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The protein kinase inhibitor 1-(5-isoquinolinylsulfonyl)-2-methyl-piperzine (H-7) prevents and reverses Ca(2+)-mediated injury in isolated rat hepatocyte couplets.

We have recently shown that protein kinase C (PKC) activation induces similar morphological and functional alterations in couplets to that caused by increments of intracellular Ca(2+). Since certain PKC isoforms are activated by Ca(2+), we tested whether the PKC inhibitor H-7 can counteract the alterations induced by this ion in couplets. The Ca(2+) ionophore A23187, which can mobilize Ca(2+) from extracellular and intracellular sources, decreased, in a dose-dependent manner, the percentage of couplets accumulating the fluorescent bile acid analogue cholyl-lysyl-fluorescein (CLF) in their canalicular vacuoles, i.e., in the canalicular vacuolar accumulation test (cVA of CLF), a measure of the overall capability of the couplets to secrete and retain CLF. To a similar extent, A23187 also decreased the percentage of couplets retaining CLF once secreted, i.e., in the canalicular vacuole retention test (cVR of CLF), a measure of tight junctional integrity. ATP (50 microM), another Ca(2+)-elevating compound, altered canalicular function in a similar extent to A23187. All these functional changes were prevented by H-7 in a dose-dependent manner. Canalicular dysfunction was accompanied by bleb formation and extensive redistribution of F-actin from the pericanalicular area to the cell body, which was also fully prevented by H-7; the intracellular Ca(2+) chelator, 1, 2-bis(o-aminophenoxy)-ethene-N,N,N',N'-tetraacetate tetrakis-(acetomethylester), (BAPTA/AM) (20 microM) had virtually the same preventive effects as H-7. Both H-7 and BAPTA/AM not only prevented but also reversed the decrease in cVA of CLF and blebbing induced by A23187. Thus, H-7 can both prevent and reverse Ca(2+)-mediated hepatocellular injury.