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PubMed1996

Functional hyperemia in striated muscle is reduced following blockade of ATP-sensitive potassium channels.

This study was designed to determine the role of ATP-sensitive potassium channels in the control of the arteriolar diameter during functional hyperemia. The hamster cremaster muscle was prepared for in vivo microscopy and stimulated electrically for 1 min before and after topical application of 10 microM glibenclamide to block ATP-sensitive potassium channels. Glibenclamide treatment resulted in a small, though not significant, decrease in resting arteriolar diameter (P > 0.05). Glibenclamide almost completely inhibited the vasodilation of the first-order and the third-order arterioles in response to topical application of 1 microM cromakalim (P < 0.05). During muscle stimulation, the first-order arterioles dilated from 69 +/- 3 to 89 +/- 3 microns (n = 7), and the third-order arterioles dilated from 16 +/- 1 to 35 +/- 2 microns (n = 7). In this set of experiments glibenclamide treatment resulted in a significant decrease (approximately 4 microns) in the resting diameters of the first-order arterioles, but had no significant effect on the resting diameter of third-order arterioles. Glibenclamide treatment significantly attenuated the vasodilation associated with muscle contraction to 72 +/- 3 and to 21 +/- 3 microns, respectively (P < 0.05). These results suggests that ATP-sensitive potassium channels are an important mediator in the vasodilatory response to muscle stimulation in the hamster cremaster muscle.

Adenosine Triphosphate↗
PubMed1991

A bursting potassium channel in isolated cholinergic synaptosomes of Torpedo electric organ.

1. Pinched-off cholinergic nerve terminals (synaptosomes) prepared from the electric organ of Torpedo ocelata were fused into large structures (greater than 20 microns) using dimethyl sulphoxide and polyethylene glycol 1500, as previously described for synaptic vesicles from the same organ. 2. The giant fused synaptosomes were easily amenable to the patch clamp technique and 293 seals with a resistance greater than 4 G omega were obtained in the 'cell-attached' configuration. In a large fraction of the experiments, an 'inside-out' patch configuration was achieved. 3. Several types of unitary ionic currents were observed. This study describes the most frequently observed single-channel activity which was found in 247 out of the 293 membrane patches (84.3%). 4. The single-channel current-voltage relation was linear between -60 and 20 mV and showed a slope conductance of 23.8 +/- 1.3 pS when the pipette contained 350-390 mM-Na+ and the bath facing the inside of the synaptosomal membrane contained 390 mM-K+. 5. From extrapolated reversal potential measurements, it was concluded that this channel has a large selectivity for K+ over Na+ (70.4 +/- 11.5, mean +/- S.E.M.). Chloride ions are not transported significantly through this potassium channel. 6. This potassium channel has a low probability of opening. The probability of being in the open state increases upon depolarization and reaches about 1% when the inside of the patch is 20 mV positive compared to the pipette side. 7. The mean channel open time increases with depolarization; thus the product current x time (= charge) also increases upon depolarization, showing properties of an outward rectifier. 8. The potassium channel in the giant synaptosome membrane has a bursting behaviour. Open-time distribution, closed-time distribution and a Poisson analysis indicate that the minimal kinetic scheme requires one open state and three closed states.

Animals↗
PubMed2006

Randomized, double-blind, placebo-controlled crossover pilot study of a potassium channel blocker in patients with septic shock.

BACKGROUND: Marked potassium efflux prevents calcium entry into vascular smooth muscle cells and may be responsible for the "vasoplegia" of septic shock. Blockade of adenosine triphosphate (ATP)-sensitive potassium channels restores vascular tone in animal studies of septic shock. The effect of such potassium channel blockade has not been previously studied in humans. OBJECTIVE: To test whether the administration of an ATP-sensitive potassium (K(ATP)) channel blocker restores norepinephrine responsiveness in patients with septic shock. DESIGN: Randomized, double-blind, placebo-controlled crossover pilot study. SETTING: Intensive care unit of a university hospital. PATIENTS: Ten patients with septic shock requiring invasive hemodynamic monitoring and infusion of norepinephrine to maintain adequate mean arterial pressure. INTERVENTION: In addition to standard therapy, patients were randomized to initially receive either the K(ATP) channel blocker glibenclamide (20 mg) or placebo. Then, after 24 hrs, each patient crossed over to receive the alternative therapy. MEASUREMENTS AND MAIN RESULTS: After the administration of the K(ATP) channel blocker glibenclamide, median norepinephrine requirements decreased from 13 to 4 microg/min compared with a change from 19 to 7 microg/min after placebo. The two changes represented a decrease of 78.9% and 71.1% in dose, respectively (p = .57, not significant). There were also no significant changes in heart rate, mean arterial blood pressure, and lactate concentration when comparing the study drug with placebo. Glibenclamide, however, induced a significant decrease in median blood glucose concentration (5.4 [inter-quartile range, 4.5-7.0] vs. 7.0 mmol/L [5.2-9.3], p < .0001) compared with placebo and increased the need for parenteral glucose administration. CONCLUSIONS: The K(ATP) channel blocker glibenclamide failed to achieve a greater reduction in norepinephrine dose than placebo in septic shock patients, although it caused a reduced glucose concentration. Our observations suggest that, in such patients, blockade of K(ATP) channels does not have a potent effect on vasomotor tone.

Aged↗
PubMed1994

[Inhibitory effect of berberine on potassium channels in guinea pig ventricular myocytes].

The effects of berberine on potassium channel subtypes were investigated by using patch-clamp whole cell recording techniques. Berberine is known to be effective in lowering blood glucose and ameliorating arrhythmia. Our results indicate that, berberine can prolong action potential duration (APD), decrease IK1 and outward Itail, but showed no effect on IK. In addition, berberine was also shown to antagonize cromakalim (BRL-34915) induced inhibition of APD and the increase of KATP. These suggest that berberine can inhibit voltage- dependent and ATP-sensitive potassium channels. It appears that the mechanisms of antiarrhythmic and antidiabetic action of berberine might be due to its potassium channel blocking effects.

Action Potentials↗
PubMed1991

Psychopharmacological evidence for a role of the ATP-sensitive potassium channel in the substantia nigra of the rat.

Recent evidence suggests that an ATP-sensitive potassium channel is present in the brain. From ligand binding studies it has been inferred that this relatively unfamiliar channel is particularly densely distributed in areas associated with motor control. The aim of this study was thus to examine whether pharmacological agents, specific for the ATP-sensitive channel in other tissues, had effects on a particular motor behaviour associated with the substantia nigra: the effects of microinfusion into the substantia nigra of diverse potassium channel blocking agents were examined on the initiation of circling behaviour in the normal rat. Application of tolbutamide and quinine, but not tetraethylammonium, caused circling behaviour in the presence of a systemically administered challenge of amphetamine. However, in the case of application of tolbutamide, the direction of circling was dependent on whether the site of infusion was in the pars compacta or pars reticulata. On the other hand, the effects of quinine were the same, irrespective of site of application within the substantia nigra, i.e. in the same direction, as seen after injection of tolbutamide into the pars compacta. Quinine and tolbutamide are different chemical species which both, unlike tetraethylammonium, principally block the ATP-sensitive potassium channel. It therefore seems that an ATP-sensitive potassium channel in the pars compacta cells of the substantia nigra could play a selective role in modifying the net activity of the nigrostriatal pathway and hence the control of movement.

Adenosine Triphosphate↗
PubMed2004

Solution structure of Phrixotoxin 1, a specific peptide inhibitor of Kv4 potassium channels from the venom of the theraphosid spider Phrixotrichus auratus.

Animal toxins block voltage-dependent potassium channels (Kv) either by occluding the conduction pore (pore blockers) or by modifying the channel gating properties (gating modifiers). Gating modifiers of Kv channels bind to four equivalent extracellular sites near the S3 and S4 segments, close to the voltage sensor. Phrixotoxins are gating modifiers that bind preferentially to the closed state of the channel and fold into the Inhibitory Cystine Knot structural motif. We have solved the solution structure of Phrixotoxin 1, a gating modifier of Kv4 potassium channels. Analysis of the molecular surface and the electrostatic anisotropy of Phrixotoxin 1 and of other toxins acting on voltage-dependent potassium channels allowed us to propose a toxin interacting surface that encompasses both the surface from which the dipole moment emerges and a neighboring hydrophobic surface rich in aromatic residues.

Amino Acid Sequence↗
PubMed1999

Interactive effects of the GABABergic modulation of calcium channels and calcium-dependent potassium channels in lamprey.

The GABAB-mediated modulation of spinal neurons in the lamprey is investigated in this study. Activation of GABAB receptors reduces calcium currents through both low- (LVA) and high-voltage activated (HVA) calcium channels, which subsequently results in the reduction of the calcium-dependent potassium (KCa) current. This in turn will reduce the peak amplitude of the afterhyperpolarization (AHP). We used the modulatory effects of GABAB receptor activation on N-methyl-D-aspartate (NMDA)-induced, TTX-resistant membrane potential oscillations as an experimental model in which to separate the effects of GABAB receptor activation on LVA calcium channels from that on KCa channels. We show experimentally and by using simulations that a direct effect on LVA calcium channels can account for the effects of GABAB receptor activation on intrinsic membrane potential oscillations to a larger extent than indirect effects mediated via KCa channels. Furthermore, by conducting experiments and simulations on intrinsic membrane potential oscillations, we find that KCa channels may be activated by calcium entering through LVA calcium channels, providing that the decay kinetics of the calcium that enters through LVA calcium channels is not as slow as the calcium entering via NMDA receptors. A combined experimental and computational analysis revealed that the LVA calcium current also contributes to neuronal firing properties.

Animals↗
PubMed2002

Prostaglandin-induced activation of uterine contractility in pregnant rats does not involve potassium channels.

OBJECTIVE: The uterus is a target for prostaglandins, especially at the end of gestation. Whether potassium channels are involved in the effect of prostaglandins is not clear. The aim of this study was to find out. STUDY DESIGN: Concentration-response relationships to prostaglandins (prostaglandin F2alpha, prostaglandin E2, and prostaglandin I2 [carbacyclin]; 10(-10) mol/L-10(-4) mol/L) were studied in isolated uterine rings from mid pregnancy (day 14) and late pregnancy (day 21) rats (Krebs solution, 5% CO2 in air, 37 degrees C; pH, 7.4). Rings were incubated for 30 minutes with either solvent or adenosine triphosphate-sensitive potassium channel inhibitor or opener glibenclamide and levcromakalim or with calcium-sensitive potassium channel inhibitor or opener NS1619 and iberiotoxin, respectively. The changes in integral activity were compared after each concentration of the agent and were expressed as a percent of the basal integral activity. RESULTS: The increases in spontaneous contractile activity induced by prostaglandin E2 and carbacyclin, but not prostaglandin F2alpha, were statistically significantly higher in tissues from late pregnancy versus mid pregnancy rats and were not affected by any of the K-channel openers or inhibitors. CONCLUSION: Adenosine triphosphate-sensitive and calcium-sensitive potassium channels are not involved in the effect of prostaglandin F2alpha, prostaglandin E2, and prostaglandin I2 on pregnant rat uterus.

Animals↗
PubMed2000

Axonal transport of TREK and TRAAK potassium channels in rat sciatic nerves.

The recent cloning, functional expression and brain localization of two new potassium channels, TREK and TRAAK, led us to examine whether both channels are present in peripheral nerves and can move along axons by means of axonal transport mechanisms. Using specific antibodies directed against TREK and TRAAK peptides, we found that immunoreactivity for both potassium channels accumulates above and below a ligature in rat sciatic nerves. The process was rapid and bidirectional suggesting that the channels are associated with vesicles. This represents the first report on the axonal transport of potassium channels.

Animals↗
PubMed2005

Focus on Kir6.2: a key component of the ATP-sensitive potassium channel.

ATP-sensitive potassium (K(ATP)) channels are found in a wide variety of cell types where they couple cell metabolism to electrical activity. In glucose-sensing tissues, these channels respond to fluctuating changes in blood glucose concentration, but in other tissues they are activated only under ischemic conditions or in response to hormonal stimulation. Although K(ATP) channels in different tissues have different regulatory subunits, in almost all cases (except vascular smooth muscle) the pore-forming subunit is the inwardly rectifying K(+) channel Kir6.2. This article reviews recent studies of Kir6.2, focussing on the relation between channel structure and function, and on naturally occurring mutations in Kir6.2 that lead to human disease. New insights into the location of the ATP-binding site, the permeation pathway for K(+), and the gating of the pore provided by homology modelling are discussed in relation to functional studies. Gain-of-function mutations in Kir6.2 cause permanent neonatal diabetes mellitus (PNDM) by reducing the ATP sensitivity of the K(ATP) channel and increasing the K(ATP) current, which is predicted to inhibit beta-cell electrical activity and insulin secretion. Mutations at specific residues, that cause a greater decrease in ATP sensitivity, are associated with additional neurological symptoms. The molecular mechanism underlying the differences in ATP sensitivity produced by these two classes of mutations is discussed. We speculate on how some mutations lead to neurological disease and why no obvious cardiac symptoms are observed. We also consider the implications of these studies for type-2 diabetes.

Adenosine Triphosphate↗
PubMed1997

Activation of ATP-sensitive potassium channels decreases neuronal injury caused by chemical hypoxia.

Cerebral ischemia is known to induce endogenous adaptive mechanisms such as the activation of ATP-sensitive potassium channels that can prevent or delay neuronal injury. This process can be therapeutically mimicked by treatment with potassium channel openers. Primary neuronal cell cultures were derived from embryonic chick telencephalon and were exposed to chemical hypoxia (1 mM cyanide) or excitotoxic injury (1 mM L-glutamate). While treatments with the potassium channel openers bimakalim (1-10 microM) and EMD 57283 (0.1-10 microM) were clearly able to maintain neuronal viability after chemical hypoxia, similar concentrations of the drugs had negligible effects on glutamate-induced neurotoxicity. In contrast, both types of neuronal injury were sensitive to the protective action of the glutamate receptor antagonist dizocilpine (MK-801; 0.1-1 microM). The neuroprotective effect of bimakalim against chemically induced hypoxic injury was reversed by tolbutamide (1 microM), an ATP-sensitive potassium channel blocker. These experiments demonstrate neuroprotective effects of potassium channel openers that could be related to inhibition of neurotransmitter release.

Adenosine Triphosphate↗
PubMed2002

Correlation studies of open and closed state fluctuations in an ion channel: Analysis of ion current through a large-conductance locust potassium channel.

Ion current fluctuations occurring within open and closed states of a large-conductance locust potassium channel (BK channel) were investigated for the existence of correlation. Both the time series, extracted from the ion current signal, were studied by the autocorrelation function and the detrended fluctuation analysis (DFA) methods. The persistent character of the short- and middle-range correlations of time series is shown by the slow decay of the autocorrelation function. The DFA exponent alpha is significantly larger than 0.5. The existence of strongly persistent long-range correlations was detected only for closed state fluctuations, with alpha=0.98+/-0.02. The long-range correlation of the BK channel action is therefore determined by the character of closed states. The main outcome of this study reveals that the memory effect is present not only between successive conducting states of the channel but also independently within the open and closed states themselves. As the ion current fluctuations give information about the dynamics of the channel protein, our results point to the correlated character of the protein movement regardless of whether the channel is in its open or closed state.

Animals↗
PubMed1997

[The anti-anaphylactic action of potassium channel openers and its mechanism].

The anti-anaphylactic action of potassium channel openers was studied and reported in this paper. Minoxidil(Min) was shown to inhibit passive cutaneous anaphylaxis in rats. Diazoxide (Dia) and Min were found to inhibit antigen-induced guinea-pig ileum smooth muscle contraction in vitro. Min was shown to antagonize 5-HT-induced capillary permeability in rat skin. Dia was demonstrated to inhibit histamine release from rat peritoneal mast cells induced by A23187 and compound 48/80, but it failed to antagonize guinea-pig ileum smooth muscle contraction induced by histamine in vitro. These results provide evidence that potassium channel openers may be a new group of inhibitors of histamine release and indicate that the mechanism of its anti-anaphylactic action may be related to its potassium channel opening effect. As a result of this effect, Ca2+ influx to the mast cells decreases and Ca2+ release from calcium storage was inhibited, thus inhibiting histamine release.

Anaphylaxis↗
PubMed1989

Effect of calcium on synaptic facilitation by potassium channel blockers in superior cervical ganglion of rat.

The effects of potassium channel blockers on synaptic transmission were studied in the isolated superior cervical ganglia of the rat by means of extracellular recordings. The ganglia were exposed to gradual increase in the concentration of calcium in the presence and absence of potassium channel blockers. At all levels of calcium (0.1-2 mM), 4-aminopyridine (4-AP) produced marked potentiation of both amplitude and duration of the compound action potential. At 0.1 mM, 4-AP completely reversed the failure of transmission regularly seen in low calcium (0.1 mM). The increase in duration, measured as time to peak, was more pronounced in low calcium and became less marked as the concentration of calcium was raised. In media containing low concentrations of calcium (0.8 mM), 4-AP induced a massive spontaneous discharge, often with rhythmic bursts. Cesium (6 mM) abolished the action potential in low calcium media, however, increasing levels of calcium in the presence of cesium resulted in recovery and later marked potentiation of both the amplitude and duration of the action potential in a calcium concentration-dependent manner. Guanidine potentiated the amplitude of the compound action potential but had no measurable effect on its duration and was unable to reverse transmission failure in low calcium. No potentiation of the amplitude or duration of the action potential was seen with tetraethylammonium. Neither guanidine nor tetraethylammonium induced a spontaneous discharge. The results suggest that some actions of 4-AP are unrelated to blockade of potassium channels.

4-Aminopyridine↗
PubMed2006

Differential expression of Kv3.1b and Kv3.2 potassium channel subunits in interneurons of the basolateral amygdala.

The expression of Kv3.1 and Kv3.2 voltage-gated potassium channel subunits appears to be critical for high-frequency firing of many neuronal populations. In the cortex these subunits are mainly associated with fast-firing GABAergic interneurons containing parvalbumin or somatostatin. Since the basolateral nuclear complex of the amygdala contains similar interneurons, it is of interest to determine if these potassium channel subunits are expressed in these same interneuronal subpopulations. To investigate this issue, peroxidase and dual-labeling fluorescence immunohistochemistry combined with confocal laser scanning microscopy was used to determine which interneuronal subpopulations in the basolateral nuclear complex of the rat amygdala express Kv3.1b and Kv3.2 subunits. Antibodies to parvalbumin, somatostatin, calretinin, and cholecystokinin were used to label separate subsets of basolateral amygdalar interneurons. Examination of immunoperoxidase preparations suggested that the expression of both channels was restricted to nonpyramidal interneurons in the basolateral amygdala. Somata and proximal dendrites were intensely-stained, and axon terminals arising from presumptive basket cells and chandelier cells were lightly stained. Immunofluorescence observations revealed that parvalbumin+ neurons were the main interneuronal subpopulation expressing the Kv3.1b potassium channel subunit in the basolateral amygdala. More than 92-96% of parvalbumin+ neurons were Kv3.1b+, depending on the nucleus. These parvalbumin+/Kv3.1b+ double-labeled cells constituted 90-99% of all Kv3.1b+ neurons. Parvalbumin+ neurons were also the main interneuronal subpopulation expressing the Kv3.2 potassium channel subunit. More than 67-78% of parvalbumin+ neurons were Kv3.2+, depending on the nucleus. However, these parvalbumin+/Kv3.2+ double-labeled cells constituted only 71-81% of all Kv3.2+ neurons. Most of the remaining neurons with significant levels of the Kv3.2 subunit were somatostatin+ interneurons. These Kv3.2-containing somatostatin+ interneurons constituted 27-50% of the somatostatin+ population, depending on the nucleus in question. These data suggest that both fast-firing and burst-firing parvalbumin+ interneurons in the basolateral amygdala express the Kv3.1b subunit. The significance of Kv3.2 expression in some parvalbumin+ and somatostatin+ interneurons remains to be determined.

Amygdala↗
PubMed2001

Blocking effects of the antiarrhythmic drug propafenone on the HERG potassium channel.

Propafenone has been shown to affect the delayed-rectifier potassium currents in cardiomyocytes of different animal models. In this study we investigated effects and mechanisms of action of propafenone on HERG potassium channels in oocytes of Xenopus laevis with the two-electrode voltage-clamp technique. Propafenone decreased the currents during voltage steps and the tail currents. The block was voltage-dependent and increased with positive going potentials (from 18% block of tail current amplitude at -40 mV to 69% at +40 mV with 100 micromol/l propafenone). The voltage dependence of block could be fitted with the sum of a monoexponential and a linear function. The fractional electrical distance was estimated to be delta=0.20. The block of current during the voltage step increased with time starting from a level of 83% of the control current. Propafenone accelerated the increase of current during the voltage step as well as the decay of tail currents (time constants of monoexponential fits decreased by 65% for the currents during the voltage step and by 37% for the tail currents with 100 micromol/l propafenone). The threshold concentration of propafenone effect was around 1 micromol/l and the concentration of half-maximal block (IC50) ranged between 13 micromol/l and 15 micromol/l for both current components. With high extracellular potassium concentrations, the IC50 value rose to 80 degrees mol/l. Acidification of the extracellular solution to pH 6.0 increased the IC50 value to 123 micromol/l, alkalization to pH 8.0 reduced it to 10 micromol/l and coexpression of the beta-subunit minK had no statistically significant effect on the concentration dependence. In conclusion, propafenone has been found to block HERG potassium channels. The data suggest that propafenone affects the channels in the open state and give some hints for an intracellular site of action.

Animals↗
PubMed1994

Quantitative analysis of potassium channel mRNA expression in atrial and ventricular muscle of rats.

The expression of 15 different potassium channel genes in rat atrial and ventricular muscle was quantitatively compared by use of an RNase protection assay. Of these genes, only five, Kv1.2, Kv1.4, Kv1.5, Kv2.1, and Kv4.2, were expressed at significant levels in cardiac muscle. In comparisons of atrial and ventricular RNA samples, transcripts from the Kv1.2 and Kv4.2 genes showed the largest differences in relative abundance. There was an approximately twofold decrease in total Kv4 subfamily mRNA expression in atrial muscle relative to ventricular muscle and a 70% increase in total Kv1 subfamily mRNA. Variation of potassium channel mRNA expression within the left ventricular wall was also examined. There was a large gradient of Kv4.2 expression across the ventricular wall, and Kv4.2 expression in epicardial muscle was more than eight times higher than in papillary muscle. Other potassium channel genes were expressed at relatively uniform levels across the ventricular wall. The results suggest that transcriptional regulation makes a significant contribution to the control of potassium channel expression in cardiac muscle and to the variation of the electrophysiological phenotype of myocytes from different regions of the myocardium.

Animals↗
PubMedDate not supplied

ATP-sensitive potassium channels and myocardial preconditioning.

The ATP-sensitive potassium channel (KATP) has been shown to serve an endogenous cardioprotective role in a number of experimental models of myocardial stunning and infarction. More importantly, a majority of evidence has also been obtained which suggests that the KATP channel may be intimately involved in both triggering and maintaining the cardioprotection afforded by the phenomenon of ischemic preconditioning particularly in large animal models such as dogs and pigs. Although the evidence for an involvement of KATP in ischemic pre-conditioning is equivocal in smaller animal species such as rabbits and rats, activation of this channel by KATP channel openers produces cardioprotection in all species studied. Whether this channel is an important mediator of ischemic preconditioning in all animal species including man and the mechanism by which this cardioprotective effect is obtained await further experimental studies. Nevertheless, the use of selective potassium channel openers to mimic preconditioning in selected clinical settings may be a desirable future therapeutic goal.

Adaptation, Physiological↗