Mechanisms of the Hepatoprotective Effect of Nitrendipine in the Isolated Perfused Cat Liver

Abstract

Nitrendipine, at a concentration of 500 ng/ml, was added to the perfusate of isolated perfused cat livers to determine if this calcium channel antagonist could protect against the cytolytic and vascular degenerative effects of hepatic hypoxia. In untreated hypoxic perfused livers, liver perfusion pressure increased 49 ± 7% (p < 0.01) over 150 min compared with only. a 7 ± 3% increase in normoxic control livers. In addition, hypoxia increased lactic acid dehydrogenase (LDH) activity in the perfusate from 2 ± 1 to 13 ± 2 U/ml in hypoxic livers, and cathepsin D activity increased from 0.6 ± 0.3 to 10.2 ± 1.1 U/ml after 150 min of hypoxia. Perfusate-free amino-nitrogen concentrations also increased 3.5-fold. Nitrendipine markedly attenuated all of these increases. Perfusion pressure rose by only 19 ± 5%, LDH activity to only 3 ± 1 U/ml, cathepsin D activity to only 5 ± 0.5 U/ml, and amino-nitrogen concentration only increased twofold. All these changes are significantly lower than in the untreated hypoxic livers (p < 0.02 to p < 0.01). Nitrendipine also exerted direct lysosomal stabilizing effects in liver lysosomal suspensions and an antivasoconstrictor effect in isolated strips of hepatic portal vein. Thus, nitrendi-pine exerts direct membrane stabilizing and antivasoconstrictor effects that may help explain its hepatoprotective actions in the intact liver.