PANCREATIC-ISLET CELLS ARE HIGHLY SUSCEPTIBLE TOWARDS THE CYTOTOXIC EFFECTS OF CHEMICALLY GENERATED NITRIC-OXIDE

To compare the sensitivity of different mammalian cell types towards t he cytotoxic action of nitric oxide, freshly isolated rat pancreatic i slet cells, hepatocytes, resident and activated macrophages, cultured aortic endothelial cells and two murine tumor cell lines were tested f or susceptibility towards exogenous nitric oxide. As sources for nitri c oxide nitroprusside, S-nitroso-N-acetyl-penicillamine and the sydnon imine-derivative SIN-1 were used. These generate nitric oxide by diffe rent mechanisms and kinetics. Among the cell types tested we found lar ge differences in their susceptibility towards the three nitric oxide donors. Islet cells were by far the most sensitive of the investigated cells and were completely lysed by all three nitric oxide donors. Hep atocytes and endothelial cells were sensitive towards nitroprusside bu t relatively resistant towards toxicity of SIN-1 and S-nitroso-N-acety l-penicillamine. Activated and resident macrophages were lysed by SIN- 1, whereas high concentrations of nitroprusside and S-nitroso-N-acetyl -penicillamine led to partial cell lysis only. The tumor cell lines we re both lysed by SIN-1 but showed differences in their sensitivity tow ards S-nitroso-N-acetyl-penicillamine. Nitric oxide, which is produced in large amounts during infection and inflammation, may play an impor tant role in the destruction of islet cells during insulitis leading t o insulin-dependent diabetes mellitus.