Yasusuke Masuda (1), Tohru Yoshizawa (1), Masanobu Ozaki (1) and Toshimitsu Tanaka (2)
(1) Division of Toxicology, Niigata College of Pharmacy, Niigata 950-21, Japan (2) Drug Development and Research Laboratories, Hoechst Japan Ltd., Kawagoe, Saitama 350-11, Japan
Abstract: Alteration of hepatic microcirculation and its effects on hepatic metabolism were examined using oxethazaine (OXZ). The infusion of OXZ into isolated perfused livers rapidly increased the portal perfusion pressure (PP) and inhibited oxygen (O2) uptake, which was followed by a decrease in tissue ATP content and an increase in lactate, pyruvate and glucose release into the perfusate. P-450-dependent reductive drug metabolism was enhanced by OXZ, whereas oxidative drug metabolism was suppressed, and this was accompanied by a decrease in substrate uptake. During OXZ infusion, a time delay between the inhibition of O2 uptake and the release of cellular and xenobiotic metabolites was observed. The actions of OXZ required Ca2+. It is unlikely that the inhibition of O2 uptake is due to the inhibition of cellular respiration. The PP increase induced by OXZ was inhibited by papaverine, but not by prazosin, sodium nitroprusside and verapamil, whereas all of these vasodilators were effective against norepinephrine. Under retrograde perfusion, the PP increase by OXZ was abolished, but norepinephrine, uridine 5'-triphosphate, angiotensin II and endothelin 1 were still effective. The extrahepatic portal vein preparation contracted at high concentrations of OXZ. The results suggest that OXZ acts differently from other known vasoconstrictors and possibly narrows hepatic sinusoids to reduce the rate of substance exchange between the sinusoids and hepatocytes, including a reduction in O2 extraction.
Oxethazaine, Perfused rat liver, Metabolic effect, Hemodynamic effect,
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