Protective action of calcium entry blockers in endotoxin shock

Calcium entry blockers (CEBs) have been reported to protect against cellular necrosis caused by experimental ischemia and the beneficial effect has been related to prevention of ischemia-induced calcium overload by the CEBs. Since circulatory shock can be expected to produce generalized tissue hypoxia, the possibility that CEBs might be beneficial in shock produced by endotoxin was investigated. In control male Wistar rats, a 10-mg/kg dose of E. coli endotoxin (Difco 0127:B8) produced a fall in blood pressure and a transient increase followed by a progressive slowing of the heart rate. Mortality 48 hours after endotoxin (10 mg/kg) was 84%. The calcium entry blockers (CEBs) verapamil, nitrendipine, and nilvadipine [corrected], administered i.v. 15 min before endotoxin, produced a dose-dependent reduction in mortality. The CEBs were less effective when given as post-treatment (15 to 30 min after endotoxin). Measurements of total tissue and mitochondrial calcium levels in control rats revealed that endotoxin did not produce an increase in the calcium content of heart, lung, pancreas, small intestine, kidney, and aorta. Since increased cellular calcium levels did not occur in response to endotoxin, the protection induced by CEBs in endotoxin shock does not appear to be related to prevention of calcium overload; however, the possibility that the CEBs may beneficially prevent an excessive accumulation of calcium in discrete cells or intracellular compartments (which may not be detected by our methods) cannot be excluded.