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Results for “Potassium Channel Blockers”

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At least 577 records · Page 32Linked to original sources

PubMed2004

Electrophysiological characterization of the SK channel blockers methyl-laudanosine and methyl-noscapine in cell lines and rat brain slices.

We have recently shown that the alkaloid methyl-laudanosine blocks SK channel-mediated afterhyperpolarizations (AHPs) in midbrain dopaminergic neurones. However, the relative potency of the compound on the SK channel subtypes and its ability to block AHPs of other neurones were unknown. Using whole-cell patch-clamp experiments in transfected cell lines, we found that the compound blocks SK1, SK2 and SK3 currents with equal potency: its mean IC(50)s were 1.2, 0.8 and 1.8 microM, respectively. IK currents were unaffected. In rat brain slices, methyl-laudanosine blocked apamin-sensitive AHPs in serotonergic neurones of the dorsal raphe and noradrenergic neurones of the locus coeruleus with IC(50)s of 21 and 19 microM, as compared to 15 microM in dopaminergic neurones. However, at 100 microM, methyl-laudanosine elicited a constant hyperpolarization of serotonergic neurones of about 9 mV, which was inconsistently (i.e. not in a reproducible manner) antagonized by atropine and hence partly due to the activation of muscarinic receptors. While exploring the pharmacology of related compounds, we found that methyl-noscapine also blocked SK channels. In cell lines, methyl-noscapine blocked SK1, SK2 and SK3 currents with mean IC(50)s of 5.9, 5.6 and 3.9 microM, respectively. It also did not block IK currents. Methyl-noscapine was slightly less potent than methyl-laudanosine in blocking AHPs in brain slices, its IC(50)s being 42, 37 and 29 microM in dopaminergic, serotonergic and noradrenergic neurones, respectively. Interestingly, no significant non-SK effects were observed with methyl-noscapine in slices. At a concentration of 300 microM, methyl-noscapine elicited the same changes in excitability in the three neuronal types than did a supramaximal concentration of apamin (300 nM). Methyl-laudanosine and methyl-noscapine produced a rapidly reversible blockade of SK channels as compared with apamin. The difference between the IC(50)s of apamin (0.45 nM) and methyl-laudanosine (1.8 microM) in SK3 cells was essentially due to a major difference in their k(-1) (0.028 s(-1) for apamin and >or=20 s(-1) for methyl-laudanosine). These experiments demonstrate that both methyl-laudanosine and methyl-noscapine are medium potency, quickly dissociating, SK channel blockers with a similar potency on the three SK subtypes. Methyl-noscapine may be superior in terms of specificity for the SK channels.

Animals↗

PubMed1996

Sleep cycle disturbances induced by apamin, a selective blocker of Ca(2+)-activated K+ channels.

Intracerebroventricular injections of low doses of apamin, a specific blocker of a class of Ca(2+)-activated K+ channels, induced insomnia and a long-lasting suppression of deep slow sleep and paradoxical sleep. Injected animals showed a late but important rebound of paradoxical sleep. Even after the recovery of a normal sleep amount, the circadian cycle remained disturbed during all the recording duration (96 h).

Animals↗

PubMed2005

Multiple actions of U-37883A, an ATP-sensitive K+ channel blocker, on membrane currents in pig urethra.

The effects of U-37883A, a vascular ATP-sensitive K(+) channel (K(ATP) channel) blocker, on membrane currents were investigated in pig urethral myocytes by use of patch-clamp techniques (conventional whole-cell recordings, nystatin-perforated patches and cell-attached configuration). Tension measurement was also performed to study the effects of U-37883A on the levcromakalim-induced urethral relaxation and the urethral resting tone in the absence and presence of Bay K 8644. Although cumulative application of U-37883A produced a concentration-dependent inhibitory effect on the levcromakalim-induced urethral relaxation, U-37883A did not abolish the relaxation. In nystatin-perforated patch recording, K(ATP) currents activated by levcromakalim were inhibited by U-37883A in a concentration-dependent manner (K(i), 4.7 microM). Approximately 10% of the K(ATP) currents still remained even in the presence of 300 microM U-37883A. In cell-attached mode, extracellular application of U-37883A (100 microM) irreversibly inhibited the activity of the levcromakalim-induced K(ATP) channels. In whole-cell configuration, U-37883A suppressed the peak amplitude of voltage-dependent Ba(2+) currents in a concentration- and voltage-dependent manner, and at 30 microM, shifted the steady-state inactivation curve of the Ba(2+) currents to the left at -90 mV. These results demonstrate that U-37883A reduces not only the activities of K(ATP) channels but also voltage-dependent Ca(2+) channels. Therefore, it is not appropriate to define U-37883A as solely a vascular K(ATP) channel blocker.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed2004

Contribution of coupling between human myometrial beta2-adrenoreceptor and the BK(Ca) channel to uterine quiescence.

The beta(2)-adrenergic receptor (beta(2)-AR) and the large-conductance Ca(2+)-activated K(+) (BK(Ca)) channel have been shown, separately, to be involved in mediating uterine relaxation. Our recent studies reveal that the levels of both beta(2)-AR and BK(Ca) channel proteins in pregnant human myometrium decrease by approximately 50% after the onset of labor. We present direct evidence in support of a structural and functional association between the beta(2)-AR and the BK(Ca) channel in pregnant human myometrium. Localization of both proteins is predominantly plasmalemmal, with 60% of beta(2)-AR colocalizing with the BK(Ca) channel. Coimmunoprecipitation studies indicate that BK(Ca) and beta(2)-AR are structurally linked by direct protein-protein interactions. Functional correlation was confirmed by experiments of human myometrial contractility in which the BK(Ca) channel blocker, paxilline, significantly antagonized the relaxant effect of the beta(2)-AR agonist ritodrine. These novel findings provide an insight into the coupling between the beta(2)-AR and BK(Ca) channel and may have utility in the application of this signaling cascade for therapeutic potential in the management of preterm labor.

Female↗

PubMed1995

Mexiletine-induced shortening of the action potential duration of ventricular muscles by activation of ATP-sensitive K+ channels.

A class Ib antiarrhythmic drug, mexiletine (100 microM) significantly shortened the action potential duration (APD) of guinea-pig ventricular muscles and this effect was completely abolished in the presence of glibenclamide (50 microM), a blocker of the ATP-sensitive K+ channel (KATP). Mexiletine significantly increased the open probability of uridine diphosphate-primed KATP channels, recorded in inside-out patches of the ventricular cells. The results suggest that mexiletine shortens the APD of ventricular muscles, at least in part, via activation of KATP.

Action Potentials↗

PubMed2002

Intestinal ischemia preconditions myocardium: role of protein kinase C and mitochondrial K(ATP) channel.

OBJECTIVE: The present study was designed to test the hypothesis that intestinal ischemia results in an early preconditioning against myocardial infarction and that the mechanism of the early preconditioning involves the activation of protein kinase C-mitochondrial K(ATP) channel signaling pathway in anesthetized rats. METHODS: Rats were either preconditioned with a 25-min occlusion of the superior mesenteric artery followed by 15 min of reperfusion or underwent a 40-min sham period. Subsequently, all rats were subjected to a sustained 30 min of coronary occlusion and 180 min of reperfusion. Infarct size was determined by triphenyltetrazolium chloride staining. RESULTS: In sham-operated rats receiving no pharmacological intervention, the percentage of myocardial infarct within the area at risk and left ventricle was 73+/-4% and 31+/-2%, respectively, and these were significantly reduced to 44+/-4% and 23+/-1% (P<0.01) after intestinal ischemia preconditioning. Intravenous injection of protein kinase C inhibitors chelerythrine (5 mg/kg) and staurosporine (50 microg/kg) or a specific mitochondrial K(ATP) channel inhibitor 5-hydroxydecanoate (5 mg/kg) 5 min before sustained myocardial ischemia abolished the preconditioning afforded by intestinal ischemia. However, hexamethonium, a ganglion blocker, did not attenuate the preconditioning. CONCLUSIONS: These data provide pharmacological evidence that protein kinase C and mitochondrial K(ATP) channel are involved in the mechanism of the early preconditioning induced by intestinal ischemia.

Alkaloids↗

PubMed1998

Histamine receptor subtypes mediating hyperpolarization in the isolated, perfused rat mesenteric pre-arteriolar bed.

Histamine is a general dilator of rat blood vessels. We investigated the relative contribution of receptor subtypes to the rat mesenteric dilator responses initiated by histamine and related agonists. Histamine initiated dose, and endothelium-dependent, dilation of constricted mesenteric beds with an ED50 of 0.4 +/- 0.1 nmol. The ED50 was increased 10-fold by 0.1 microM chlorpheniramine (a histamine H1-receptor selective antagonist). Histamine H2 receptor blockade with tiotidine (0.1 microM) slightly decreased, while thioperamide (1 microM), a selective histamine H3 receptor antagonist, did not block histamine-induced dilation. Mesenteric bed dilation initiated by histamine H2 receptor selective agonists, amthamine and dimaprit, were antagonized markedly by tiotidine. However, the dilation initiated by the putative histamine H3 receptor selective agonists, R(-)- or S(+)-alpha-methylhistamine and imetit were not affected by thioperamide (1 microM). Histamine H2- and H3-receptor mediated dilator effects were endothelium-independent and were blocked by either excess (80 mM) extracellular K+, or 1 mM tetrabutylammonium (a non-selective K+ channel blocker), as well as by 1 microM dequalinium, a non-peptide blocker of the small conductance Ca2+-activated (SKCa) K+ channels. We conclude that (i) histamine H1 receptor subtype predominantly mediates endothelium-dependent dilator effect of histamine, and (ii) vascular hyperpolarization through opening of K+ channels (SKCa) mediate the dilator responses to histamine H2 receptor (amthamine and dimaprit) and the putative histamine H3 receptor (R(-)-alpha-methylhistamine and imetit) agonists.

Animals↗

PubMed1994

Role of endothelium and arterial K+ channels in mediating hypoxic dilation of middle cerebral arteries.

Isolated middle cerebral arteries of rats were perfused and superfused simultaneously with physiological salt solution (PSS) equilibrated with control (21% O2) or with reduced O2 concentrations (15, 10, 5, or 0% O2). Arterial dilation in response to reduced PO2 was unaffected by the nitric oxide synthase inhibitor N omega-nitro-L-arginine (10 microM) but was inhibited by selective perfusion of the lumen with 21% O2 PSS (0% O2 in the superfusion), endothelial removal, and 1 microM indomethacin. Arterial dilation during reduced PO2 was unaffected by 1 mM tetraethylammonium to block the Ca(2+)-dependent "maxi-K+" channel but was eliminated by 1 microM glibenclamide, a blocker of the ATP-sensitive K+ channel. Glibenclamide also inhibited dilation of the vessels in response to the stable prostacyclin analogue, iloprost. The results of this study suggest that dilation of rat middle cerebral arteries in response to reduced PO2 is mediated by an endothelium-dependent cyclooxygenase product, which activates glibenclamide-sensitive K+ channels.

Animals↗

PubMedDate not supplied

Decreased vasodilation induced by a new nitric oxide donor in two kidney, one clip hypertensive rats is due to impaired k channel activation.

1. We studied the effect of the new compound trans-[RuCl([15]aneN(4))NO](2+) (15-ane) in denuded aortic rings of two kidney (2K) normotensive and two kidney, one clip (2K-1C) hypertensive rats. 2. The compound 15-ane releases nitric oxide (NO) when reduced by a catecholamine (noradrenaline). 3. Oxyhemoglobin (HbO(2)), an NO scavenger, completely abolished the effect of 15-ane in both 2K and 2K-1C rats, indicating that the relaxation is really due to NO release. 4. We tested the hypothesis that an impairment of K(+) channels plays an important role in the vasodilation induced by 15-ane. 5. The selective inhibitor of soluble guanylyl-cyclase, namely 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ; 1 micromol/L) reduced the relaxation induced by 15-ane. In 2K-1C rat aortic rings, ODQ reduced the maximum effect (E(max)) of 15-ane, whereas in 2K rat aortic rings ODQ reduced E(max) and pD(2) values to 15-ane. 6. The selective K(+) channel blockers glibenclamide (blocks K(ATP); 3 micromol/L), 4-aminopyridine (blocks K(V); 1 mmol/L) and the small conductance K(Ca) channel blocker apamin (1 micromol/L) reduced E(max) and pD(2) values for 15-ane-induced relaxation responses of aortas from 2K rats. However, iberiotoxin, a blocker of large conductance K(Ca) channels, reduced only the E(max) to 15-ane. None of these K(+) channel blockers had any effect on the relaxation induced by 15-ane of aortas from 2K-1C rats. 7. These data indicate that an impaired functional activity of K(+) channels contributes to the deficient relaxation induced by the NO donor 15-ane in renal hypertensive 2K-1C rat aortas.

Animals↗

PubMed2000

Glucose- and arginine-induced insulin secretion by human pancreatic beta-cells: the role of HERG K(+) channels in firing and release.

The human ether-a-go-go-related genes (herg) are expressed in tissues other than heart and brain where the HERG K(+) channels are known to regulate the repolarization of the heart action potential and the neuronal spike-frequency accommodation. We provide evidence that herg1 transcripts are present in human pancreatic islets that were used to study both insulin secretion and electrical activity with radioimmunoassay and single cell perforated patch-clamp techniques, respectively. Glucose- and arginine-induced islets insulin secretion data suggested a net increase of release under perfusion with antiarrhythmic drugs known to selectively block HERG channels. Indeed we could routinely isolate a K(+) current that was recognized as biophysically and pharmacologically similar to the HERG current. An analysis of the glucose- and arginine-induced electrical activity (several applications during 30 min) in terms of firing frequency and putative insulin release was done in control and in the presence of selective blockers of HERG channels: the firing frequency and the release increased by 32% and 77%, respectively. It is concluded that HERG channels have a crucial role in regulating insulin secretion and firing of human beta-cells. This raises the possibility that some genetically characterized hyperinsulinemic diseases of unknown origin might involve mutations in the HERG channels.

ATP-Binding Cassette Transporters↗

PubMed2003

Streptozotocin-diabetes alters action potentials in rat diaphragm.

This study tested the hypothesis that diabetes alters diaphragm action potentials and electrophysiological responses to K(+) channel blockade. Intracellular recordings were performed in vitro in diaphragm fibers from streptozotocin-induced diabetic and normal Wistar rats (glucose 670+/-31 vs. 252+/-14 mg/dl). Comparing diabetic to normal muscle properties, resting membrane potential was significantly depolarized (-72.2+/-0.8 vs. -77.4+/-1.1 mV), action potential 50% repolarization time was significantly accelerated (0.33+/-0.01 vs. 0.39 +/-0.01 msec), and action potential area was significantly decreased (59.4+/-2.3 vs. 70.7+/-2.2 mV msec). The K(+) channel blocker 3,4-diaminopyridine (DAP) depolarized resting membrane potential of normal but not diabetic muscle. DAP significantly prolonged action potential repolarization and significantly increased action potential area, but significantly more in normal than diabetic muscle. These data indicate that diabetes shortens diaphragm action potentials, which appears to be due to altered K(+) channels.

4-Aminopyridine↗

PubMed1998

Blockade of HERG channels by the class III antiarrhythmic azimilide: mode of action.

1. The class III antiarrhythmic azimilide has previously been shown to inhibit I(Ks) and I(Kr) in guinea-pig cardiac myocytes and I(Ks) (minK) channels expressed in Xenopus oocytes. Because HERG channels underly the conductance I(Kr), in human heart, the effects of azimilide on HERG channels expressed in Xenopus oocytes were the focus of the present study. 2. In contrast to other well characterized HERG channel blockers, azimilide blockade was reverse use-dependent, i.e., the relative block and apparent affinity of azimilide decreased with an increase in channel activation frequency. Azimilide blocked HERG channels at 0.1 and 1 Hz with IC50s of 1.4 microM and 5.2 microM respectively. 3. In an envelope of tail test, HERG channel blockade increased with increasing channel activation, indicating binding of azimilide to open channels. 4. Azimilide blockade of HERG channels expressed in Xenopus oocytes and I(Kr) in mouse AT-1 cells was decreased under conditions of high [K+]e, whereas block of slowly activating I(Ks) channels was not affected by changes in [K+]e. 5. In summary, azimilide is a blocker of cardiac delayed rectifier channels, I(Ks) and HERG. Because of the distinct effects of stimulation frequency and [K+]e on azimilide block of I(Kr) and I(Ks) channels, we conclude that the relative contribution of block of each of these cardiac delayed rectifier channels depends on heart frequency. [K+]e and regulatory status of the respective channels.

Animals↗

PubMed2002

K+ currents generated by NMDA receptor activation in rat hippocampal pyramidal neurons.

Long lasting outward currents mediated by Ca2+-activated K+ channels can be induced by Ca2+ influx through N-methyl-D-aspartate (NMDA)-receptor channels in voltage-clamped hippocampal pyramidal neurons. Using specific inhibitors, we have attempted to identify the channels that underlie these outward currents. At a holding potential of -50 mV, applications of 1 mM NMDA to the soma of cultured hippocampal pyramidal neurons induced the expected inward currents. In 44% of cells tested, these were followed by outward currents (average amplitude 60 +/- 7 pA) that peaked 2.5 s after the initiation of the inward NMDA currents and decayed with a time constant of 1.4 s. In 43% of those cells exhibiting an outward current, SK channel inhibitors, UCL 1848 (100 nM) and apamin (100 nM) abolished the outward current. In the remainder of the cells, the outward currents were either insensitive or only partly inhibited (44 +/- 4%) by 100 nM UCL 1848. In these cells, the outward currents were reduced by the slow afterhyperpolarization (sAHP) inhibitors, muscarine (3 microM; 43 +/- 9%), UCL 1880 (3 microM; 34 +/- 10%), and UCL 2027 (3 microM; 57 +/- 6%). Neither the BK channel inhibitor, charybdotoxin (100 nM), nor the Na+/K+ ATPase inhibitor, ouabain (100 microM), reduced these outward currents. Irrespective of the pharmacology, the time course of the outward current did not differ. Interestingly, no correlation was observed between the presence of a slow apamin-insensitive afterhyperpolarization and an outward current insensitive to SK channel blockers following NMDA-receptor activation. It is concluded that an NMDA-mediated rise in [Ca2+]i can result in the activation of apamin-sensitive SK channels and of the channels that underlie the sAHP. The activation of these channels may, however, depend on their location relative to NMDA receptors as well as on the spatial Ca2+ buffering within individual neurons.

Action Potentials↗

PubMed2005

Predicting drug-hERG channel interactions that cause acquired long QT syndrome.

Avoiding drug-induced cardiac arrhythmia is recognized as a major hurdle in the successful development of new drugs. The most common problem is acquired long QT syndrome caused by drugs that block human ether-a-go-go-related-gene (hERG) K(+) channels, delay cardiac repolarization and increase the risk of torsades de pointes arrhythmia (TdP). Not all hERG channel blockers induce TdP because they can also modulate other channels that counteract the hERG channel-mediated effect. However, hERG channel blockade is an important indicator of potential pro-arrhythmic liability. The molecular determinants of hERG channel blockade have been defined using a site-directed mutagenesis approach. Combined with pharmacophore models, knowledge of the drug-binding site of hERG channels will facilitate in silico design efforts to discover drugs that are devoid of this rare, but potentially lethal, side-effect.

Animals↗

PubMed1994

Role of ATP-sensitive K+ channels in antinociception induced by R-PIA, an adenosine A1 receptor agonist.

The influence of several K+ channel-acting drugs on antinociception induced by the adenosine A1 receptor agonist (-)-N6-(2-phenylisopropyl)-adenosine (R-PIA) was evaluated with a tail flick test in mice. The subcutaneous administration of R-PIA (0.5-8 mg/kg) induced a dose-dependent antinociceptive effect. The ATP-sensitive K+ (KATP) channel blocker gliquidone (2-8 micrograms/mouse, i.c.v.) produced a dose-dependent displacement to the right of the R-PIA dose-response line, whereas the KATP channel opener cromakalim (32 micrograms/mouse, i.c.v.) shifted it to the left. Several KATP channel blockers dose-dependently antagonized the antinociceptive effect of R-PIA, the order of potency being gliquidone > glipizide > glibenclamide (i.e., the same order of potency shown by these drugs in blocking KATP channels in neurons). In contrast, the K+ channel blockers 4-aminopyridine and tetraethylammonium did not antagonize the effect of R-PIA. These data suggest that antinociception produced by adenosine A1 receptor agonists is mediated by the opening of ATP-sensitive K+ channels. The present results, together with those of previous studies, further support a role for K+ channel opening in the antinociceptive effect of agonists of receptors coupled to Gi/Go proteins.

4-Aminopyridine↗

PubMed2006

Physiological volume regulation by spermatozoa.

Maturing spermatozoa passing through the epididymis experience increasing osmolality in the luminal environment and mature cells are stored in fluids hyper-osmotic to serum. When ejaculated into the female tract, they encounter a hypo-osmotic challenge which initiates the process of regulatory volume decrease (RVD). Defects in RVD result in hindrance of mucus penetration in man and failure of utero-tubal passage in mice. Epididymal sperm from the mouse and cynomolgus monkey and ejaculated sperm from man and monkey have been isolated and dispersed in media with osmolalities mimicking those of uterine fluid or cervical mucus. The effects of specific and broad-spectrum ion channel blockers indicate the involvement of separate K+ and Cl- channels as well as organic osmolytes in physiological sperm RVD, with mechanisms developed during epididymal maturation. Western blotting and immuno-cytochemistry identify and localise some of these channels which play a crucial role in fertilisation in vivo and could be targets for post-testicular contraception.

Animals↗

PubMed1997

Mapping the receptor site for hanatoxin, a gating modifier of voltage-dependent K+ channels.

Hanatoxin (HaTx) binds to multiple sites on the surface of the drk1 voltage-gated K+ channel and modifies channel gating. We set out to identify channel residues that contribute to form these HaTx binding sites. Chimeras constructed using the drk1 and shaker K+ channels suggest that the S3-S4 linker may contain influential residues. Alanine scanning mutagenesis of the region extending from the C terminal end of S3 through S4 identified a number of residues that likely contribute to form the HaTx binding sites. The pore blocker Agitoxin2 and the gating modifier HaTx can simultaneously bind to individual K+ channels. These results suggest that residues near the outer edges of S3 and S4 form the HaTx binding sites and are eccentrically located at least 15 A from the central pore axis on the surface of voltage-gated K+ channels.

Amino Acid Sequence↗

PubMed2004

Study of the involvement of K+ channels in the peripheral antinociception of the kappa-opioid receptor agonist bremazocine.

The involvement of the nitric oxide (NO)/cyclic GMP pathway in the molecular mechanisms of antinociceptive drugs like morphine has been previously shown by our group. Additionally, it is known that the desensitisation of nociceptors by K(+) channel opening should be the final target for several analgesic drugs including nitric oxide donors and exogenous micro-opioid receptor agonists. In our previous study, we demonstrated that bremazocine, a kappa-opioid receptor agonist, induces peripheral antinociception by activating nitric oxide/cyclic GMP pathway. In the current study, we assessed whether bremazocine is capable to activate K(+) channels eliciting antinociception. Bremazocine (20, 40 and 50 microg) dose-dependently reversed the hyperalgesia induced in the rat paw by local injection of carrageenan (250 microg) or prostaglandin E(2) (2 microg), measured by the paw pressure test. Using the selective kappa-opioid receptor antagonist nor-binaltorphimine (Nor-BNI, 200 microg/paw), it was confirmed that bremazocine (50 microg/paw) acts specifically on the kappa-opioid receptors present at peripheral sites. Prior treatment with the ATP-sensitive K(+) channel blockers glibenclamide (40, 80 and 160 microg) and tolbutamide (40, 80 and 160 microg) did not antagonise the antinociceptive effect of bremazocine (50 microg). The same results were obtained when we used prostaglandin E(2) (2 microg) as the hyperalgesic stimulus. The supposed participation of other types of K(+) channels was tested using the Ca(2+)-activated K(+) channel blockers dequalinium (12.5, 25 and 50 microg) and charybdotoxin (0.5, 1 and 2 microg) and different types of the non-selective K(+) channel blockers tetraethylammonium (25, 50 and 100 microg) and 4-aminopyridine (10, 25 and 50 microg). None of the K(+) channel blockers reversed the antinociceptive effect of bremazocine. On the basis of these results, we suggest that K(+) channels are not involved in the peripheral antinociceptive effect of bremazocine, although this opioid receptor agonist induces nitric oxide/cGMP pathway activation.

4-Aminopyridine↗