Cocaine and Lidocaine Interfere with Epinephrine-Induced Changes in Intracellular Calcium Concentration and Glucose Efflux from Rat Hepatocytes

Abstract

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.