cAMP-mediated intracellular pathway. It is therefore speculated that alterations in metabolic endocrine regulation may contribute to cocaine's hepatotoxic effect.
Engelking
L R
LR
Department of Medicine, Tufts University School of Veterinary Medicine, North Grafton, Mass.
Anwer
M S
MS
McConnell
J
J
Sullivan
D
D
Shuster
L
L
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D008012:Lidocaine / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats
D003994:Bucladesine; D006003:Glycogen; D008012:Lidocaine; D000242:Cyclic AMP; D003042:Cocaine; D005947:Glucose; D002118:Calcium; D004837:Epinephrine