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Results for “Potassium Channel Blockers”

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PubMed1998

[Adenosine facilitates carotid baroreflex in rats].

The effects of adenosine (Ado) on the carotid baroreflex were studied in 27 anesthetized rats with isolated carotid sinus perfusion. The results obtained were as follows: (1) By perfusing the isolated carotid sinus with adenosine (125 mumol/L), the functional curve of baroreflex was shifted to the left and downward, with the peak slope (PS) increased from 0.37 +/- 0.02 to 0.55 +/- 0.02 kPa/kPa (P < 0.001) and the reflex decrease in mean arterial pressure (RD) enhanced from 5.53 +/- 0.12 to 7.76 +/- 0.36 kPa (P < 0.001). Meanwhile, the threshold pressure (TP), equilibrium pressure (EP) and saturation pressure (SP) were significantly decreased from 8.60 +/- 0.27 to 5.63 +/- 0.11 kPa (P < 0.001), 12.53 +/- 0.30 to 10.89 +/- 0.29 kPa (P < 0.01) and 23.69 +/- 0.15 to 20.18 +/- 0.55 kPa (P < 0.001), respectively. Among the functional parameters of carotid baroreflex, the changes of RD, PS and TP induced by Ado were dose-dependent. (2) By pretreatment with (8-cyclopentyl-1, 3-dipropylxanthine, 0.134 mmol/L), a selective adenosine A1-receptor antagonist, the above effects of Ado on carotid baroreflex were abolished. (3) The Ado-induced changes of baroreflex were also eliminated as the carotid sinus was pretreated with KATP channel blocker glibenclamide (10 mumol/L). The results strongly suggest that the carotid baroreflex could be facilitated by Ado. It is proposed that the facilitatory action of Ado on carotid baroreflex may be resulted from the opening of KATP channels mediated by Ado A1-receptors.

Adenosine↗

PubMed2003

UV-induced corneal epithelial cell death by activation of potassium channels.

PURPOSE: The purpose of the present study is to determine the role of K+ channel activity as an early event in UV-induced corneal epithelial cell apoptosis. METHOD: Both cell-attached and nystatin-perforated patch-clamping were performed to record K+ channel activity in rabbit corneal epithelial (RCE) and primary cultured rabbit corneal epithelial (PRCE) cells exposed to UV irradiation. On exposure of corneal epithelial cells or intact corneas to UV-C irradiation or treatment of corneal epithelial cells with etoposide, cell apoptosis was determined by DNA fragmentation, ethidium bromide-acridine orange nuclear stain and TdT-mediated dUTP nick-end labeling (TUNEL). RESULTS: In the present study, UV-irradiation-induced corneal epithelial cell apoptosis through activation of a K+ channel in the cell membrane was an early event in response to UV irradiation. UV-C irradiation (42 microJ/cm(2)) activated robust K+ channel activity in RCE and PRCE cells at both the single-channel and whole-cell levels, when measured with the cell-attached and nystatin-perforated patch clamps, respectively. Suppression of UV-irradiation-induced K+ channel activity with the specific K+ channel blocker 4-aminopurydine (4-AP) prevented UV-irradiation-induced apoptosis in the RCE and PRCE cells, loss of the superficial layer of corneal epithelium, and apoptosis in the basal layer corneal epithelium. However, suppression of K+ channel activity did not protect RCE and PRCE cells from etoposide, a topoisomerase II inhibitor, which induced cell death by bypassing the membrane. Furthermore, application of valinomycin, a K+ ionophore, to mimic the effect of mass activation of the K+ channel in RCE and PRCE cells caused cell apoptosis. CONCLUSIONS: The results indicate that UV irradiation induces superactivity of K+ channels in the membrane is an early event mediating signaling transduction and resulting in corneal epithelial cell death in response to UV irradiation.

4-Aminopyridine↗

PubMedDate not supplied

Inhibition of alpha-adrenergic responses in the rat liver by lipophilic K+ channel blockers or depolarizing Cl- gradients. Evidence for a potential-sensitive step in the signal transduction path.

To study the role of K+ channels and membrane potential in alpha-adrenergic responses of the rat liver, lipophilic K+ channel blockers quinidine and 4-aminopyridine were used or external Cl- was replaced with gluconate, an impermeant ion. Glucose release, O2 uptake, portal pressure, and K+ flux were measured in the isolated perfused liver. The alpha-agonist phenylephrine caused biphasic changes in each parameter, a fast transient followed by sustained elevated responses. Infusion of 5 mM 4-aminopyridine, 0.1 mM quinidine, or gluconate prior to phenylephrine inhibited each parameter, with the greatest inhibition occurring during the second phase. A similar pattern was seen with 2 mM EGTA. This contrasts with the full inhibition of all responses following exposure to the alpha-antagonist phentolamine. Infusion of each inhibitor at the peak of the sustained phase inhibited all responses. Phenylephrine-stimulated release of K+ was augmented in the presence of EGTA and was inhibited by 4-aminopyridine or quinidine. In contrast, beta-adrenergic stimulation of glucose release and K+ flux were not affected by the K+ channel blockers. Phenylephrine-stimulated glucose release from hepatocyte suspensions decreased by about 50% in the presence of 4-aminopyridine, EGTA, or gluconate. The results are discussed in terms of a potential role for K+ channels in alpha-adrenergic signal transduction in the liver.

4-Aminopyridine↗

PubMed2001

The expression and regulation of depolarization-activated K+ channels in the insulin-secreting cell line INS-1.

The aim of the present study was to characterize depolarization-activated outward currents in insulin-secreting INS-1 cells and to investigate the role of K+ channels other than the KATP channels in the regulation of insulin release. Outward currents were inhibited by 4-aminopyridine (4-AP, 10 mmol/l), tetraethylammonium (TEA, 10 mmol/l) and tetrapentylammonium (TPeA, 100 mumol/l) by 55.1 +/- 3.8% (n = 3), 78.1 +/- 3.2% (n = 6) and 98.7 +/- 0.8% (n = 5), respectively. Margatoxin (5 nmol/l) and charybdotoxin (3 mumol/l) had no effect. 4-AP inhibited mainly a fast-activating, slowly inactivating current, whereas the TEA- and TPeA-sensitive current components were slowly activating and non-inactivating. Forskolin and the forskolin analogue 1,9-dideoxyforskolin, which does not stimulate adenylyl cyclase, also inhibited the outward current, suggesting a direct effect on the channels. Using reverse transcriptase polymerase chain reaction (RT/PCR). Kv channel mRNAs of Kv1.4, Kv1.5, Kv2.1, Kv2.2, Kv3.1 and Kv3.2 were detected whereas other Kv channels, Kv1.1, Kv1.2, Kv1.3, Kv1.6 and Kv3.4 were not detected. Insulin secretion in the presence of tolbutamide (100 mumol/l) was increased by 4-AP, TEA and TPeA by 65%, 41% and 150%, respectively. Basal secretion was not affected by these blockers. Our study reveals that the opening of voltage-dependent K+ channels negatively controls insulin secretion in depolarized cells, probably by shortening the action potential thus reducing Ca2+ influx.

1-Methyl-3-isobutylxanthine↗

PubMed2006

A new ATP-sensitive potassium channel opener protects endothelial function in cultured aortic endothelial cells.

OBJECTIVE: Endothelial dysfunction is an early risk factor for cardiovascular disease and hypertension. Mechanisms that participate in endothelial dysfunction include reduced nitric oxide (NO) generation and increased endothelin-1 (ET-1) generation. Endothelial ATP-sensitive potassium (K(ATP)) channels are responsible for maintaining the resting potential of endothelial cells and modulating the release of vasoactive compounds. We hypothesized that activation of endothelial K(ATP) channels might result in the protection against endothelial dysfunction. METHODS: Using cultured bovine or rat aortic endothelial cells, we examined the effects of a new K(ATP) channels opener, iptakalim, on the secretion of vasoactive substances. We also investigated its effects on the expression of adhesion molecules in metabolically disturbed cultured endothelial cells. RESULTS: In cultured aortic endothelial cells, iptakalim caused a concentration-dependent inhibition of ET-1 release and synthesis that correlated with reduced levels of mRNA for ET-1 and endothelin-converting enzyme. These effects of iptakalim were significantly inhibited by pretreatment with glibenclamide (a K(ATP) channel blocker) for 1 h. Similarly, iptakalim enhanced the release of NO in a concentration-dependent manner and increased basal levels of free intracellular calcium. Iptakalim at the concentrations of 100 and 1000 microM increased the activities of NO synthase (NOS) significantly. After the activity of NOS was blocked by L-N(omega)-nitro-arginine methyl ester (L-NAME), the inhibition of iptakalim on ET-1 release was abolished. In endothelial cell models of metabolic disturbance induced by low-density lipoprotein, homocysteine, or hyperglycemia, treatment with iptakalim could inhibit the overexpression of monocyte chemoattractant protein-1 (MCP-1), Intercellular adhesive molecule-1 (ICAM-1), and vascular cell adhesive molecule-1 (VCAM-1) mRNA. CONCLUSION: Iptakalim is a promising drug that could protect against endothelial dysfunction through activating K(ATP) channels in endothelial cells.

ATP-Binding Cassette Transporters↗

PubMed1999

Renin secretion from permeabilized juxtaglomerular cells requires a permeant cation.

The cytosolic concentration of chloride correlates directly with renin secretion from renal juxtaglomerular granular (JG) cells. In the present study, the mechanism by which chloride stimulates renin release was investigated in a preparation of permeabilized rat glomeruli with attached JG cells. An isosmotic increase in the concentration of chloride by 129 mM stimulated renin release 16- to 20-fold. Substitution of K+ by the impermeant cation N-methyl-d-glucamine (NMDG) abolished this response, while substitution with Na+ caused marginal inhibition. Substitution with Cs+ had no effect. Addition of sucrose, which permeates the secretory granules poorly, also abolished the stimulation of renin secretion by KCl. The response to KCl was not affected by K+-channel antagonists or by agonists of K+ channels. Chloride channel blockers were also without effect on the secretory response to KCl. When the ATP concentration was lowered from 1 to 0.1 mM renin release was stimulated, while an increase in the ATP concentration from 1 to 5 mM had no effect. Blockers of ATP-sensitive (KATP) channels did not modify the response to chloride. The present data suggest that chloride stimulates renin release after entry of KCl into the renin secretory granules which results in swelling and release of renin.

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

PubMed1995

Pinacidil relaxes porcine and human coronary arteries by activating ATP-dependent potassium channels in smooth muscle cells.

We investigated the effect of the potassium channel opener pinacidil on ATP-dependent K+ channels (KATP) in the relaxation of porcine and human coronary arteries by means of isometric contraction experiments in arterial rings. We also measured whole cell currents in freshly isolated porcine and human coronary artery vascular smooth muscle cells with patch clamp. We first characterized serotonin-induced precontractions in our vessels and proved that the contractions were mediated by Ca2+ influx through voltage-dependent Ca2+ channels. Similarly, we observed that serotonin-induced contractions were strongly enhanced by small K(+)-induced depolarizations. Pinacidil completely relaxed rings preconstricted with 5 microM serotonin and produced dose-dependent relaxations of 5 microM serotonin-preconstricted rings, with an IC50 of 1.26 microM. Similar results were observed (IC50 = 1.15 microM) when the endothelium was removed. The KATP blocker glibenclamide (3 microM), inhibited pinacidil-induced relaxations (5-10 microM) by approximately 25% although the KATP blocker tetrapentylammonium (10 microM), inhibited pinacidil-induced (5-10 microM) relaxations completely. Pinacidil 10 microM had only a minimal effect on rings precontracted with a 50 mM external K+ concentration (IC50 = 60 microM). Porcine and human arterial rings did not differ qualitatively in their responses. Moreover, in the patch clamp experiments pinacidil (1 microM and 20 microM) induced a large, nonrectifying, outward current in both human and porcine cells. The reversal potential was close to the K+ equilibrium potential, suggesting an induction of pinacidil-activated K+ current. The pinacidil-induced (1 microM) current was strongly inhibited by glibenclamide (3 microM). These data show that the relaxation of porcine and human coronary arteries by pinacidil is primarily induced by an opening of KATP in smooth muscle cells. Furthermore, the vasorelaxant effect of pinacidil is not endothelium dependent.

Animals↗

PubMed2001

Mitochondrial K(ATP) channel as an end effector of cardioprotection during late preconditioning: triggering role of nitric oxide.

Nitric oxide (NO) has been implicated in the "second-window" of ischemic preconditioning (PC). However, the identity of the end effector after initiation of preconditioning by NO is not known. It is likely that NO is involved in opening of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels. We hypothesized that NO is an important trigger for the opening of mitoK(ATP) channels in the late phase of preconditioning and inducible nitric oxide synthase (iNOS) up-regulation via NF kappa B plays a critical role in diazoxide-induced cardioprotection. To examine this, diazoxide (7 mg/kg) was administered to wild-type (WT) mice and mice lacking the gene 24 hours before 40 minutes of global ischemia. Hearts were perfused in a Langendorff mode and effects of activation of mitoK(ATP) channel and other interventions on functional, biochemical and pathological changes in ischemic hearts were assessed. In hearts from WT mice treated diazoxide, left-ventricular-developed pressure, end-diastolic pressure and coronary flow were significantly improved after ischemia/reperfusion (I/R); lactate dehydrogenase (LDH) release was also significantly decreased, while ATP contents were significantly higher. Administration of 5-HD, a specific blocker of mitoK(ATP) channel or l -NAME, an inhibitor of iNOS before I/R, during diazoxide-pretreatment completely blocked the late cardioprotection against ischemia. Late cardioprotection was also blocked by inhibition of either PKC- delta by rottlerin or NF kappa B by DDTC before diazoxide pretreatment. Diazoxide pretreatment significantly increased nuclear translocation of p65 which was blocked by protein kinase C (PKC) or nitric oxide synthase (NOS) inhibition. Diazoxide was totally inefffective in iNOS knockout mice. These results suggest that diazoxide activates NF kappa B via PKC signaling pathway and that leads to iNOS up-regulation after 24 hours. NO which is generated upon ischemic stress triggers the opening of mitoK(ATP)channel as an end effector of cardioprotection during late PC.

Acetophenones↗

PubMed1995

ATP-sensitive K+ channels mediate regulation of substance P release via the prejunctional histamine H3 receptor.

Perfusion of histamine (10(-3) M) elicited a significant increase of immunoreactive substance P release in the subcutaneous perfusate in the rat hindpaw. The active L-enantiomer of cromakalim, lemakalim (50 micrograms/kg, i.v.), a selective K+ channel activator, significantly inhibited the immunoreactive substance P release. Glibenclamide (10 mg/kg, i.v.), an ATP-sensitive K+ channel blocker, abolished the response to lemakalim on the release of immunoreactive substance P. R(-)-alpha-methylhistamine (1 mg/kg, i.v.), a specific histamine H3 receptor agonist, significantly inhibited the release of immunoreactive substance P. Glibenclamide (10 mg/kg, i.v.) antagonized the inhibitory effect of R(-)-alpha-methylhistamine. Tetraethylammonium (10 mg/kg, i.p.), a K+ channel blocker, also reduced the inhibitory effect significantly. These results suggest that the inhibition of substance P release from sensory nerve endings via prejunctional histamine H3 receptors may be achieved by activating the ATP-sensitive K+ channel coupled to the histamine H3 receptor in the rat skin.

Adenosine Triphosphate↗

PubMed2002

Endogenous Kv channels in human embryonic kidney (HEK-293) cells.

The human embryonic kidney cells (HEK-293) have been widely used as one mammalian expression system in the study of voltage-gated K+ (Kv) channels. Understanding the endogenous Kv channels in these cells is the prerequisite for the characterization of the heterogeneously expressed Kv channels in these cells. In the present study we screened the transcriptional expression of different Kv genes in HEK-293 cells using reverse transcribed DNApolymerase chain reaction (RT-PCR) method. Among 16 Kv genes examined in native HEK-293 cells 10 Kv genes were reproducibly amplified, including those Kv a subunits encoding for the delayed rectifier (IK) [Kv1.1, Kv1.2, Kv1.3, Kv1.6, and Kv3.1], and for the transient outward Kv channels (IA) [Kv1.4, Kv3.3, Kv3.4, and Kv4.1] as well as a Kvbeta2 subunit. The whole-cell outward rectifier IK currents in the native HEK-293 cells were recorded (203 +/- 13 pA at +30 mV, n = 82) with the patch-clamp technique. In about 42% of the examined cells, IA coexisted with IK currents. IK currents were inhibited by tetraethylammonium chloride (TEA) at 1 and 10 mM by 39.5 and 48.4%, respectively. A 39.6% inhibition of IK currents was also observed in the presence of4-aminopyridine (4-AP, 5 mM). Interestingly, both TEAand 4-AP also inhibited IA currents. 4-acelamido-4'-isothiocyanalostilbene-2, 2'-disulfonic acid (1 mM), a Cl- channel blocker, had no effect on the endogenous outward currents. We concluded that multiple endogenous Kv genes were expressed in native HEK-293 cells, which possessed significant endogenous IK and IA currents with unique pharmacological properties.

Cell Line↗

PubMed2003

Alpha2-adrenoreceptor activation inhibits LTP and LTD in the basolateral amygdala: involvement of Gi/o-protein-mediated modulation of Ca2+-channels and inwardly rectifying K+-channels in LTD.

Activation of adrenoreceptors modulates synaptic transmission in the basolateral amygdala. Here, we investigated the effects of alpha2-adrenoreceptor activation on long-term depression and long-term potentiation in an in vitro slice preparation of the mouse basolateral amygdala. Field potentials and excitatory postsynaptic currents were evoked in the basolateral amygdala by stimulating the lateral amygdala. Norepinephrine (20 micro m) reduced synaptic transmission and completely blocked the induction of long-term potentiation and long-term depression. The alpha2-adrenoreceptor antagonist yohimbine (2 micro m) reversed this effect. The alpha2-adrenoreceptor agonist clonidine (10 micro m) mimicked the effects of norepinephrine. The Gi/o-protein inhibitor pertussis toxin (5 micro g/mL) reversed the effect of clonidine. Long-term depression was blocked in the presence of omega-conotoxin GVIA, but not omega-agatoxin IVA. Clonidine inhibited voltage-activated Ca2+ currents mediated via N- or P/Q-type Ca2+-channels. The inhibitory action of clonidine on long-term depression was reversed when inwardly rectifying K+-channels were blocked by Ba2+ (300 micro m). The present data suggest that alpha2-adrenoreceptor activation impairs the induction of long-term depression in the basolateral amygdala by a Gi/o-protein-mediated inhibition of presynaptic N-type Ca2+-channels and activation of inwardly-rectifying K+-channels.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1996

[Nicorandil, as ATP-sensitive K+ channel opener, potentiated morphine analgesia].

Recent reports demonstrated that K+ channels could contribute to signal transmission in the brain and spinal cord, and opioids' action may be related to K+ channels' functions. We investigated the antinociceptive effect of epidurally injected ATP-sensitive K+ channel opener, nicorandil, using tail flick test in rats. Epidural nicorandil (100 micrograms.rat-1) increased % maximum possible effect (%MPE) of epidural morphine (1, 10 micrograms.rat-1) from -3% to 40% (P < 0.05) and 46% to 65%, respectively. Epidural glibenclamide (10 micrograms.rat-1), ATP-sensitive K+ channel blocker, antagonized this effect. Epidural nicorandil alone (10 approximately 100 micrograms.rat-1) showed no antinociceptive effects. Systemic nicorandil (100 micrograms.rat-1, i.m.) did not increase the epidural morphine analgesia. These data suggest that the K+ channel opener could point the way to a new approach to pain treatment.

Adenosine Triphosphate↗

PubMed2004

Novel neuroprotective K+ channel inhibitor identified by high-throughput screening in yeast.

Discovery of K+ channel modulators is limited by low-throughput capacity of existing K+ channel assays. To enable high-throughput screening for novel pharmacological modulators of K+ channels, we developed an assay based on growth of yeast that functionally expresses mammalian Kir2.1 channels. Screening of 10,000 small molecules from a combinatorial chemical library yielded 42 potential Kir2.1 inhibitors. One compound, 3-bicyclo[2.2.1]hept-2-yl-benzene-1,2-diol, was confirmed to inhibit K+ channels in patch-clamp measurements in mammalian cells with EC50 values of 60 and 1 microM for Kir2.1 and Kv2.1 channels, respectively. Inhibition of Kv2.1 channels decreased in the presence of the external pore blocker tetraethylammonium (TEA) and depended on a residue required for extracellular TEA action, suggesting that the identified compound targets the external mouth of the channel. Furthermore, at the nontoxic concentration of 3 microM, the identified compound completely abolished in vitro neuronal apoptosis mediated by Kv2.1 channels. Therefore, yeast-based screening has identified a novel uncharged neuroprotective mammalian K+ channel inhibitor.

Animals↗

PubMed2004

Risk of ventricular proarrhythmia with selective opening of the myocardial sarcolemmal versus mitochondrial ATP-gated potassium channel.

Myocardial ATP-gated potassium channels (K-ATPs) are critical in the intracellular signaling cascade resulting in ischemic preconditioning (IP). Mitochondrial K-ATP channels seem to be responsible for IP, whereas the functions of K-ATP channels in the sarcolemmal membrane are less well understood. The proarrhythmic potential of specific versus nonspecific opening of K-ATP channels has not been investigated. In this study, Langendorff-perfused rabbit hearts were exposed to either pinacidil (1.25 microM), a nonselective K-ATP channel agonist, or selective mitochondrial or sarcolemmal K-ATP channel agonists or antagonists. The hearts were then subjected to 12 min of hypoxic perfusion and 40 min of reoxygenation. Hearts were monitored for the induction of ventricular fibrillation (VF). No heart subjected to hypoxia-reoxygenation without drug treatment developed VF (0 of 5). Pinacidil pretreatment induced VF (12 of 14; p = 0.004 versus control). Pinacidil's effect was blocked by HMR-1098 (1-[5-[2-(5-chloro-o-anisamide)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea) (1 microM), a selective sarcolemmal K-ATP channel antagonist (1 of 7; p = 0.007 versus pinacidil; N.S. versus control). Hearts pretreated with 5-hydroxydecanoate (5-HD) (100 microM), a putatively selective mitochondrial K-ATP channel blocker developed VF in one of eight trials (N.S. versus control). 5-HD did not alter the effects of pinacidil (6 of 8; p < 0.05 versus control; N.S. versus pinacidil alone). Selective mitochondrial K-ATP channel activation with [(3R)-trans-4-((4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl-2H-1-benzopyran-6-carbonitril monohydrochloride] (BMS-191095) (6 microM) resulted in zero of five hearts developing VF (N.S. versus control). Our data suggest that selective opening of the sarcolemmal K-ATP channel during hypoxia-reoxygenation induced VF, whereas opening of the mitochondrial channel was not associated with VF. The findings suggest that caution should be exercised when developing compounds aimed at inducing IP, and nonspecific opening of the K-ATP channel should be avoided.

Animals↗

PubMed2003

Wheel-running exercise alters rat diaphragm action potentials and their regulation by K+ channels.

Endurance exercise modifies regulatory systems that control skeletal muscle Na+ and K+ fluxes, in particular Na+-K+-ATPase-mediated transport of these ions. Na+ and K+ ion channels also play important roles in the regulation of ionic movements, specifically mediating Na+ influx and K+ efflux that occur during contractions resulting from action potential depolarization and repolarization. Whether exercise alters skeletal muscle electrophysiological properties controlled by these ion channels is unclear. The present study tested the hypothesis that endurance exercise modifies diaphragm action potential properties. Exercised rats spent 8 wk with free access to running wheels, and they were compared with sedentary rats living in conventional rodent housing. Diaphragm muscle was subsequently removed under anesthesia and studied in vitro. Resting membrane potential was not affected by endurance exercise. Muscle from exercised rats had a slower rate of action potential repolarization than that of sedentary animals (P = 0.0098), whereas rate of depolarization was similar in the two groups. The K+ channel blocker 3,4-diaminopyridine slowed action potential repolarization and increased action potential area of both exercised and sedentary muscle. However, these effects were significantly smaller in diaphragm from exercised than sedentary rats. These data indicate that voluntary running slows diaphragm action potential repolarization, most likely by modulating K+ channel number or function.

4-Aminopyridine↗

PubMed2003

Substitution of a single residue in Stichodactyla helianthus peptide, ShK-Dap22, reveals a novel pharmacological profile.

ShK, a peptide isolated from Stichodactyla helianthus venom, blocks the voltage-gated potassium channels, K(v)1.1 and K(v)1.3, with similar high affinity. ShK-Dap(22), a synthetic derivative in which a diaminopropionic acid residue has been substituted at position Lys(22), has been reported to be a selective K(v)1.3 inhibitor and to block this channel with equivalent potency as ShK [Kalman et al. (1998) J. Biol. Chem. 273, 32697-32707]. In this study, a large body of evidence is presented which indicates that the potencies of wild-type ShK peptide for both K(v)1.3 and K(v)1.1 channels have been previously underestimated. Therefore, the affinity of ShK-Dap(22) for both channels appears to be ca. 10(2)-10(4)-fold weaker than ShK. ShK-Dap(22) does display ca. 20-fold selectivity for human K(v)1.3 vs K(v)1.1 when measured by the whole-cell voltage clamp method but not in equilibrium binding assays. ShK-Dap(22) has low affinity for K(v)1.2 channels, but heteromultimeric K(v)1.1-K(v)1.2 channels form a receptor with ca. 200-fold higher affinity for ShK-Dap(22) than K(v)1.1 homomultimers. In fact, K(v)1.1-K(v)1.2 channels bind ShK-Dap(22) with only ca. 10-fold less potency than ShK and reveal a novel pharmacology not predicted from the homomultimers of K(v)1.1 or K(v)1.2. The concentrations of ShK-Dap(22) needed to inhibit human T cell activation were ca. 10(3)-fold higher than those of ShK, in good correlation with the relative affinities of these peptides for inhibiting K(v)1.3 channels. All of these data, taken together, suggest that ShK-Dap(22) will not have the same in vivo immunosuppressant efficacy of other K(v)1.3 blockers, such as margatoxin or ShK. Moreover, ShK-Dap(22) may have undesired side effects due to its interaction with heteromultimeric K(v)1.1-K(v)1.2 channels, such as those present in brain and/or peripheral tissues.

Amino Acid Substitution↗

PubMed2000

Control of cell proliferation by cell volume alterations in rat C6 glioma cells.

K+ and Cl- channels are involved in regulating the proliferation of a number of cell types. Two main hypotheses have been proposed to explain the mechanism by which these channels influence cell proliferation: regulation of membrane potential and regulation of cell volume. In order to test these hypotheses, we measured, under different experimental conditions, the volume, membrane potential and rate of proliferation of C6 glioma cells. Cells cultured in control medium for 1-4 days were compared with cells cultured for the same period of time in the presence of broad spectrum channel blockers: tetraethylammonium, 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and Cs+, in hypertonic media (29% increased osmolarity with NaCl, KCl or sucrose), in hypotonic medium (23% decreased osmolarity with H2O) or in the presence of the specific channel blockers, i.e. mast cell degranulating peptide, charybdotoxin or chlorotoxin. In all of these conditions, we observed a close correspondence between the rate of proliferation and the mean cell volume. The proliferation decreased when volume increased. Moreover, whereas control cells were flattened, spindle-shaped, bipolar or multipolar, cells cultured in media supplemented with NPPB, KCl or CsCl were round with few processes. Of the agents tested, only KCl and Cs+ depolarized the cells. These results show that alterations of the rate of proliferation by K+ and Cl- channel blockers or anisotonia are closely related with changes in cell volume or form but are not correlated with changes in membrane potential.

Animals↗

PubMed2004

Antiarrhythmic effect of ischemic preconditioning during low-flow ischemia. The role of bradykinin and sarcolemmal versus mitochondrial ATP-sensitive K(+) channels.

Short episodes of ischemia (ischemic preconditioning) protect the heart against ventricular arrhythmias during zero-flow ischemia and reperfusion. However, in clinics, many episodes of ischemia present a residual flow (low-flow ischemia). Here we examined whether ischemic preconditioning protects against ventricular arrhythmias during and after a low-flow ischemia and, if so, by what mechanism(s). Isolated rat hearts were subjected to 60 min of low-flow ischemia (12% residual coronary flow) followed by 60 min of reperfusion. Ischemic preconditioning was induced by two cycles of 5 min of zero-flow ischemia followed by 5 and 15 min of reperfusion, respectively. Arrhythmias were evaluated as numbers of ventricular premature beats (VPBs) as well as incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF) during low-flow ischemia and reperfusion. Ischemic preconditioning significantly reduced the number of VPBs and the incidence of VT and of VF during low-flow ischemia. This antiarrhythmic effect of preconditioning was abolished by HOE 140 (100 nM), a bradykinin B(2) receptor blocker. Similar to preconditioning, exogenous bradykinin (10 nM) reduced the number of VPBs and the incidence of VT and of VF during low-flow ischemia. Furthermore, the antiarrhythmic effects of both ischemic preconditioning and bradykinin were abolished by glibenclamide (1 microM), a non-specific blocker of ATP-sensitive K(+) (K(ATP)) channels. Finally, the antiarrhythmic effects of both ischemic preconditioning and bradykinin were abolished by HMR 1098 (10 microM), a sarcolemmal K(ATP) channel blocker but not by 5-hydroxydecanoate (100 microM), a mitochondrial K(ATP) channel blocker. In conclusion, ischemic preconditioning protects against ventricular arrhythmias induced by low-flow ischemia, and this protection involves activation of bradykinin B(2) receptors and subsequent opening of sarcolemmal but not of mitochondrial K(ATP) channels.

Animals↗