Garhart C A, Anwer M S, Shuster L
Department of Pharmacology, Tufts University School of Medicine, Boston, MA 02111.
Biochem Pharmacol. 1989 Jul 1;38(13):2139-45. doi: 10.1016/0006-2952(89)90068-3.
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).
可卡因会产生肝毒性。为研究可卡因对肝脏的急性影响，我们使用了离体的单通道灌流大鼠肝脏。在恒流系统中测量灌注压力时，输注15分钟的可卡因（1.47 mM）会使灌注压力升高（136±15%），胆汁流量减少（61±5%），氧摄取量减少（82±5%）。血管收缩呈浓度依赖性且可逆。可卡因引起的压力升高不受α受体拮抗剂酚妥拉明、哌唑嗪或育亨宾的抑制。这些拮抗剂确实能抑制去氧肾上腺素引起的灌注压力升高。浓度高达1 mM的血清素以及与可卡因等摩尔浓度的利多卡因或普鲁卡因均未使灌注压力升高。吲哚美辛（5 μM）、SKF - 525A和氯霉素也未能阻断可卡因诱导的血管收缩。高浓度的可卡因具有胆汁淤积作用，而浓度低于0.6 mM时则具有利胆作用。这些结果表明，可卡因在肝脏中诱导的血管收缩不是由α受体激活或前列腺素介导的，也不需要可卡因的代谢激活。可卡因对灌流肝脏的急性影响是血管性的（血管收缩）和功能性的（胆汁形成改变）。
