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PubMed1989

Effects of alaproclate, potassium channel blockers, and lidocaine on the release of 3H-acetylcholine from the guinea-pig ileum myenteric plexus.

The guinea-pig ileum longitudinal muscle-myenteric plexus preparation, preincubated with 3H-choline or 3H-noradrenaline, was mounted in an organ bath and superfused with Tyrode's solution. Alaproclate (2-(4-chlorophenyl)-1,1-dimethyl 2-aminopropanoate) (0.01-0.5 mmol/l) reduced (IC50 = 0.1 mmol/l) and at about 0.5 mmol/l completely blocked the electrically evoked 3H-acetylcholine secretion. The depressing effect of alaproclate (0.2 mmol/l) was not counteracted by atropine (0.01, 1 or 10 mumol/l), hexamethonium (0.1 mmol/l), phentolamine (1 mumol/l) yohimbine (1 mumol/l), haloperidol (1 mumol/l), 8-phenyltheophylline (10 mumol/l), cyproheptadine (1 mumol/l), metitepine (1 mumol/l), bicuculline (10 mumol/l), picrotoxinin (0.1 mmol/l), forskolin (25 mumol/l), 3-isobutyl-1-methylxanthine (5 mmol/l), nifedipine (1 mumol/l), verapamil (1 mumol/l), dilitiazem (1 mumol/l), high calcium (6 mmol/l), high potassium (10 or 15 mmol/l), tetraethylammonium (2 mmol/l), 4-aminopyridine (0.5 mmol/l), apamin (0.5 mumol/l), barium (0.5 mmol/l) or quinine (0.1 mmol/l). Among the potassium channel blockers tested only quinine (at 0.5 or 1 mmol/l), in the same manner as lidocaine, reduced the evoked secretion of 3H-acetylcholine. The results are in agreement with the hypothesis that the effect of alaproclate on the evoked 3H-acetylcholine secretion is not mediated by a neurotransmitter receptor, or a potassium channel sensitive to tetraethylammonium, 4-aminopyridine, apamin, or barium or quinine, but is due to a local anaesthetic effect. In contrast to the evoked secretion, the spontaneous release of 3H-acetylcholine was enhanced by high concentrations of alaproclate (0.4-1 mmol/l). The mechanism underlying the effect of alaproclate on the spontaneous release remains to be established. Alaproclate (0.25 or 0.5 mmol/l) also enhanced the spontaneous release and reduced the electrically evoked 3H-noradrenaline secretion.

Acetylcholine↗

PubMed1988

Differential effects of potassium channel blockers on neurohypophysial release of oxytocin and vasopressin. Evidence for frequency-dependent interaction with the endogenous opioid inhibition of oxytocin release.

Isolated rat neurohypophyses were fixed by their stalks to a platinum wire electrode and superfused with Krebs-HEPES solution. Vasopressin and oxytocin released into the medium were determined by specific radioimmunoassays. Hormone secretion was increased by electrical stimulation of the pituitary stalk at different frequencies. The effects of several potassium channel blockers, tetraethyl-ammonium (TEA) ions, 4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP) were tested. The release of vasopressin and oxytocin evoked by electrical stimulation with 900 pulses at 15 Hz (about 900 and 1,000 microU, respectively) was about 10 times higher than that evoked by 900 pulses at 3 Hz. Both 10 and 30 mmol/l TEA enhanced the release of vasopressin evoked by stimulation at 3 and 15 Hz, by 25- and 2-fold, respectively, to attain a maximum release of about 1,800 microU per stimulation. The stimulated release of oxytocin attained a maximum of about 9,000 microU at 15 Hz in the presence of 10 mmol/l TEA or at 3 Hz with 30 mmol/l TEA. Thus, in the presence of maximally effective concentrations of TEA both stimulation frequencies (3 and 15 Hz) were equieffective in evoking release of vasopressin and oxytocin. 4-AP or 3,4-DAP enhanced the release of vasopressin evoked by 15 Hz stimulation maximally to about 1,600 microU. In the presence of 4-AP or 3,4-DAP the release of oxytocin evoked by stimulation at 15 Hz increased maximally to about 8,000 microU and that evoked by stimulation at 3 Hz to about 1,500 microU.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminopyridine↗

PubMed1980

Calcium- and potassium-channel blockers interact with alpha-adrenoceptors.

The so-called calcium antagonist D-600 and agents that enhance the influx of calcium ions into nerve terminals during action potentials (4-aminopyridine, tetraethylammonium, guanidine) interact with alpha-adrenoceptors. The interaction was revealed by binding experiments in vitro with the alpha 2- and alpha 1-specific ligands [3H]clonidine and [3H]prazosin, resp. D-600 binds in a competitive manner to alpha 2- and alpha 1-adrenoceptors in rat-brain membranes. [3H]Prazosin was used to identify alpha 1-adrenoceptors in rat-heart-membrane fragments. D-600 inhibited the binding of the tritiated antagonist, in a manner similar to that seen in rat-brain membranes. 4-Aminopyridine, guanidine and tetraethylammonium blocked no-competitvely the binding of [3H]clonidine in brain membranes. There ws little or no effect of these agents on the binding of [3H]prazosin to alpha 1-adrenoceptors in rat heart or brain. The results indicate that D-600 binds to a region common to alpha 1- and alpha 2-adrenoceptors, whereas the potassium-channel blockers reveal a structural feature of the alpha 2-adrenoceptors in brain membranes which is also present in voltage-dependent potassium channels but is not shared by alpha 1-adrenoceptors.

Aminopyridines↗

PubMed1990

Inhibition of mucin secretion in a colonic adenocarcinoma cell line by DIDS and potassium channel blockers.

The factors which influence the exocytosis of mucins are not well characterized. Since the physical properties of mucins may be affected significantly by the co-secretion of electrolytes and water, we studied the relationship between ion movement and mucin secretion in T84 cells, a human colonic adenocarcinoma cell line which has been well characterized with respect to apical chloride secretion. Secretion of mucin was assessed by immunoassay of mucin appearing in the medium within 30 min of stimulation. Cells were grown on plastic in DMEM/Ham's F12 medium and experiments were carried out at 70% confluence. Mucin secretion was stimulated by the calcium ionophore A23187, or A23187 plus vasoactive intestinal polypeptide. Stimulated mucin secretion was not affected by loop diuretics (furosemide (1 x 10(-3) M) or bumetanide (1 x 10(-4) M)), with or without the addition of ouabain (5 x 10(-5) M) and amiloride (1 x 10(-5) M), making it unlikely that transcellular chloride movements in necessary for mucin secretion. However, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS; (1 x 10(-5) and 5 x 10(-5) M) and three potassium channel blockers BaCl2 (1 x 10(-3) and 5 x 10(-3) M), tetraethylammonium chloride (1 x 10(-2) M) and quinine (5 x 10(-4) M) inhibited mucin secretion. A DIDS-sensitive chloride channel or chloride/bicarbonate exchanger and a Ca2(+)-dependent potassium channel may play important roles in mucin secretion. Since plasma membranes are sparingly permeable to DIDS, the DIDS-sensitive site is likely to be on the apical plasma membrane, perhaps at an initiation locus for exocytosis.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed2000

Solution structure of BmP02, a new potassium channel blocker from the venom of the Chinese scorpion Buthus martensi Karsch.

BmP02 is a 28-amino acid residue peptide purified from the venom of the Chinese scorpion Buthus martensi Karsch, which had been demonstrated to be a weak blocker of apamin-sensitive calcium-activated potassium channels. Two-dimensional NMR spectroscopy techniques were used to determine the solution structure of BmP02. The results show that BmP02 formed a alpha/beta scorpion fold, the typical three-dimensional structure adopted by most short chain scorpion toxins whose structures have been determined. However, in BmP02 this alpha/beta fold was largely distorted. The alpha-helix was shortened to only one turn, and the loop connecting the helix to the first beta-strand exhibited conformational heterogeneity. The instability of BmP02 could be attributed to a proline at position 17, which is usually a glycine. Because the residue at this position makes intense contact with the alpha-helix, it was supposed that the bulky side chain of proline had pushed the helix away from the beta-sheet. This had a significant influence on the structure and function of BmP02. The alpha-helix rotated by about 40 degrees to avoid Pro17 while forming two disulfides with the second beta-strand. The rotation further caused both ends of the helix to be unwound due to covalent restrictions. According to its structure, BmP02 was supposed to interact with its target via the side chains of Lys11 and Lys13.

Amino Acid Sequence↗

PubMed2000

The effects of potassium channel blockers on progesterone-induced suppression of rat portal vein contractility.

The suppression of contractility of rat portal vein caused by progesterone appears to be due to the potassium (K+) channel opening effect of this hormone. The identity of the specific K+ channels involved has been investigated using a variety of K+ channel blockers. Incubation with 100 nM iberiotoxin antagonised the progesterone-induced inhibition of spontaneous and 20 mM K+-induced phasic activity of the portal vein such that the contractions resembled those of the non-progesterone, non-iberiotoxin control tissues treated with the corresponding solvent vehicles. Incubation with barium chloride (20 and 100 microM), 4-aminopyridine (1 mM), tetraethylammonium chloride (1 mM), glibenclamide (1 microM) or apamin (1 microM) did not, however, have the same antagonistic effect. These results suggest that progesterone's selective suppression of rat portal vein contractility is mediated by the opening of BKCa channels.

4-Aminopyridine↗

PubMed2001

Potassium channel blocker TEA prevents CA1 hippocampal injury following transient forebrain ischemia in adult rats.

It has been recently reported that potassium channel increases activities in CA1 pyramidal neurons of rat hippocampus following transient forebrain ischemia. To understand the role of the enhanced potassium current in the pathogenesis of neuronal damage after ischemia, we examined the effects of tetraethylammonium (TEA) and 4-aminopyridine (4-AP) on the neuronal injury of CA1 region induced by 15 min forebrain ischemia using a four-vessel occlusion model. Adult rats received intracerebroventricular administration of either TEA or 4-AP after ischemia or TEA before ischemia and once each day for 7 days. In the postischemic TEA treated-rats, the neuronal injury in hippocampal CA1 region was significantly less than that of the controls. In contrast, neither preischemic infusion of TEA nor postischemic treatment of 4-AP had any neuroprotective effects. The present study demonstrates that postischemic application of TEA protects hippocampal CA1 pyramidal neurons against ischemic insult, suggesting that potassium channels may play important roles in the pathogenesis of CA1 neuronal death after transient forebrain ischemia.

4-Aminopyridine↗

PubMed1994

Effects of potassium channel blockers on basal vascular tone and reactive hyperemia of canine diaphragm.

Glibenclamide, iberiotoxin, and apamin (blockers of ATP-sensitive, large-conductance, and small-conductance Ca(2+)-activated potassium channels, respectively) were infused into the diaphragmatic vasculature of anesthetized dogs to assess the contribution of these channels in the regulation of basal tone and the response to brief occlusions of the left phrenic artery (reactive hyperemia). Baseline phrenic flow (Qphr), peak postocclusive flow, and reactive hyperemia duration in response to 10-, 30-, 60-, and 120-s arterial occlusions were measured before (control) and after the infusion of K+ channel blockers in three groups of animals. Glibenclamide at 5 x 10(-6), 1 x 10(-5), and 8 x 10(-5) M increased baseline phrenic resistance to 140, 204, and 192% of control values, respectively. Peak postocclusive Qphr and duration of hyperemia in response to all occlusion durations were significantly attenuated after glibenclamide infusion. Iberiotoxin infusion at 1 x 10(-8), 3 x 10(-8), and 1 x 10(-7) M increased phrenic resistance to 141, 133, and 146% of control values, respectively. By comparison, baseline phrenic resistance rose to 159 and 145% of control in response to 1 x 10(-7) and 1 x 10(-6) M apamin, respectively. Iberiotoxin and apamin reduced peak postocclusive flow and duration of hyperemia only in response to 10- and 30-s occlusions. We infused K+ channel blockers along with lemakalim into the diaphragm during constant flow perfusion in separate groups of animals. When infused alone, lemakalim reduced phrenic resistance by 60-70%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

86Rubidium efflux and negative inotropy induced by P1- and muscarinic-receptor agonists in guinea-pig left atria. Effects of potassium channel blockers.

Guinea-pig isolated left atria, paced at 2 Hz were incubated with 86rubidium (86Rb) for 120 min. They were then washed every 2 min for 2 hr, each sample being retained for scintillation counting. Left atrial isometric tension was recorded simultaneously. A concentration-response curve for the muscarinic agonist carbachol or the P1-receptor agonists adenosine and L-N6-phenyl-isopropyladenosine (L-PIA) was obtained. Antagonists were present from 20 min before agonist exposure. The rate constant (k) for 86Rb efflux was calculated for each 2 min sample and the mean increase for each concentration of agonist determined. In the absence of drugs there was no significant alteration in the rate constant during the 2 hr experimental period. Adenosine, L-PIA and carbachol produced concentration-related increases in rate constant for 86Rb efflux. The adenosine and L-PIA concentration-response curves were virtually superimposed upon the curves for the negative inotropic responses. The 86Rb efflux induced by adenosine was antagonized in an apparently parallel manner by 8-phenyltheophylline (8-PT) indicating involvement of P1-receptors. Alone, the putative potassium channel blockers, 4-aminopyridine (4-AP) and bromobenzoylmethyladamantylamine (BMA) caused, respectively, no change and a reduction in resting 86Rb efflux immediately prior to the agonist exposure. 4-AP reduced the L-PIA- and adenosine-induced increases in 86Rb efflux and, to a lesser extent, the negative inotropic response to adenosine. BMA caused "flattening" of the dose-response curves for 86Rb efflux induced by L-PIA, adenosine and carbachol with a significant reduction in response at the highest concentrations of adenosine and carbachol. The negative inotropic response to adenosine was also reduced. These results suggest that 4-AP and BMA block the P1-receptor-linked potassium channels and that BMA interacts with common K+ channels linked to P1- and muscarinic receptors. The negative inotropic responses of the guinea-pig left atrium to P1- and muscarinic agonists can be attributed, at least in part, to the opening of outward K+ channels.

4-Aminopyridine↗

PubMed1995

Apamin, a selective SK potassium channel blocker, suppresses REM sleep without a compensatory rebound.

To determine the role of neuronal potassium conductance in rapid-eye-movement (REM)-sleep homeostasis, we have administered small doses of apamin (2-5 ng), a selective blocker of the calcium-dependent SK potassium channel, injected into the lateral ventricle in rats, and characterized the resultant effects on REM-sleep expression. Apamin produces a dose-dependent reduction in REM-sleep expression without an increase in the frequency of attempts to enter REM sleep, suggesting that accumulation of REM-sleep propensity is suppressed. The vast majority (84-95%) of lost REM sleep is not recovered 40 h after apamin administration. These findings suggest that accumulation of REM-sleep propensity is linked to the increased neuronal potassium conductance in nonREM sleep.

Animals↗

PubMedDate not supplied

ATP-regulated potassium channel blocker, glibenclamide, uncouples mitochondria.

The purpose of the present study was to investigate the effect exerted by the antidiabetic sulfonylurea, glibenclamide, a well known blocker of ATP-regulated potassium channels, on membrane potential and proton gradient in rat liver mitochondria. Membrane potential of mitochondria was determined using a TPP+ selective electrode. Mitochondrial proton gradient value was measured with 2',7',bis(carboxyethyl)-5,6-carboxyfluorescein, the pH-sensitive fluorescent probe. Mitochondrial membrane potential and proton gradient were found to be dissipated by glibenclamide in a concentration-dependent manner, with IC50 of 70 +/- 7 microM. The present results provide evidence that the antidiabetic sulfonylurea, glibenclamide, uncouples rat liver mitochondria.

Adenosine Triphosphate↗

PubMed1998

Ionisation behaviour and solution properties of the potassium-channel blocker ShK toxin.

The effects of pH, temperature and polypeptide concentration on the solution structure and side chain interactions of ShK toxin, a potassium-channel-blocking polypeptide from the sea anemone Stichodactyla helianthus, have been investigated by means of one-dimensional and two-dimensional 1H-NMR spectroscopy. Resonance assignments have been obtained for most protons in the molecule, and for the alpha and beta carbon atoms. The lack of concentration dependence of the 1H chemical shifts and linewidths indicates that self-association is not significant and cannot account for the sheet-like structure near the N terminus. The structure is stable to high temperature, showing little change even at 353 K. This stability allowed backbone-amide temperature coefficients to be interpreted, and the correlation of these values with hydrogen bonds observed in the structures and with solvent exchange rates is discussed. pKa values have been measured for Asp5, His19 and Tyr23, and the contributions to these pKa values from other residues investigated using the analogues R11Q (denoting substitution of Argll with Gln), R11E, H19K, K22A, Y23A and K30A. These results show that Asp5 (pKa 2.8) makes an electrostatic interaction with Lys30, which may be partially responsible for the importance of these side chains in the folding of synthetic toxin. The phenolic pKa of Tyr23 is reduced to 8.7 in the native toxin, as a result of interactions with the positively charged side chains of Arg11 and to a lesser extent Lys22. Several hydrogen bonds between the Arg11 guanidino group and the Tyr23 phenolic group are found in the solution structures. As these three residues are implicated in the tight binding of ShK toxin to the T-lymphocyte voltage-gated potassium channel Kv1.3, their close interactions should be taken into account in models of binding of this toxin to the pore and vestibule of this and other potassium channels.

Amino Acid Sequence↗

PubMed1996

Myocardial ischemia/reperfusion protection using monophosphoryl lipid A is abrogated by the ATP-sensitive potassium channel blocker, glibenclamide.

OBJECTIVES: Monophosphoryl lipid A (MLA), a detoxified derivative of the lipid A portion of the endotoxin molecule, given as a pretreatment 24 h prior to cardiac ischemia/reperfusion reduces myocardial stunning and infarction in dogs. This study was undertaken to evaluate the ability of MLA pretreatment to reduce infarct size in a rabbit model of in situ regional myocardial ischemia and reperfusion. Secondly, the potential role of modulation of ATP-sensitive potassium (KATP) channel in MLA's cardioprotection was evaluated using in vivo pharmacologic antagonism with a KATP channel blocker, as was the role of tumor necrosis factor using an enzyme-linked immunosorbent assay method of serum cytokine analysis. METHODS: Rabbits were pretreated intravenously with MLA or vehicle injection 24 h prior to initiation of 30 min in situ left anterior descending coronary artery occlusion followed by 3 h reperfusion. In animals receiving glibenclamide, the potassium channel antagonist was administered 30 min prior to inducing ischemia. Animals receiving glibenclamide, which possesses hypoglycemic effects, underwent serial blood glucose evaluation prior to drug and throughout the ischemia and reperfusion periods. Hemodynamics were monitored; infarct size and area at risk were assessed by contrast dye staining (triphenyltetrazolium chloride). Serum tumor necrosis factor was measured by enzyme-linked immunosorbent method in animals administered cardioprotective doses of MLA as well as pyrogenic doses of MLA and endotoxin (positive control) to determine if elaboration of this cytokine could be associated with the cardioprotective effect of MLA. RESULTS: MLA administered as a single intravenous dose 24 h prior to ischemia reduced infarct size, expressed as a percent of the area at risk, 64 and 71% at doses of 35 and 10 micrograms/kg, respectively. Lower doses of MLA (2.5 and 5 micrograms/kg) did not significantly reduce infarct size. Administration of glibenclamide (300 micrograms/kg) 30 min prior to ischemia completely blocked the ability of MLA pretreatment to limit infarct size, while MLA vehicle-glibenclamide-treated control rabbits displayed infarcts not significantly different from MLA-vehicle-treated control rabbits. A cardioprotective dose of MLA (35 micrograms/kg) did not induce the elaboration of tumor necrosis factor into rabbit serum (within the limits of assay sensitivity). CONCLUSIONS: Single-dose pretreatment with MLA administered intravenously to rabbits substantially reduces infarct size when administered 24 h prior to ischemia. Pharmacologic preconditioning with MLA appears to be mediated through KATP channels as the channel blocker, glibenclamide, reversed the cardioprotective activity of MLA when administered 1 day following MLA pretreatment, yet 30 min prior to ischemia. In this model the cardioprotective does not appear to be associated with increases in serum tumor necrosis factor.

Adenosine Triphosphate↗

PubMed1994

Kaliotoxin (1-37) shows structural differences with related potassium channel blockers.

The three-dimensional structure of kaliotoxin (1-37), KTX(1-37), a toxin from the scorpion Androctonus mauretanicus mauretanicus that blocks calcium-dependent potassium channels, has been determined by NMR. This toxin is homologous with other scorpion toxins such as charybdotoxin (ChTX) or iberiotoxin (IbTX) for which the structures are already known, but the presence of prolines in the expected alpha-helical region suggested that there may be some major difference in the structure of KTX that could be related to its different selectivity. Proline residues are also found in the homologous region of other scorpion toxins such as noxiustoxin or margatoxin. Our results indicate that KTX(1-37) contains the same sequence of secondary structure elements as ChTX but that the helical region is shorter and distorted due to the presence of two prolines. The distortion consists of a bending in the alpha-helix and in the presence of a 3(10) helix turn in the last three residues. Furthermore, the increased length of the extended structure preceding the helix favors a different packing of this part of the molecule with respect to the secondary structure elements. This change in folding modifies the accessibility of the conserved 27Lys which is known, from mutation studies, to be involved in channel blocking by ChTX.

Amino Acid Sequence↗

PubMed1999

ATP-sensitive potassium channel blocker HMR 1883 reduces mortality and ischemia-associated electrocardiographic changes in pigs with coronary occlusion.

ATP-sensitive potassium (K(ATP)) channels are activated during myocardial ischemia. The ensuing potassium efflux leads to a shortening of the action potential duration and depolarization of the membrane by accumulation of extracellular potassium favoring the development of reentrant arrhythmias, including ventricular fibrillation. The sulfonylthiourea HMR 1883 was designed as a cardioselective blocker of myocardial K(ATP) channels for the prevention of arrhythmic sudden death in patients with ischemic heart disease. We investigated the effect of HMR 1883 on sudden cardiac arrhythmic death and electrocardiography (ECG) changes induced by 20 min of left anterior descending coronary artery occlusion in pentobarbital-anesthetized pigs. HMR 1883 (3 mg/kg i.v.) protected pigs from arrhythmic death (91% survival rate versus 33% in control animals; n = 12; p<.05). Ischemic areas were of a similar size. The compound had no effect on hemodynamics and ECG, including Q-T interval, under baseline conditions and no effect on hemodynamics during occlusion. In control animals, left anterior descending coronary artery occlusion lead to a prompt and significant depression of the S-T segment (-0.35 mV) and a prolongation of the Q-J time (+46 ms), the former reflecting heterogeneity in the plateau phase of the action potentials and the latter reflecting irregular impulse propagation and delayed ventricular activation. Both ischemic ECG changes were significantly attenuated by HMR 1883 (S-T segment, -0.14 mV; Q-J time, +15 ms), indicating the importance of K(ATP) channels in the genesis of these changes. In conclusion, the K(ATP) channel blocker HMR 1883, which had no effect on hemodynamics and ECG under baseline conditions, reduced the extent of ischemic ECG changes and sudden death due to ventricular fibrillation during coronary occlusion.

Anesthesia↗

PubMed2005

An unusual fold for potassium channel blockers: NMR structure of three toxins from the scorpion Opisthacanthus madagascariensis.

The Om-toxins are short peptides (23-27 amino acids) purified from the venom of the scorpion Opisthacanthus madagascariensis. Their pharmacological targets are thought to be potassium channels. Like Csalpha/beta (cystine-stabilized alpha/beta) toxins, the Om-toxins alter the electrophysiological properties of these channels; however, they do not share any sequence similarity with other scorpion toxins. We herein demonstrate by electrophysiological experiments that Om-toxins decrease the amplitude of the K+ current of the rat channels Kv1.1 and Kv1.2, as well as human Kv1.3. We also determine the solution structure of three of the toxins by use of two-dimensional proton NMR techniques followed by distance geometry and molecular dynamics. The structures of these three peptides display an uncommon fold for ion-channel blockers, Csalpha/alpha (cystine-stabilized alpha-helix-loop-helix), i.e. two alpha-helices connected by a loop and stabilized by two disulphide bridges. We compare the structures obtained and the dipole moments resulting from the electrostatic anisotropy of these peptides with those of the only other toxin known to share the same fold, namely kappa-hefutoxin1.

Amino Acid Sequence↗

PubMed2004

Electro-acupuncture preconditioning abrogates the elevation of c-Fos and c-Jun expression in neonatal hypoxic-ischemic rat brains induced by glibenclamide, an ATP-sensitive potassium channel blocker.

This study aimed to clarify the neuroprotective mechanism of electro-acupuncture (EA) preconditioning on hypoxic-ischemic brain injury (HIBI). Using Western blot, the expression of c-fos protein (c-Fos) and c-jun protein (c-Jun) induced by glibenclamide, an ATP-sensitive potassium (K(ATP)) channel blocker was examined from cerebral cortical and hippocampal samples in neonatal hypoxic-ischemic rats, with or without EA preconditioning. EA was performed on Hegu (LI4), a well-known acupoint commonly used in Oriental medicine for the treatment of neuronal injury resulting from hypoxia-ischemia (HI). Preconditioned rats were treated with either diazoxide, a K(ATP) channel opener, glibenclamide, or sterile saline injected into the left lateral ventricle (i.c.v.), with or without EA administration before HI insult. Interestingly, low c-Fos and c-Jun expressions were found both in diazoxide and EA groups, 24 h after HI. Furthermore, significant differences in relative optical density (ROD) were found between glibenclamide and HI control groups (P< or =0.05), as well as between the group administered glibenclamide after EA and the HI control group (P< or =0.05). However, the level of c-Fos and c-Jun expression in the group administered glibenclamide after EA was significantly lower than in the glibenclamide group (P< or =0.05). The present findings indicate that the effectiveness of EA preconditioning against HIBI may be mediated via the opening of K(ATP) channels.

Animals↗

PubMed1978

3,4-diaminopyridine. A potent new potassium channel blocker.

3,4-diaminopyridine has been found to act very potently in selectively blocking the potassium channels of squid axon membranes. The apparent dissociation constants for this action are estimated to be 5.8 micron and 0.7 micron for external and internal applications, respectively, the potency being about 50 times higher than that of 4-aminopyridine. The block depends upon the membrane potential, time, and stimulus frequency. 3,4-diaminopyridine shows great promise as a useful tool for the study of membrane ionic channels.

Action Potentials↗