title: Nateglinide, but not repaglinide, stimulates growth hormone release in rat pituitary cells by inhibition of K channels and stimulation of cyclic AMP-dependent exocytosis.
abstract: OBJECTIVE
  GH causes insulin resistance, impairs glycemic control and increases the risk of vascular diabetic complications. Sulphonylureas stimulate GH secretion and this study was undertaken to investigate the possible stimulatory effect of repaglinide and nateglinide, two novel oral glucose regulators, on critical steps of the stimulus-secretion coupling in single rat somatotrophs.
  
  
  METHODS
  Patch-clamp techniques were used to record whole-cell ATP-sensitive K(+) (K(ATP)) and delayed outward K(+) currents, membrane potential and Ca(2+)-dependent exocytosis. GH release was measured from perifused rat somatotrophs.
  
  
  RESULTS
  Both nateglinide and repaglinide dose-dependently suppressed K(ATP) channel activity with half-maximal inhibition being observed at 413 nM and 13 nM respectively. Both compounds induced action potential firing in the somatotrophs irrespective of whether GH-releasing hormone was present or not. The stimulation of electrical activity by nateglinide, but not repaglinide, was associated with an increased mean duration of the action potentials. The latter effect correlated with a reduction of the delayed outward K(+) current, which accounts for action potential repolarization. The latter effect had a K(d) of 19 microM but was limited to 38% inhibition. When applied at concentrations similar to those required to block K(ATP) channels, nateglinide in addition potentiated Ca(2+)-evoked exocytosis 3.3-fold (K(d)=3 microM) and stimulated GH release 4.5-fold. The latter effect was not shared by repaglinide. The stimulation of exocytosis by nateglinide was mimicked by cAMP and antagonized by the protein kinase A inhibitor Rp-cAMPS.
  
  
  CONCLUSIONS
  Nateglinide stimulates GH release by inhibition of plasma membrane K(+) channels, elevation of cytoplasmic cAMP levels and stimulation of Ca(2+)-dependent exocytosis. By contrast, the effect of repaglinide was confined to inhibition of the K(ATP) channels.
authors.affiliation: Novo Nordisk A/S, Novo Alle, DK-2880 Bagsvaerd, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Gromada
authors.forename: Krister
authors.initials: K
authors.lastname: Bokvist
authors.forename: Marianne
authors.initials: M
authors.lastname: Høy
authors.forename: Hervør L
authors.initials: HL
authors.lastname: Olsen
authors.forename: Per
authors.initials: P
authors.lastname: Lindström
authors.forename: Birgit S
authors.initials: BS
authors.lastname: Hansen
authors.forename: Carsten F
authors.initials: CF
authors.lastname: Gotfredsen
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.forename: Mads Krogsgaard
authors.initials: MK
authors.lastname: Thomsen
mesh_terms: D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003510:Cyclohexanes / Q000494:pharmacology*; D051668:Delayed Rectifier Potassium Channels; D005089:Exocytosis / Q000187:drug effects; D013006:Growth Hormone / Q000378:metabolism*; D013007:Growth Hormone-Releasing Hormone / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D000077715:Nateglinide; D018408:Patch-Clamp Techniques; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002219:Carbamates; D003510:Cyclohexanes; D051668:Delayed Rectifier Potassium Channels; D007004:Hypoglycemic Agents; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D000077715:Nateglinide; D010649:Phenylalanine; C072379:repaglinide; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011188:Potassium; D002118:Calcium