title: Inhibition of insulin secretion from rat pancreatic islets by dexmedetomidine and medetomidine, two sedatives frequently used in clinical settings.
abstract: The aim of this study was to determine whether dexmedetomidine (DEX) and medetomidine (MED), α2-adrenergic agonists clinically used as sedatives, influence insulin secretion from rat pancreatic islets. Islets were isolated from adult male Wistar rats after collagenase digestion. Static incubation was used to determine effects of DEX or MED on insulin secretion and ionic-channel currents of β-cells. Results indicate that both drugs dose-dependently inhibit insulin secretion, DEX more potently than MED. The inhibitory effects were attenuated by addition of yohimbine or by pretreatment of rats with pertussis toxin (PTX). 10 nM DEX decreased the current amplitude of voltage-dependent Ca2+ channels, but this did not occur when the N-type Ca2+ channel blocker ω-conotoxin was added. In the presence of tetraethylammonium, a classical voltage-gated K+ channel (Kv channel) blocker, the magnitude of inhibition of insulin secretion by MED was reduced. However, when tolbutamide, a specific blocker of the ATP-sensitive K+ channel (KATP channel), was present, the magnitude of MED inhibition of insulin secretion was not influenced, suggesting that Kv-channel activity alteration, but not that of KATP channels, is involved in MED-associated insulin secretory inhibition. The Kv-channel currents were increased during 1 nM MED exposure at membrane potentials ranging from -30 mV to -10 mV, where action potentials were generated in response to glucose stimulation. These results indicate that DEX and MED inhibit insulin secretion through an α2-adrenoceptor and PTX-sensitive GTP-binding protein pathway that eventually involves Kv channel activation and Ca2+ channel inhibition.
authors.affiliation: Division of Anesthesiology, Second Department of General Medicine, Saitama Medical Center, Jichi Medical University School of Medicine, Omiya 330-8503, Japan.
authors.forename: Shiho Yamato
authors.initials: SY
authors.lastname: Kodera
authors.forename: Masashi
authors.initials: M
authors.lastname: Yoshida
authors.forename: Katsuya
authors.initials: K
authors.lastname: Dezaki
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yada
authors.forename: Takanori
authors.initials: T
authors.lastname: Murayama
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kawakami
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kakei
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D020927:Dexmedetomidine / Q000009:adverse effects* / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000502:physiology; D006993:Hypnotics and Sedatives / Q000009:adverse effects* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D007329:Insulin Antagonists; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020926:Medetomidine / Q000009:adverse effects* / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology; D019789:Tetraethylammonium / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology; D020960:omega-Conotoxins / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D006993:Hypnotics and Sedatives; D007328:Insulin; D007329:Insulin Antagonists; D024642:Potassium Channels, Voltage-Gated; D018341:Receptors, Adrenergic, alpha-2; D020960:omega-Conotoxins; D015016:Yohimbine; D019789:Tetraethylammonium; D020927:Dexmedetomidine; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D020926:Medetomidine