Pharmacological inhibition of nitric oxide synthase (NOS) or enhancement of nitric oxide (NO) in experimental acute pancreatitis (AP) has yielded mixed results, in part because three NOS isoforms exist: neuronal- (nNOS), endothelial- (eNOS) and inducible- (iNOS). Our preliminary data clarifies the role of NO during the initiation of AP and shows that pharmacologic NOS blockade and eNOS deletion, but not nNOS or iNOS deletion, enhance the initiation of an in vivo caerulein hyperstimulation model of AP. By contrast pharmacologic NOS blockade during in vitro caerulein AP has no effect on conversion of intraacinar trypsinogen to trypsin, a hallmark of AP, suggesting that eNOS-derived NO arises from a non-acinar source and/or acts on a non-acinar target. Our data also suggests that upregulation of endothelial eNOS by Simvastatin and Cytochalasin D may attenuate in vivo caerulein AP. We hypothesize that eNOS-derived NO indirectly inhibits initiation of AP by enhancing pancreatic microvascular perfusion. We plan to confirm whether eNOS-derived NO acts on a non-acinar target by using an in vitro caerulein model of AP in isolated eNOS KO acini vs. WT acini. Secondly we plan to assess differences in pancreatic perfusion between eNOS KO mice and WT mice during AP using dye-labeled microspheres. Third we plan to determine whether the enhanced initiation of in vivo AP in eNOS KO mice (compared with WT mice) may be normalized by augmenting pancreatic perfusion with NO donors. Fourth we plan to upregulate eNOS pharmacologically in WT and eNOS KO mice to assess for protection against in vivo caerulein AP. We hope that this study may further clarify the role of NO in the pathogenesis of AP.
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