Association between remote organ injury and tissue polyamine homeostasis in acute experimental pancreatitis - treatment with a polyamine analogue bismethylspermine.

Experimental pancreatitis is associated with activation of polyamine catabolism. The polyamine analog bismethylspermine (Me(2)Spm) can ameliorate pancreatic injury. We investigated the roles of polyamine catabolism in remote organs during pancreatitis and explored the mechanism of polyamine catabolism by administering Me(2)Spm. Acute pancreatitis was induced by an infusion of 2 or 6% taurodeoxycholate before Me(2)Spm administration. Blood, urine and tissues were sampled at 24 and 72 h to assess multi-organ injury and polyamine catabolism. The effect of Me(2)Spm on mortality in experimental pancreatitis was tested separately. Liver putrescine levels were elevated following liver injury. Me(2)Spm increased the activity of spermidine/spermine N(1)-acetyltransferase (SSAT) and depleted the spermidine, spermine or putrescine levels. Lung putrescine levels increased, and SSAT and spermine decreased following lung injury. Me(2)Spm enhanced the activity of SSAT and decreased the spermidine and spermine levels. Renal injury was manifested as an increase in creatinine or a decrease in urine output. Decreases in kidney SSAT, spermidine or spermine and an increase in putrescine were found during pancreatitis. In the 2% taurodeoxycholate model, Me(2)Spm decreased urine output and raised plasma creatinine levels. Me(2)Spm increased SSAT and decreased polyamines. Excessive Me(2)Spm accumulated in the kidney, and greater amounts were found in the 6% taurodeoxycholate model in which this mortality was not reduced by Me(2)Spm. In the 2% taurodeoxycholate model, Me(2)Spm dose-dependently induced mortality at 72 h. Like pancreatic injury, remote organ injury in pancreatitis is associated with increased putrescine levels. However, Me(2)Spm could not ameliorate multi-organ injury. Me(2)Spm administration was associated with significant renal toxicity and induced mortality, suggesting that the current dose is too high and needs to be modified.