title: Epinephrine impairs insulin release by a mechanism distal to calcium mobilization. Similarity to lipoxygenase inhibitors.
abstract: The mechanisms that enable epinephrine (EPI) and lipoxygenase inhibitors to impede insulin secretion are unknown. We examined the possibility that EPI inhibits Ca2+ fluxes as its major mechanism by studying 45Ca efflux from prelabeled, intact rat islets. EPI (2.5 x 10(-7) to 1 x 10(-5) M) inhibited insulin release induced by the influx of extracellular Ca2+ (46 mM K+) or the mobilization of intracellular Ca2+ stores (2 mM Ba2+), but it did not reduce the 45Ca efflux stimulated by either agonist. EPI also nullified insulin release induced by isobutylmethylxanthine or dibutyryl cAMP, with minimal or no effects on 45Ca efflux, and blocked the insulinotropic effects of 12-O-tetradecanoylphorbol-13-acetate (a direct activator of protein kinase C), which is believed primarily to sensitize the exocytotic apparatus to Ca2+ without mobilizing additional Ca2+. Previously we reported that similar effects were induced by inhibitors of pancreatic islet lipoxygenase. In this study, however, pretreatment with either the alpha 2-adrenergic antagonist yohimbine or pertussis toxin did not block the effects of lipoxygenase inhibitors, although either agent did block the effects of EPI. Thus, EPI, via an alpha 2-receptor mechanism, is able to reduce exocytosis largely distal to, or independent of, changes in Ca2+ flux, cAMP formation or its Ca2+-mobilizing action, or generation of protein kinase C activators. Therefore, EPI may reduce the sensitivity of the exocytotic apparatus to Ca2+. Inhibition of islet lipoxygenase may have a similar effect; however, in this case, the effect would have to be unrelated, or distal, to stimulation of alpha 2-receptors.
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002132:Calcium Radioisotopes; D004837:Epinephrine / Q000494:pharmacology*; D005089:Exocytosis / Q000187:drug effects; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors; D037342:Pertussis Toxin; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D002132:Calcium Radioisotopes; D007328:Insulin; D016859:Lipoxygenase Inhibitors; D011942:Receptors, Adrenergic, alpha; D010566:Virulence Factors, Bordetella; D015016:Yohimbine; D003994:Bucladesine; D037342:Pertussis Toxin; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine; D004837:Epinephrine