Cocaine-induced changes in perfusion pressure and bile flow in perfused rat livers.

Cocaine produces hepatotoxicity. To study the acute effect of cocaine on the liver, we used the isolated, single-pass perfused rat liver. When perfusion pressure was measured in a constant flow system, a 15-min infusion of cocaine (1.47 mM) increased perfusion pressure (136 +/- 15%), decreased bile flow (61 +/- 5%), and decreased oxygen uptake (82 +/- 5%). The vasoconstriction was concentration-dependent and reversible. The pressure increase elicited by cocaine was not inhibited by the alpha-receptor antagonists phentolamine, prazosin, or yohimbine. These antagonists did inhibit phenylephrine-induced increases in perfusion pressure. Neither serotonin at concentrations up to 1 mM nor lidocaine or procaine in concentrations equimolar to cocaine increased the perfusion pressure. Indomethacin (5 microM), SKF-525A, and chloramphenicol also failed to block vasoconstriction induced by cocaine. High concentrations of cocaine were cholestatic, while concentrations lower than 0.6 mM were choleretic. These results indicate that cocaine-induced vasoconstriction in the liver is not mediated by alpha-receptor activation or prostaglandins and does not require metabolic activation of cocaine. The acute effects of cocaine in the perfused liver are vascular (vasoconstriction) and functional (alteration in bile formation).