THE IMPORTANCE OF CALCIUM-RELATED EFFECTS ON ENERGETICS AT HYPOTHERMIA - EFFECTS OF MEMBRANE-CHANNEL ANTAGONISTS ON ENERGY-METABOLISM OF RAT-LIVER

During normothermic metabolism, the active pumping of Ca2+ across the cell membrane, mitochondria, and specialized sequestration organelles accounts for a large proportion of total energy expenditure in the cel l. This study was designed to determine the effects of Ca2+ channel an tagonists (chlorpromazine, verapamil, nifedipine, prenylamine, and nis oldipine) on energy metabolism and levels of glycolytic substrate (glu cose) and anaerobic endproduct (lactate) during cold ischemia in rat l ivers. We hypothesized that if the passive channels were blocked durin g cold ischemia, then the ATP requirement of active ion pumping would be reduced and ATP levels and energy charge ratios would remain higher throughout the ischemic period; thus, viability of the liver would al so be increased after prolonged ischemia. The most positive effect on energy metabolism was observed in the chlorpromazine-treated livers, f ollowed by verapamil treatment. In the chlorpromazine treatment total adenylate (TA) contents were 0.5-1.0 mu mol/g (P < 0.05) higher than t he sham group for most of the 24-h time course. Energy charge (EC) rat ios were 0.05-0.07 higher than sham values up to 4-10 h ischemia. Vera pamil treatment was less effective, but still exhibited positive effec ts on TA levels at several rime points (20 min, 10 h, and 24 h) throug hout the entire 24-h period. In both of these groups, TA values by 24 h ischemia were similar to levels at 10 h in the sham group (3.1 mu mo l/g), thus showing a considerable effect in maintaining adenylate leve ls. Despite similar pharmacological antagonist activities, ATP levels in the nifedipine, prenylamine, and nisoldipine treatment groups were 1.0-1.5 mu mol/g (P < 0.05) less than the corresponding sham group (wi thout Ca2+ antagonists) over the first 1 h ischemia. The decreases in high energy adenylate levels were reflected in lower EC ratios in thes e three groups; values were 0.06-0.17 (P < 0.05) lower than correspond ing sham values. Finally, it was an unexpected finding that the sham i njection (0.5 mg/kg ethanol + PEG400) resulted in the sustained elevat ion of ATP, total adenylates, and EC values over the first h; EC ratio s remained at initial (t = 0) values (EC = 0.71 +/- 0.01) up to 1 h. ( C) 1995 Academic Press, Inc.