IMPROVEMENT OF THE ENERGY STATUS OF HYPOXIC HEPATOCYTES BY CALCIUM-CHANNEL BLOCKERS

Isolated hepatocytes from rat liver in primary culture rapidly lost vi ability under hypoxic conditions. Hypoxic injury was significantly dec reased by the calcium channel blockers nifedipine (5 muM) and diltiaze m (10 muM). The concentrations of the inhibitors which afforded maximu m protection also produced the maximum increase in the energy level of the hypoxic. hepatocytes, as evidenced by their ATP, ADP, AMP, and to tal adenine nucleotide content and by their energy charge. The increas ed hypoxic energy level caused by these calcium channel blocking agent s was not due to an increased rate of anaerobic glycolysis; nifedipine did not have any effect on lactate production while diltiazem slightl y decreased its rate. During the first 2 h under hypoxic conditions th e cytosolic Ca2+ concentration remained constant around 100 nM, subseq uently increasing to 400 nM first slowly and later more rapidly. The c alcium channel blockers delayed the Ca2+ increase by about 1 h but wer e without any effect on the rate of this increase. The results suggest that the well-known beneficial effects of calcium channel blockers m hypoxic liver injury are due m large measure to an improved energetic situation of the hepatocytes rather than to the increase in the cytoso lic Ca2+ concentration being blocked.