Intrahepatic flow disturbance by clomipramine in the isolated perfused rat liver

Intrahepatic flow disturbance may have important pharmacological and toxicological significance. However, apart from pathological conditions, flow disturbance by drugs has received little attention. In the isolated perfused rat liver (IPRL), we found that infusion of tricyclic antidepressants increased portal perfusion pressure (PP) with a coincidental decrease in oxygen uptake at concentrations of 3-30 microM; the order of potency was clomipramine > amitriptyline > imipramine approximately nortriptyline >> desipramine. The characteristics of clomipramine action were as follows: (1) The extrahepatic portal vein was much less sensitive to clomipramine than the IPRL. (2) Changes in PP and oxygen uptake required Ca(2+) in the perfusate and were inhibited by papaverine, staurosporine, sodium nitroprusside and indomethacin. (3) Compared with endothelin-1, clomipramine produced a greater decrease in the ratio of oxygen uptake/PP together with a greater overflow of loaded indocyanine green for an increase in PP by about 2 cm H(2)O. (4) Vital staining with trypan blue and rhodamine 6G and histological examinations revealed that 3-10 microM clomipramine produced marked flow redistribution due to the constriction of portal vein branches. Portal flow was short-circuited to the hepatic vein at a deeper and hilar portion of the liver, with minimal perfusion of the periphery. These results demonstrate an example of drug-induced intrahepatic flow disturbance in vitro. Its contribution to the development of toxicity in vivo remains to be studied.