title: Differential effects of K(ATP) channel blockers on [(3)H]-noradrenaline overflow after short- and long-term exposure to (+)-oxaprotiline or desipramine.
abstract: To test whether prolonged uptake blockade can lead to changes in the function of ATP-dependent potassium (K(ATP)) channels we investigated in rat neocortex slices the effects of K(ATP) channel blockers on electrically evoked [(3)H]-noradrenaline ([(3)H]-NA) overflow after short- (45 min) and long-term (210 min) exposure to the NA uptake blockers (+)-oxaprotiline or desipramine (1 microM each). The K(ATP) channel blocker glibenclamide (1 micro M) increased the evoked [(3)H]-NA overflow by 42% after short-term uptake inhibition. This effect was confirmed by tolbutamide and glipizide, two other K(ATP) channel antagonists. The evoked [(3)H]-NA overflow was enhanced by 73% following short-term uptake blockade (15 min) and by 110% following long-term blockade (180 min). After long-term blockade (210 min), however, glibenclamide failed to further enhance the overflow of [(3)H]-NA. The alpha(2)-autoreceptor-mediated feedback control was not involved in the glibenclamide-induced increase in [(3)H]-NA overflow after short-term uptake blockade or in the increase in [(3)H]-NA overflow due to long-term uptake blockade per se. The Na(+)/K(+)-ATPase inhibitor ouabain diminished the glibenclamide-induced enhancement of [(3)H]-NA overflow after short-term uptake blockade, suggesting that an operative Na(+)/K(+)-ATPase is the prerequisite of activation of K(ATP) channels. These results suggest that short-term uptake blockade activates the Na(+)/K(+)-ATPase, thereby reducing intracellular ATP which allows transient opening of K(ATP) channels. Activation of the Na(+)/K(+)-ATPase may increase the Na(+) gradient, probably over the membrane of noradrenergic nerve terminals. The resulting hyperpolarisation leads to inhibition of the evoked overflow which can be reversed, i.e. enhanced, by K(ATP) channel blockers. In contrast, longer lasting uptake blockade seems to reduce the activity of the Na(+)/K(+)-ATPase and hence the consumption of ATP. As a consequence, reduced Na(+) and K(+) gradients may facilitate transmitter release. Closure of K(ATP) channels by accumulating ATP may further promote membrane depolarisation and transmitter release. The unexpected effect of longer exposure to uptake blockers could be somehow related to the clinical time latency of the antidepressant efficacy of monoamine uptake blockers.
authors.affiliation: Sektion Klinische Neuropharmakologie, Neurologische Universitätsklinik Freiburg, Breisacherstrasse 64, 79106, Freiburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Eckhardt
authors.forename: Patrick
authors.initials: P
authors.lastname: Roth
authors.forename: Thomas
authors.initials: T
authors.lastname: Günter
authors.forename: Sascha
authors.initials: S
authors.lastname: Schmidt
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Feuerstein
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017660:Autoreceptors / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology; D003891:Desipramine / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008376:Maprotiline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D013997:Time Factors
chemical_list: D000316:Adrenergic alpha-Agonists; D000928:Antidepressive Agents; D017660:Autoreceptors; D026902:Potassium Channel Blockers; D018341:Receptors, Adrenergic, alpha-2; D008376:Maprotiline; C027299:hydroxymaprotilin; D000255:Adenosine Triphosphate; D003000:Clonidine; D005905:Glyburide; D003891:Desipramine; D009638:Norepinephrine