Influence of K+ channel openers on interferon-gamma dependent immune response in experimental allergic neuritis (EAN).
We examined the influence of the K+ channel opening drugs BRL 38227, pinacidil and diazoxide on cellular immune response and clinical course of experimental allergic neuritis (EAN) actively induced in Lewis rats by bovine peripheral myelin (BPM). T cell functions of EAN lymph node cells were assessed by measurement of proliferation and by counting of interferon-gamma secreting cells (IFN-gamma sc) in response to the specific antigen BPM and the T cell mitogen phytohemagglutinin (PHA). BRL 38227 and diazoxide at concentrations of 10(-5)M-10(-6)M and pinacidil at concentrations of 10(-5)M-10(-7)M enhanced the proliferative response to both BPM and PHA. The number of IFN-gamma sc was suppressed by the K+ channel openers in the same concentration range. There was a tendency of stronger suppression of cultures with high numbers of BPM-reactive IFN-gamma sc than of cultures with low numbers of BPM-reactive IFN-gamma sc. The applied K+ channel openers are primarily acting on ATP-sensitive K+ channels, which have not been found in T cells so far. The drugs may, therefore, exert non-selective effects on conventional voltage- and/or Ca(++)-dependent channels of T cells. A first trial with in vivo administration of 2.5 mg/kg x day of the drugs resulted in more severe neurological deficits in the early phase of EAN with BRL 38227, whereas pinacidil and diazoxide had no significant effects.
Karolinska Institute, Department of Neurology, Huddinge University Hospital, Sweden.
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D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D019806:Cromakalim; D003981:Diazoxide / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism / Q000502:physiology*; D015640:Ion Channel Gating / Q000187:drug effects*; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation / Q000187:drug effects; D009444:Neuritis, Autoimmune, Experimental / Q000276:immunology*; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew
D001578:Benzopyrans; D006146:Guanidines; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D020110:Pinacidil; D007371:Interferon-gamma; D003981:Diazoxide