Nicorandil inhibits degranulation and TNF-alpha release from RBL-2H3 cells.
OBJECTIVE
Nicorandil is a potassium channel opener and nitric oxide (NO) donor, and the hypothesis was tested that these modes of action may inhibit cellular degranulation and release of tumour necrosis factor-alpha (TNF-alpha).


METHODS
TNF-alpha and beta-hexosaminidase secretion were measured from rat basophilic leukemia cells (RBL-2H3) activated via the high affinity IgE receptor with dinitrophenyl-albumin (DNP-A) challenge in the presence of nicorandil. Inhibitors of K+ openers and NO were pre-incubated with the RBL-2H3 cells to determine the principal mode of action.


RESULTS
Nicorandil significantly inhibited the release of TNF-alpha in a dose-dependent manner (p < 0.001, ANOVA) reaching a maximum inhibition of DNP-A 74.1% at 10(-3) M, (p < 0.001). Similarly it inhibited beta-hexosaminidase release (p < 0.001, ANOVA) with maximal inhibition at 10(-3) M (p < 0.001). Other K+ openers did not show this effect. Neither the potassium channel blocker glibenclamide nor the guanylyl cyclase inhibitor, ODQ, could reverse this inhibition, but when added in combination reduced the effect by 47%.


CONCLUSIONS
Nicorandil is able to inhibit degranulation and TNF-alpha release of RBL cells stimulated through the IgE receptor, and requires both the K+ opening and nitric oxide donor activity, which may represent a novel method for inhibiting cytokine release.
Heywood
G J
GJ
Inflammation Research Unit, School of Pathology, Faculty of Medicine, UNSW, Australia.
Thomas
P S
PS
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects*; D002460:Cell Line; D003594:Cytoplasmic Granules / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D004140:Dinitrophenols / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006454:Hemoglobins / Q000494:pharmacology; D007202:Indicators and Reagents; D008407:Mast Cells / Q000187:drug effects / Q000648:ultrastructure; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D020110:Pinacidil / Q000494:pharmacology; D011188:Potassium; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D004140:Dinitrophenols; D004791:Enzyme Inhibitors; D006454:Hemoglobins; D007202:Indicators and Reagents; D020030:Nitric Oxide Donors; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D014409:Tumor Necrosis Factor-alpha; D009536:Niacinamide; D020108:Nicorandil; D009569:Nitric Oxide; D020110:Pinacidil; C035663:SG 209; D001619:beta-N-Acetylhexosaminidases; D006162:Guanylate Cyclase; D011188:Potassium; D005905:Glyburide; D002118:Calcium