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Naunyn Schmiedebergs Arch Pharmacol. 2003 Feb;367(2):168-75. Epub 2003 Jan 18.
Differential effects of K(ATP) channel blockers on [(3)H]-noradrenaline overflow after short- and long-term exposure to (+)-oxaprotiline or desipramine.

Eckhardt K, Roth P, Gunter T, Schmidt S, Feuerstein TJ.

Sektion Klinische Neuropharmakologie, Neurologische Universitatsklinik Freiburg, Breisacherstrasse 64, 79106, Freiburg, Germany.

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.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12595958&dopt=Abstract

fmmu.edu.cn

To investigate the relaxation effect and underlying mechanism of U50,488H (a selective kappa-opioid receptor agonist) on aorta in the rat, isolated aortic ring was perfused and the tension of the vessel was measured. It was shown: (1) kappa-opioid receptor stimulation with U50,488H relaxed rat aorta dose-dependently; (2) the relaxation effect of U50,488H on aorta was partially endothelium-dependent; (3) the relaxation effect of U50,488H was significantly attenuated in the presence of glybenclamide and glipizide, two ATP-sensitive K(+) channel (K(ATP)) blockers; and (4) the relaxation effect of U50,488H on vessel bore no relationship to muscarinic-receptor, beta-adrenoceptor, prostaglandin and nitric oxide (NO). These results indicate that kappa-opioid receptor stimulation with U50,488H relaxes the aortic artery at least partially via K(ATP) channel in the rat.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12598942&dopt=Abstract [PubMed - in process]




Mol Pharmacol. 1999 Jun;55(6):1060-6.
Stoichiometry of sulfonylurea-induced ATP-sensitive potassium channel closure.

Dorschner H, Brekardin E, Uhde I, Schwanstecher C, Schwanstecher M.

Institut fur Pharmakologie und Toxikologie, Universitat Braunschweig, Mendelssohnstrabetae 1, 38106 Braunschweig, Germany.

Hypoglycemic sulfonylureas (e.g., glibenclamide, glipizide, and tolbutamide) exert their stimulatory effect on excitatory cells by closure of ATP-sensitive potassium (KATP) channels. These channels are heteromultimers composed with a 4:4 stoichiometry of an inwardly rectifying K+ channel (KIR) subunit 6.x plus a sulfonylurea receptor (SUR). SUR1/KIR6.2 reconstitutes the neuronal/pancreatic beta-cell channel, whereas SUR2A/KIR6.2 and SUR2B/KIR6.1 (or KIR6.2) are proposed to reconstitute the cardiac and the vascular smooth muscle-type KATP channels, respectively. SUR2A and SUR2B are splice variants of a single gene differing only in their C-terminal 42 amino acids. Affinities of sulfonylureas for rat SUR2A, rat or human SUR2B, and a SUR2 chimera containing the C-terminal 42 amino acids of SUR1 did not differ significantly, implying that the C terminus does not form part of the binding pocket. Consistent with these findings, reconstituted SUR2A/KIR6.2 and SUR2B/KIR6.2 channels revealed similar sensitivities for glibenclamide and tolbutamide. Dissociation constants of sulfonylureas for SUR2A and SUR2B were 10- to 400-fold higher than for SUR1, however, amazingly the benzoic acid derivative meglitinide did not show lower affinity for SUR2 isoforms. Potencies of glibenclamide, glipizide, tolbutamide, and meglitinide to inhibit activity of SUR1/KIR6.2 and SUR2B/KIR6.2 channels were 3- to 6-fold higher than binding affinities of these drugs with concentration-inhibition relations being significantly steeper (Hill coefficients 1.23-1.32) than binding curves (Hill coefficients 0.93-1.06). The data establish that the C terminus of SURs does not affect sulfonylurea affinity and sensitivity. We conclude that occupation of one of the four SUR sites per channel complex is sufficient to induce KATP channel closure.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10347249&dopt=Abstract












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