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1 Department of Internal Medicine, The University of Michigan Medical School, Ann Arbor, MI, USA; Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI, USA
2 Department of Internal Medicine, The University of Michigan Medical School, Ann Arbor, MI, USA
* To whom correspondence should be addressed. E-mail: mdimagno{at}umich.edu.
Nitric oxide (NO) and NO synthase (NOS) play controversial roles in pancreatic secretion. NOS inhibition reduces CCK-stimulated in vivo pancreatic secretion, but it is unclear which NOS isoform is responsible because NOS inhibitors lack specificity and three NOS isoforms exist: neuronal- (nNOS), endothelial- (eNOS) and inducible- (iNOS). Mice having individual NOS gene deletions were used to clarify the NOS species and cellular interactions influencing pancreatic secretion. In vivo secretion was performed in anesthetized mice by collecting extra-duodenal pancreatic duct juice and measuring protein output. Non-selective NOS blockade was induced with L-NNA (10 mg/kg). In vivo pancreatic secretion was maximal at 160 pmol/kg/h CCK-8 and was reduced by NOS blockade (45%) and eNOS deletion (44%). Secretion was unaffected by iNOS deletion, but increased by nNOS deletion (91%). To determine whether the influence of NOS on secretion involved non-acinar events, in vitro CCK-8 stimulated secretion of amylase from isolated acini was studied and found to be unaltered by NOS blockade and eNOS deletion. The influence of NOS on in vivo secretion was further examined with carbachol. Protein secretion, which was maximal at 100 nmol/kg/h carbachol, was reduced by NOS blockade and eNOS deletion but unaffected by nNOS deletion. NOS blockade by L-NNA had no effect on carbachol-stimulated amylase secretion in vitro. Thus constitutive NOS isoforms can exert opposite effects on in vivo pancreatic secretion. eNOS likely plays a dominant role, since eNOS deletion mimics NOS blockade by inhibiting CCK-8 and carbachol-stimulated secretion, while nNOS deletion augments CCK-8 but not carbachol-stimulated secretion.
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