Calcium channel blockade inhibits release of TNFα and improves survival in a rat model of acute pancreatitis

Tumor necrosis factor-α (TNF-α) has been implicated as one of the numerous likely mediators of the systemic complications of acute pancreatitis. Recent suggestions that calcium (Ca2+) acts as a signal not only for TNFα release but also for TNFα action at distant sites led us to hypothesize that the calcium channel blocker diltiazem could inhibit TNFα release in acute pancreatitis, ameliorating the severity of the disease and improving overall survival. A rat model of acute pancreatitis induced by retrograde ductal infusion of bile was used for two experiments (n = 120). Experiment 1 was designed to determine the effects of calcium channel blockade using diltiazem on the severity of pancreatitis as measured by changes in biochemistry, pathology, and serum TNFα levels. In experiment 2, effects of calcium channel blockade on animal survival were measured over 72 h. Calcium channel blockade was associated with a significant reduction in serum TNFα levels as well as amelioration of pancreatitis by biochemical and pathological criteria. Overall survival from bile-induced pancreatitis was dramatically improved in rats pretreated with diltiazem (80%) compared to untreated animals (40%). Our data suggest that calcium channel blockade is associated with TNFα inhibition and improved outcome in a rat model of acute pancreatitis.