title: Secretagogue-stimulated pancreatic secretion is differentially regulated by constitutive NOS isoforms in mice.
abstract: 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 extraduodenal pancreatic duct juice and measuring protein output. Nonselective NOS blockade was induced with N(omega)-nitro-L-arginine (L-NNA; 10 mg/kg). In vivo pancreatic secretion was maximal at 160 pmol.kg(-1).h(-1) CCK octapeptide (CCK-8) and was reduced by NOS blockade (45%) and eNOS deletion (44%). Secretion was unaffected by iNOS deletion but was increased by nNOS deletion (91%). To determine whether the influence of NOS on secretion involved nonacinar 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. Influence of NOS on in vivo secretion was further examined with carbachol. Protein secretion, which was maximal at 100 nmol.kg(-1).h(-1) 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, because eNOS deletion mimics NOS blockade by inhibiting CCK-8 and carbachol-stimulated secretion, whereas nNOS deletion augments CCK-8 but not carbachol-stimulated secretion.
authors.affiliation: Department of Internal Medicine, The University of Michigan Medical School, 1500 E. Medical Center Dr., 3912 Taubman Center, Ann Arbor, MI 48109-0362, USA. mdimagno@umich.edu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: DiMagno
authors.forename: Yibai
authors.initials: Y
authors.lastname: Hao
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tsunoda
authors.forename: John A
authors.initials: JA
authors.lastname: Williams
authors.forename: Chung
authors.initials: C
authors.lastname: Owyang
mesh_terms: D000681:Amylases / Q000378:metabolism; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine / Q000494:pharmacology; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D012844:Sincalide / Q000494:pharmacology; D013268:Stimulation, Chemical
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011506:Proteins; D019335:Nitroarginine; D002217:Carbachol; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D000681:Amylases; D012844:Sincalide