Intrahepatic flow disturbance: possibility of a hidden cause of drug toxicity

The liver has an intricate microvascular system that allows homogenous perfusion throughout the organ. However, the regulatory mechanisms of intrahepatic circulation are still unclear, and the effects of drugs on this system have rarely been reported. Oxethazaine, a topical anesthetic, was incidentally found to induce a consistent increase in portal pressure in the isolated perfused rat liver, which led us to characterize this phenomenon. For this, a vital staining method was developed to detect microcirculatory alterations in the isolated liver. Using this method, not only vasoconstrictors like endothelin-1, but the drugs oxethazaine and clomipramine, a tricyclic antidepressant, were found to induce flow redistribution to the deeper and hilar portions of the liver with minimal perfusion at the periphery, which was due to a short-circuit flow at the center owing to the constriction of the intrahepatic portal vein branches. Hepatic nerve stimulation also produced a similar flow disturbance. Since the portal pressure increases by these compounds were inhibited by the Rho-kinase inhibitors Y27632 and HA1077, portal vein branches may employ a Rho-kinase-dependent pathway for sustained contraction. However, oxethazaine, clomipramine, and endothelin-1 may activate this pathway differently. The intrahepatic flow disturbance could play a hidden role in drug toxicity of certain drugs.