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PubMed1989

Potassium channel blockers differentially affect carbachol and (-)-N6-phenylisopropyladenosine on guinea-pig atria.

1. The effect of three different potassium channel blockers (tetraethylammonium, TEA; 4-aminopyridine, 4-AP; and apamin) and of variations in the concentration of K+ and Ca2+ in the medium, have been studied on the responses of guinea-pig isolated atria to (-)-N6-phenylisopropyladenosine (R-PIA), a stable adenosine A1-receptor agonist, and to carbachol, a muscarinic agonist. R-PIA and carbachol showed the same negative inotropic effects over a similar range of concentrations (3-300 microM), both in spontaneously beating and in electrically driven atria. 2. TEA (0.1 to 20 mM) and 4-AP (0.3 to 3 mM), both antagonized the negative inotropic and chronotropic effects of carbachol in a concentration-dependent manner. In contrast, these compounds failed to inhibit the effects induced by R-PIA. Apamin, a specific blocker of a low conductance Ca2+-activated K+ channel, was ineffective in accordance with the absence of these channels in atrial tissue. 3. TEA (0.1 to 20mM) inhibited the negative inotropic effect of carbachol, but not that of R-PIA, in atria paced and depolarized by a high K+ medium (22 mM). In this preparation Na+ current is abolished and the contraction induced by noradrenaline and electrical stimulation is solely dependent on Ca2+ influx currents. 4. Stepwise addition of Ca2+ to a calcium-depleted perfusing medium of electrically driven atria, induced a positive inotropic effect which was inhibited by R-PIA. In contrast, carbachol had no effect. 5. In agreement with our previous study, the data suggest that R-PIA acts on isolated atria by inhibiting Ca2+ influx through L-channels.

4-Aminopyridine↗
PubMed1998

Effects of the potassium channel blockers, apamin and 4-aminopyridine, on scopolamine-induced deficits in the delayed matching to position task in rats: a comparison with the cholinesterase inhibitor E2020.

The effects of the muscarinic antagonists, scopolamine HBr and MeBr, a cholinesterase inhibitor, E2020, and K+ channel blockers, 4-aminopyridine (4-AP) and apamin, on the performance of rats in a delayed matching to position (DMTP) task were examined. The percentage of correct choices (choice accuracy), number of trials completed and intertrial intervals were measured. Discriminability and response bias were also calculated, using signal detection analysis. Scopolamine HBr (0.1 mg/kg), but not scopolamine MeBr (0.1 mg/kg), significantly and consistently reduced the choice accuracy and discriminability, but neither affected the other measurements. E2020 (0.03-1.0 mg/kg) had no effect on the baseline performance in the DMTP task, but at 1.0 mg/kg, it significantly attenuated the deficits in choice accuracy induced by scopolamine. 4-AP (0.001-0.1 mg/kg) had no effect on either baseline performance or deficits induced by scopolamine. Apamin (0.1-0.4 mg/kg) had no effect on choice accuracy and discriminability. Apamin also failed to attenuate the scopolamine-induced deficits. When administered in combination with scopolamine, apamin at 0.4 mg/kg significantly decreased the number of trials completed and increased the intertrial interval relative to that of the control group. Taken together, these results demonstrate that K+ channel blockers (4-AP and apamin), unlike a cholinesterase inhibitor (E2020), fail to reverse the scopolamine-induced deficits in the DMTP task.

4-Aminopyridine↗
PubMedDate not supplied

Effects of potassium channel blockers on synaptic plasticity in the corticostriatal pathway.

High-frequency stimulation (HFS) of the cerebral cortex or underlying white matter usually induces long-term depression (LTD) in the corticostriatal pathway. Long-term potentiation (LTP) has been described in striatal cells exposed to extracellular tetraethylammonium (TEA). The facilitating effect of TEA may be due to blockade of K+ channels in the postsynaptic neurone or alternatively to presynaptic effects on the release of neurotransmitters such as glutamate or dopamine. We compared the effects of HFS on LTP in striatal cells in four groups of neurones. HFS in control conditions induced LTD (-28.6 +/- 2.0% at 20 min, n = 10) whereas HFS in extracellular TEA (30 mM) induced LTP (+51.0 +/- 24.2% at 20 min, n = 7). LTP was not induced in cells loaded with intracellular Cs (-20.3 +/- 11.4% at 20 min, n = 10) or intracellular TEA (-11.8 +/- 8.9% at 20 min, n = 10), despite comparable effects on postsynaptic responses to HFS. Since the effects of the intracellular K+ channel blockers are limited to the cell being recorded from. these findings suggest that the facilitating effect of extracellular TEA on LTP induction involves a presynaptic action.

Animals↗
PubMed2005

The ATP-sensitive potassium channel blocker glibenclamide prevents renal ischemia/reperfusion injury in rats.

BACKGROUND: Renal ischemia/reperfusion (I/R) is a complex neutrophil-mediated syndrome. Adenosine-triphosphate (ATP)-sensitive potassium (K(ATP)) channels are involved in neutrophil migration in vivo. In the present study, we have investigated the effects of glibenclamide, a K(ATP) channel blocker, in renal I/R injury in rats. METHODS: The left kidney of the rats was excised through a flank incision and ischemia was performed in the contralateral kidney by total interruption of renal artery flow for 45 minutes. Renal perfusion was reestablished, and the kidney and lungs were removed for analysis of vascular permeability, neutrophil accumulation, and content of cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-10] 4 and 24 hours later. Renal function was assessed by measuring creatinine, Na(+), and K(+) levels in the plasma and by determination of creatinine clearance. Drugs were administered subcutaneously after the onset of ischemia. RESULTS: Reperfusion of the ischemic kidney induced local (kidney) and remote (lung) inflammatory injury and marked renal dysfunction. Glibenclamide (20 mg/kg) significantly inhibited the reperfusion-associated increase in vascular permeability, neutrophil accumulation, increase in TNF-alpha levels and nuclear factor-kappaB (NF-kappaB) translocation. These inhibitory effects were noticed in the kidney and lungs. Moreover, glibenclamide markedly ameliorated the renal dysfunction at 4 and 24 hours. CONCLUSION: Treatment with glibenclamide is associated with inhibition of neutrophil recruitment and amelioration of renal dysfunction following renal I/R. Glibenclamide may have a therapeutic role in the treatment of renal I/R injury, such as after renal transplantation.

Adenosine Triphosphate↗
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↗
PubMed2004

Treatment of episodic ataxia type 2 with the potassium channel blocker 4-aminopyridine.

Patients with episodic ataxia type 2 (EA2) can often be successfully treated with acetazolamide. The authors report three patients with EA2 (two with proven mutations in the CACNA1A gene) whose attacks were prevented with the potassium channel blocker 4-aminopyridine (4-AP; 5 mg tid). Attacks recurred after treatment was stopped; subsequent treatment alleviated the symptoms (mean follow-up time 6 months). These effects might be due to an improvement of the impaired functioning of Purkinje cells.

4-Aminopyridine↗
PubMed1993

The ATP-sensitive potassium channel blocker glibenclamide (glyburide) does not abolish preconditioning in isolated ischemic rat hearts.

Previous studies have indicated that the ATP-sensitive potassium channels blocker glibenclamide (glyburide) can abolish preconditioning in canine models of myocardial ischemia. Recently, an isolated rat heart model of preconditioning has been developed that may be ideal for studying the mechanisms of preconditioning. In the present study, we determined the effect of glyburide on preconditioning in isolated rat hearts. Rat hearts were isolated and retrogradely perfused with oxygenated Krebs'-Henseleit solution. They were then subjected to four periods of total global ischemia of 5-min duration, separated by 5-min reperfusion. The hearts were then subjected to 30-min global ischemia followed by 30-min reperfusion and contractile function and lactate dehydrogenase release determined. Non-preconditioned hearts sustained severe damage. Glyburide (1-100 microM) pretreatment had no effect on the severity of 30-min global ischemia and 30-min reperfusion. Preconditioning caused significant improvements in reperfusion contractile function (25-fold increase in left ventricular developed pressure) and reductions in reperfusion lactate dehydrogenase release and reperfusion end diastolic pressure (contracture). Glyburide had modest preischemic cardiodepressant and vasoconstrictor effects at 1-30 microM, whereas 100 microM caused a 50% reduction in preischemic coronary flow. Despite these effects, none of these concentrations of glyburide affected the efficacy of preconditioning. These studies indicate that preconditioning in isolated rat hearts does not occur via a glyburide- (and thus presumably ATP-sensitive potassium channel) sensitive mechanism.

Adenosine Triphosphate↗
PubMed2005

A potassium channel blocker induces a long-lasting enhancement of corticostriatal responses.

Disruptions in synaptic plasticity in the dorsal striatum may contribute to the pathophysiology underlying Parkinson's disease. Here we report a novel, chemically-induced form of plasticity induced by application of the potassium channel blocker tetraethylammonium (TEA) in the dorsolateral striatum of the adult rat. Transient application of TEA persistently increased synaptically-evoked extracellularly-recorded corticostriatal responses in an activity-, concentration- and time-dependent manner. Pharmacological experiments suggest that this plasticity is dependent on L-type calcium channel and protein kinase C (PKC) activation. Striatal dopamine depletion induced by nigrostriatal dopamine lesions with 6-hydroxydopamine significantly reduced, but did not abolish, TEA-mediated enhancement of the corticostriatal response. Intracellular recordings demonstrate that this TEA-mediated plasticity is associated with an increase in EPSP size and slope, as well as input resistance. Collectively, these findings demonstrate a novel form of L-type calcium channel-dependent plasticity in the adult dorsal striatum that is induced in the absence of dopaminergic input.

Animals↗
PubMed1998

Terikalant, an inward-rectifier potassium channel blocker, does not abolish the cardioprotection induced by ischemic preconditioning in the rat.

Recent results have shown that the sulfonylurea receptor couples to several types of inward-rectifier potassium (KIR) channels, which suggests that sensitivity to blockade of a pathophysiological phenomenon such as ischemic preconditioning (PC) by glibenclamide may not be the result of this compound selectively blocking the ATP-sensitive potassium (KATP) channel. Therefore, to address this possibility, a role for myocardial KIR v KATP channels in ischemic PC was evaluated in the rat. To test this hypothesis, anesthetized, open-chest, male Wistar rats were assigned to one of seven experimental protocols. Animals assigned to group I (control) received 30 min of occlusion and 2 h of reperfusion. Ischemic PC was produced by 3x5-min occlusion and 2-h reperfusion periods (group II). Terikalant (TK), an inward-rectifier potassium channel blocker, was used to test the role of other K+ channels, most notably the KIR, in the cardioprotective effect of ischemic PC in the rat. TK was given at a dose of 3 mg/kg, i.v., 15 min before the prolonged occlusion and reperfusion periods (group III). In groups IV, V, and VI terikalant (1, 3 and 6 mg/kg, i.v.) was given 15 min before ischemic PC (lowTK+PC, medTK+PC and hiTK+PC, respectively). Group VII consisted of glibenclamide (0.3 mg/kg, i.v.) given 30 min prior to ischemic PC (GLY+PC). Infarct size (IS) as a percent of the area at risk (AAR) was measured using the histochemical stain, 2,3, 5-triphenyltetrazolium chloride. The average IS/AAR for the control was 49.9+/-2.1%. Ischemic PC markedly reduced infarct size (8.6+/-1. 8%; * P<0.05 v control). Terikalant (TK; 1, 3 and 6 mg/kg, i.v.) did not abolish the cardioprotective effect of ischemic PC at any dose (15.5+/-6.4, 16.4+/-5.2 and 8.8+/-1.6%, respectively; * P<0.05 v control). TK itself had no effect on infarct size. GLY completely abolished the cardioprotective effect of ischemic PC (48.2+/-6.4%). In addition, the high dose of TK significantly (P<0.05) increased the action potential duration at 50% repolarization from 48+/-3 to 64+/-4 ms and 30 microM of TK, a concentration which produced a 39% decrease in the inward-rectifier potassium channel current in isolated guinea-pig ventricular myocytes in the whole-cell patch-clamp mode did not block the increase in K ATP current produced by the KATP opener bimakalim (3 microM). These results demonstrate that although the myocardial KATP channel belongs to the K IR superfamily, the endogenous myocardial KIR channel does not mediate ischemic PC in the rat heart; however, the K ATP channel does mediate its cardioprotective effect.

ATP-Binding Cassette Transporters↗
PubMed1987

Potassium channel blockers and impulse propagation in murine motor endplate disease.

An electrophysiologic study has been performed on motor nerves of mice affected with hereditary "motor endplate disease" (MED). Bath application of potassium channel blockers, such as tetraethylammonium and 3,4-diaminopyridine, which are almost without effect on the monophasic compound action potential of normal nerves, considerably enhanced the action potential duration in nerves from mutant mice. Furthermore, external current recordings from motor endings revealed an absence of the K-dependent waveform component in MED mice, which indicates a similar K current intensity in the terminal part of the endings and in the heminode. These observations suggest that in the mutant, unlike in normal mice, K channels play a role in action potential electrogenesis. Possible relationships with paranodal dysmyelination are discussed.

4-Aminopyridine↗
PubMed2006

Effects of the treatment with glibenclamide, an ATP-sensitive potassium channel blocker, on intestinal ischemia and reperfusion injury.

Intestinal ischemia and reperfusion injury is dependent on the recruitment and activation of neutrophils. Glibenclamide, an ATP-sensitive potassium channel (K(ATP)) blocker, has been shown to suppress neutrophil migration and chemotaxis during acute inflammatory responses by a mechanism dependent on its K(ATP) channel blocking activity. In the present study, we evaluated whether the treatment with glibenclamide prevented local, remote and systemic injury following reperfusion of the ischemic superior mesenteric artery in rats. The artery was made ischemic for a period of 30 or 120 min followed by 30 (mild I/R) or 120 (severe I/R) min of reperfusion, respectively. Glibenclamide (0.8 to 20 mg/kg) or vehicle was administered subcutaneously 40 min prior to the reperfusion. Glibenclamide dose-dependently inhibited the reperfusion-associated increase in vascular permeability and neutrophil accumulation in mild I/R. In the severe injury model, glibenclamide inhibited inflammatory parameters, as assessed by Evans blue extravasation, neutrophil influx and haemoglobin content, and the increase in TNF-alpha (tumor necrose factor-alpha) and IL (interleukin)-6 levels in the intestine and lung. The drug did not affect the increase in IL-1beta and IL-10 levels. TEA, a nonselective potassium channel blocker, also inhibited reperfusion injury in both intestine and lungs of animals submitted to mild and severe I/R. Our experiments suggest a role for K(ATP) channels in mediating neutrophil influx and consequent reperfusion-associated injury in rats. The lack of effect of these drugs on the reperfusion-associated hypotension and lethality may limit their usefulness after severe reperfusion injury.

Adenosine Triphosphate↗
PubMed1986

Phasic contractions of canine and human coronary arteries induced by potassium channel blockers.

To gain insight into mechanisms underlying phasic coronary vasospasm in patients with variant angina pectoris, we studied whether phasic contractions could be induced in isolated canine and human coronary arteries by agents which block potassium channels. Phasic contractions of canine coronary arteries were always induced by 3,4-diaminopyridine (10(-2) M) and less frequently by 4-aminopyridine (10(-2) M). These agents also caused phasic contractions in human, swine and monkey coronary arteries and in canine basilar, carotid, renal and femoral arteries. The cycle length of phasic coronary contractions ranged from 30 sec to 1 hour, and the developed tension was 2.5 times greater than for potassium contractions. The contractions continued for more than 11 hours. Morphologically, perinuclear vacuolization, a characteristic change of vasospasm, appeared in the coronary smooth muscles. The phasic contractions were not eliminated by tetrodotoxin, atropine, phentolamine or yohimbine, but they were eliminated by nicorandil which activates potassium channels and nifedipine which blocks slow calcium channels. The results indicate that potassium channel blockers can induce phasic arterial contractions.

4-Aminopyridine↗
PubMed1991

Potassium channel blockers inhibit D2 dopamine, but not A1 adenosine, receptor-mediated inhibition of striatal dopamine release.

D2 dopamine autoreceptors and A1 adenosine heteroreceptors inhibit the evoked release of dopamine from rat striatum. We examined the role of potassium channels in this modulation by determining the effects of two potassium channel blockers, 4-aminopyridine and tetraethylammonium, on the modulation of electrically stimulated release of endogenous dopamine from rat striatal slices. Maximally effective concentrations of the D2 dopamine receptor agonist N-0437 (10 nM) and of adenosine (50 microM) caused a 30% inhibition of evoked dopamine overflow, and their effects were additive. When coperfused with N-0437, both 4-aminopyridine and tetraethylammonium blocked the inhibition caused by N-0437 in a dose-dependent manner. 4-Aminopyridine was approximately three orders of magnitude more potent than tetraethylammonium, with complete blockade occurring at 3 microM and 1 mM, respectively. Binding experiments confirmed that neither 4-aminopyridine nor tetraethylammonium was a direct-acting D2 dopamine receptor antagonist at the concentration necessary to block the release-modulatory effect of D2 receptor activation. In contrast, the inhibitory modulation produced by adenosine was not affected by 4-aminopyridine (30 microM) or tetraethylammonium (1 mM). These results suggest that D2 dopamine and A1 adenosine receptors inhibit dopamine release in the striatum by different mechanisms. D2 dopamine autoreceptor action appears to involve potassium channels, whereas A1 adenosine receptor action does not.

4-Aminopyridine↗
PubMed2005

Potassium channel blockers inhibit the triggers of attacks in the calcium channel mouse mutant tottering.

Humans with the disorder episodic ataxia type 2 (EA2) and the tottering mouse mutant exhibit episodic attacks induced by emotional and chemical stress. Both the human and mouse disorders result from mutations in CACNA1A, the gene encoding the alpha(1)2.1 subunit of Ca(v)2.1 voltage-gated calcium channels. These mutations predict reduced calcium currents, particularly in cerebellar Purkinje cells, where these channels are most abundant. 4-Aminopyridine (4-AP), a nonselective blocker of K(v) voltage-gated potassium channels, alleviates attacks of ataxia in EA2 patients. To test the specificity of the effect for K(v) channels, aminopyridine analogs were assessed for their ability to ameliorate attacks of dyskinesia in tottering mice. 4-AP and 3,4-diaminopyridine (3,4-DiAP), which have relatively high affinities for K(v) channels, reduced the frequency of restraint- and caffeine-induced attacks. Furthermore, microinjection of 3,4-DiAP into the cerebellum completely blocked attacks in tottering mice. Other aminopyridine analogs reduced attack frequency but, consistent with their lower affinities for K(v) channels, required comparatively higher doses. These results suggest that aminopyridines block tottering mouse attacks via cerebellar K(v) channels. That both stress- and caffeine-induced attacks were blocked by aminopyridines suggests that these triggers act via similar mechanisms. Although 4-AP and 3,4-DiAP were effective in preventing attacks in tottering mice, these compounds did not affect the severity of "breakthrough" attacks that occurred in the presence of a drug. These results suggest that the aminopyridines increase the threshold for attack initiation without mitigating the character of the attack, indicating that attack initiation is mediated by mechanisms that are independent of the neurological phenotype.

4-Aminopyridine↗
PubMed1993

Interaction between selected sodium and potassium channel blockers in guinea pig papillary muscle.

Previous studies have reported that enhanced antiarrhythmic effects occur when agents that prolong repolarization are combined with agents that block the sodium channels. The mechanism(s) of this interaction have not been elucidated. In this study, the interactions between the prolongation of action potential duration (APD) by a potassium channel blocker and the reduction in the maximal upstroke velocity of phase 0 of action potential (Vmax) by sodium channel blockers were investigated in guinea pig papillary muscle using conventional microelectrode techniques. Agents that produce selective electrophysiologic effects were chosen, including low concentrations of barium chloride (BaCl2), which selectively blocks the inwardly rectifying potassium current without effects on other repolarizing or depolarizing currents, O-demethyl-encainide (ODME), which blocks the activated sodium channel with slow onset/offset kinetics, and mexiletine, which preferentially blocks the inactivated sodium channel with rapid onset/offset kinetics. Mexiletine (4 x 10(-6) M) decreased Vmax from 195 +/- 29 V/sec at baseline to 180 +/- 26 V/sec (P < .05). Whereas BaCl2 (10(-5) M) prolonged action potential duration, it had no effect on Vmax. However, the addition of BaCl2 to mexiletine synergistically decreased Vmax from 180 +/- 26 V/sec with mexiletine to 166 +/- 18 V/sec (P < .05). ODME (3 x 10(-7) M) decreased Vmax from 179 +/- 17 V/sec at baseline to 133 +/- 15 V/sec (P < .01). However, the addition of BaCl2 to ODME did not produce a further decrease in Vmax as compared with ODME alone. In summary, a synergistic effect on Vmax was observed when BaCl2 and mexiletine were combined.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1992

Influence of ATP-sensitive potassium channel blocker on hypoxia-induced damage of isolated guinea pig heart.

1. Isolated guinea pig hearts were perfused under constant flow conditions with Krebs-Henseleit buffer. Hearts were subjected to 15 min of hypoxia followed by reoxygenation in the presence and in the absence of 100 microns glyburide, an ATP-sensitive potassium channel blocker. Heart rate, left ventricular pressure and lactate dehydrogenase (LDH) release were measured at 5 min intervals. 2. Small decreases in heart rate and left ventricular pressure were observed during glyburide infusion with hypoxia, however LDH release, which was used as an index of cellular damage, was dramatically elevated. 3. Neither glyburide, nor the vehicle in which it was dissolved, appeared to produce myocardial damage under normoxic conditions. 4. It is concluded that ATP-sensitive potassium channels are important in the protection of the myocardium during hypoxia in isolated guinea pig hearts perfused under constant flow conditions.

Adenosine Triphosphate↗
PubMed1997

The contrasting effects of dendrotoxins and other potassium channel blockers in the CA1 and dentate gyrus regions of rat hippocampal slices.

1. The effects of potassium channel blocking compounds on synaptic transmission in the CA1 and dentate gyrus regions of the rat hippocampus were examined by means of simultaneous field potential recording techniques in brain slices. 2. 4-Aminopyridine (4-AP) enhanced the excitatory postsynaptic potential (e.p.s.p.) and induced multiple population spike responses in both regions. EC50 values were 6.7 microM in the CAI (n = 5) and 161.7 microM (n = 5) in the dentate gyrus. 3. Tetraethylammonium (TEA) increased the amplitude and induced broadening of the population spike in both regions. In the dentate gyrus (n = 5) a single slow spike response was introduced (EC50 12.8 mM) and in the CA1 region (n = 5) the response was transformed into two wide spikes (EC50 2.6 mM). 4. In the CA1 region all of the dendrotoxins (toxin I, toxin K, alpha-Dtx and delta-Dtx) induced multiple population spikes and enlarged e.p.s.p. responses. Potentials recorded simultaneously in the dentate gyrus exhibited comparatively minor enhancements. The EC50 value for toxin 1 in the CA1 was calculated to be 237 nM (n = 4). Estimated EC50 values were obtained for alpha-Dtx (1.1 microM, n = 3), toxin K (411 nM, n = 4) and delta-Dtx (176 nM, n = 3). 5. In the presence of toxin 1, DL-2-amino-5-phosphonovaleric acid (APV) induced slight reduction of the late e.p.s.p. phase (n = 3). 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX) abolished all population spikes leaving a late slow positive waveform (n = 3). Co-application of APV and CNQX abolished all postsynaptic responses. 6. Charybdotoxin (CbTx) was significantly less potent than the dendrotoxins and had mixed actions in the CA1 region (n = 3). Again the dentate gyrus exhibited reduced sensitivity (n = 3). 7. In the presence of mast cell degranulating peptide (MCDP), enhancement of the CA1 field potential response (n = 5) was greater than that observed in the dentate gyrus (n = 5). 8. The results show that some potassium channel modulators can profoundly enhance CA1 region synaptic responses in the absence of notable changes in dentate gyrus excitability. Selective enhancement of defined synaptic pathways by potassium channel modulators may prove to have considerable therapeutic potential.

4-Aminopyridine↗
PubMed2001

Potassium channel blocker activates extracellular signal-regulated kinases through Pyk2 and epidermal growth factor receptor in rat cardiomyocytes.

OBJECTIVES: We sought to determine whether potassium (K(+)) channel blockers (KBs) can activate extracellular signal-regulated kinase (ERK) and to characterize the upstream signals leading to ERK activation in cardiomyocytes. BACKGROUND: Because KBs attenuate K(+) outward current, they may possibly prolong the duration of action potentials, leading to an increase in calcium (Ca(2+)) transient ([Ca(2+)](i)) in cardiomyocytes. Elevation of intracellular Ca(2+) levels can trigger various signaling events. Influx of Ca(2+) through L-type Ca(2+) channels after membrane depolarization induced activation of MEK and ERK through activation of Ras in neurons. Although KBs are frequently used to treat cardiac arrhythmias, their effect on signaling pathways remains unknown. METHODS: Primary cultured rat cardiomyocytes were stimulated with four different KBs-4-aminopyridine (4-AP), E-4031, tetra-ethylammonium and quinidine-and phosphorylation of ERK, proline-rich tyrosine kinase 2 (Pyk2) and epidermal growth factor receptor (EGFR) was detected. Action potentials were recorded by use of a conventional microelectrode. (Ca(2+))(i) was monitored by the fluorescent calcium indicator Fluo-4. RESULTS: E-4031, 4-AP, tetra-ethylammonium and quinidine induced phosphorylation of ERK. 4-Aminopyridine prolonged the duration of action potentials by 37% and increased (Ca(2+))(i) by 52% at 1 mmol/l. Pre-incubation of ethyleneglycoltetraacetic acid, 1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis and diltiazem completely blocked this phosphorylation, whereas flufenamic acid and benzamil did not. 4-Aminopyridine induced tyrosine phosphorylation of Pyk2 and EGFR, which peaked at 5 and 10 min, respectively. Cytochalasin D, AG1478 and dominant-negative EGFR strongly inhibited the phosphorylation of ERK, whereas calphostin C, calmidazolium and KN62 did not. CONCLUSIONS: These findings indicate that KBs induce ERK activation, which starts with Ca(2+) entry through the L-type Ca(2+) channel in cardiomyocytes, and that EGFR and Pyk2 are involved in this activation.

4-Aminopyridine↗