CALCIUM-CHANNEL BLOCKADE INHIBITS RELEASE OF TNF-ALPHA AND IMPROVES SURVIVAL IN A RAT MODEL OF ACUTE-PANCREATITIS

Tumor necrosis factor-alpha (TNF alpha) has been implicated as one of the numerous Likely mediators of the systemic complications of acute p ancreatitis. Recent suggestions that calcium (Ca2+) acts as a signal n ot only for TNF alpha release but also for TNF alpha action at distant sites led us to hypothesize that the calcium channel blocker diltiaze m could inhibit TNF alpha release in acute pancreatitis, ameliorating the severity of the disease and improving overall survival. A rat mode l of acute pancreatitis induced by retrograde ductal infusion of bile was used for two experiments (n = 120). Experiment 1 was designed to d etermine the effects of calcium channel blockade using diltiazem on th e severity of pancreatitis as measured by changes in biochemistry, pat hology, and serum TNF alpha levels. In experiment 2, effects of calciu m channel blockade on animal survival were measured over 72 h. Calcium channel blockade was associated with a significant reduction in serum TNF alpha levels as well as amelioration of pancreatitis by biochemic al and pathological criteria. Overall survival from bile-induced pancr eatitis was dramatically improved in rats pretreated with diltiazem (8 0%) compared to untreated animals (40%). Our data suggest that calcium channel blockade is associated with TNF alpha inhibition and improved outcome in a rat model of acute pancreatitis.