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At least 865 records · Page 48Linked to original sources
PubMed1995

Potassium channels in the cardiovascular system.

In vitro and in vivo studies suggest that opening of ATP-sensitive potassium channels following ischaemia enhances recovery of myocardial contraction, dilates blood vessels and has an antiarrhythmic effect. Different sulphonylurea compounds that block the ATP-sensitive potassium channels exert different effects on cardiac functions. Glibenclamide decrease, arrhythmogenesis during acute myocardial infarction in rats and reduces strophanthin cardiotoxicity in rabbits. Other sulphonylurea compounds, but not glibenclamide, increase arterial blood pressure and myocardial contractility. These effects may be partly secondary to blockade of ATP-sensitive potassium channels and partly due to independent cardiac and extracardiac actions. Glimepiride may have a more advantageous cardiovascular effect than glibenclamide. The studies suggest the hypothesis that deleterious cardiovascular effects of some hypoglycaemic sulphonylurea drugs may contribute to the high cardiovascular mortality rate in diabetes mellitus. An observational study suggested glibenclamide decreased the incidence of fatal myocardial infarction and development of ventricular fibrillation in patients suffering from acute myocardial infarction. Glibenclamide may also decrease the incidence of ventricular ectopic beats in digitalized patients compared with other sulphonylurea compounds. The studies suggested the survival of subjects treated with glibenclamide, insulin, or diet alone after the first attack of angina pectoris or after first acute myocardial infarction may be longer compared with those on other sulphonylurea therapies. Further large scale prospective, randomised studies are needed to determine whether the reported effects can be verified and are sufficiently large to affect clinical prescribing.

Adenosine Triphosphate↗
PubMed1982

Sodium and potassium channels in regenerating and developing mammalian myelinated nerves.

A study has been made of how the normal complementary distribution of sodium and potassium channels in mammalian myelinated nerve fibres (all the sodium channels being in the node with all the potassium channels in the internode) is altered in regenerating and in developing rabbit sciatic nerves. In regenerating nerve fibres, where a marked increase in the number of nodes per unit length occurs, there is a corresponding increase in the sodium channel content (determined from the maximum saturable binding of labelled saxitoxin), consistent with the idea that the number of sodium channels per node remains roughly constant. The use of 4-aminopyridine, which by blocking potassium channels prolongs the action potential, has shown that both in regenerating nerve fibres and in developing nerve fibres potassium currents contribute to the mammalian action potential. In both cases, with the passage of time, the sensitivity to 4-aminopyridine progressively decreases.

Action Potentials↗
PubMed1998

Biochemical and ultrastructural evaluations of the effect of ischemic preconditioning on ischemic myocardial injury--role of the adenosine triphosphate-sensitive potassium channel.

The aim of this study was to clarify the role of the adenosine triphosphate (ATP)-sensitive potassium channel on the mechanism of ischemic preconditioning (IP). Thirty-five anesthetized dogs were divided into 5 groups: (1) Control (C), (2) IP, (3) intravenous infusion of nicorandil (Ni) prior to IP, (4) glibenclamide (G1) pretreated with IP (G1+IP), and (5) G1 pretreated with Ni (G1+Ni). All groups had 60 min ischemia followed by 60 min reperfusion, and were analyzed by biochemical and morphological procedures. At the end of the 60-min reperfusion, %segment shortening in C indicated paradoxical bulging. This value had significantly recovered in IP and Ni groups, but it was still negative in the G1+IP and G1+Ni groups. Ca++-ATPase activity of the sarcoplasmic reticulum (SR) was significantly decreased in C. In the IP and Ni groups, this activity was significantly maintained; however, in the G1+IP and G1+Ni groups it was similar to that in C. State 3 respiration of mitochondria showed similar changes in the SR. In the ultrastructural observations, severely damaged cells were not observed in the IP and Ni groups. These results indicated that an ATP-sensitive potassium channel opener enhanced the effects of IP and its blockade abolished these phenomena. It was conclude that the ATP-sensitive potassium channel may play a key role in the mechanism of IP.

Adenosine Triphosphate↗
PubMed2001

G protein-gated inwardly rectifying potassium channels are targets for volatile anesthetics.

G protein-gated inwardly rectifying potassium channels (GIRKs) are a family of homo- and hetero-oligomeric K(+) channels composed of different subunits (GIRK1 to 4 in mammals). GIRK4 and GIRK1 are found mainly in the atrium, whereas neuronal cells predominantly express the GIRK1, GIRK2, and GIRK3 isoforms. When activated, GIRK channels slow the firing rate of atrial myocytes and neuronal cells. Because of their key role in controlling excitability, we investigated the influence of a prototypic anesthetic, halothane, on GIRK channels of different subunit composition expressed in Xenopus laevis oocytes. Halothane enhanced background currents through hetero-oligomeric GIRK1/GIRK4 and homo-oligomeric GIRK1(F137S) channels but not through homo-oligomeric GIRK2 channels. This activation of basal current did not depend on the presence of coexpressed G protein-coupled receptors but instead required the presence of G(beta/gamma). In contrast to basal GIRK currents, the agonist-induced GIRK current (via coexpressed m2 muscarinic receptors) was inhibited by halothane. For GIRK1/GIRK4 and GIRK1(F137S) channels this inhibition was most pronounced at low concentrations of the anesthetic (0.1-0.3 mM) and occurred also when channels had been activated by guanosine-5'-O-(3-thio)triphosphate. This inhibition, however, was overridden by high concentrations of halothane (0.9 mM) and augmentation of the agonist-induced current was observed. This increase in agonist-induced current was never seen with GIRK2 homo-oligomeric channels. Agonist-induced currents mediated by GIRK2 channels were always inhibited by halothane with an IC(50) value of approximately 60 microM. These data suggest a direct interaction of halothane with GIRK channels.

Anesthetics, Inhalation↗
PubMed1993

Mechanism and modulation of inactivation of the Kv3 potassium channel.

The mechanism and modulation of inactivation of the rat brain voltage-gated potassium channel, Kv3, expressed in Xenopus oocytes, were examined. In the cell-attached patch recording mode, Kv3 macroscopic current amplitude remains constant from one pulse to the next when a series of short (15 ms) repetitive depolarizing pulses are given. However, when the membrane patch is detached from the cell, the current amplitude decreases substantially from one depolarizing pulse to the next, even though there is no significant inactivation-like behaviour within a single current trace. In contrast, the closely related Kv2 potassium channel does not show a similar modulation of inactivation on changing from the cell-attached to the detached-patch recording mode. The data indicate the existence of a prolonged non-conducting state which the Kv3 channel enters in response to a series of short depolarizing pulses; this state is identical to the C-type inactivation state into which channels are driven during individual long depolarizing pulses. The probability of finding the channel in this state differs between the cell-attached and detached-patch modes, indicating that it is modulated by some cytoplasmic factor.

Animals↗
PubMed2003

Immunohistochemical localization of the voltage-gated potassium channel subunit Kv1.4 in the central nervous system of the adult rat.

A large set of voltage-gated potassium channels is involved in regulating essential aspects of neuronal function in the central nervous system, thus contributing to the ability of neurons to respond to a given input. In the present study, we used immunocytochemical methods to elucidate the regional, cellular and subcellular distribution of the voltage-gated potassium channel subunit Kv1.4, a member of the Shaker subfamily, in the brain. At the light microscopic level, the Kv1.4 subunit showed a unique distribution pattern, being localized in specific neuronal populations of the rat brain. The neuronal regions expressing the highest levels of Kv1.4 protein included the cerebral cortex, the hippocampus, the posterolateral and posteromedial ventral thalamic nuclei, the dorsolateral and medial geniculate nuclei, the substantia nigra and the dorsal cochlear nucleus. The Kv1.4 subunit was also present in other neuronal populations, with different levels of Kv1.4 immunoreactivity. In all immunolabeled regions, the Kv1.4 subunit was mostly diffusely distributed and, to a lesser extent, it stained cell bodies and proximal dendrites. Furthermore, Kv1.4 immunoreactivity was also detected in nerve terminals and axonal terminal fields. At the electron microscopic level, Kv1.4 was located postsynaptically in dendritic spines and shafts at extrasynaptic sites, as well as presynaptically in axon and active zone of axon terminals, in the neocortex and hippocampus. The findings indicate that Kv1.4 channels are widely distributed in the rat brain and suggest that activation of this channel would have different modulatory effects on neuronal excitability.

Age Factors↗
PubMed1990

An ATP, calcium and voltage sensitive potassium channel in porcine coronary artery smooth muscle cells.

There is increasing interest in the roles played by potassium channels of smooth muscle in protecting against ischemic and anoxic insults. Hence, potassium-selective channels were studied in freshly dispersed porcine coronary artery smooth muscle cells using the inside-out variant of the patch-clamp technique. The most abundant potassium channel had a conductance of 148 pS in a 5.4/140 mM K+ gradient, at 0 mV, and was regulated by cytoplasmic ATP (0.05-3.0 mM), cytoplasmic Ca2+ (0.1-10 microM) and voltage. ATP and AMP-PNP (0.5 mM) reduced the probability of channel opening (Po) by 87 and 92%, respectively. This inhibition was partially reversed by the addition of 0.5 mM ADP. ADP on its own (2 mM) reduced Po by 46%. It appears, therefore, that this channel shares properties with both the ATP-sensitive and the calcium-regulated potassium channels, raising the possibility that it plays a central role in the regulation of coronary blood flow.

Adenosine Diphosphate↗
PubMed1998

Involvement of a Gardos-type potassium channel in head activator-induced mitosis of BON cells.

The human neuroendocrine cell line BON was used to study second messengers involved in signal transduction for entry into mitosis. BON cells produce the neuropeptide head activator (HA) and use it as autocrine growth factor. HA stimulates BON cell proliferation by triggering entry into mitosis. HA-induced mitosis is mediated by an inhibitory G protein, the action of which is blocked by pertussis toxin. HA signaling requires inhibition of the cAMP pathway, calcium influx, and hyperpolarization of cells. The latter is a very important and sensitive step involving a calcium-activated potassium channel. Cell cycle progression and proliferation of BON cells are most efficiently inhibited with specific inhibitors of this potassium channel. Pharmacology and RNA analysis suggest identity with the recently cloned Gardos-type potassium channel.

Autocrine Communication↗
PubMed1996

Potassium channels and the coronary circulation.

1. Mechanisms responsible for the regulation of coronary blood flow during physiologically important situations, such as reactive hyperaemia, hypoxia, ischaemia, coronary artery occlusion and increased metabolic demand, have eluded the scientific community. 2. As knowledge regarding potassium channel physiology and biophysics has expanded, the potential role of these channels in regulating coronary blood flow has been studied. 3. Recent data have demonstrated that ATP-sensitive potassium channels (K+[ATP]) play an important role in maintaining basal coronary blood flow, contribute to the regulation of coronary blood flow during hypoxia, acidosis, ischaemia, reactive hyperaemia and ischaemic preconditioning. The role of potassium channels in the regulation of coronary blood flow during increases in metabolic stimulation is controversial. 4. Thus, potassium channels, particularly K+[ATP], appear to play an important role in regulating coronary blood flow during physiologically important stimuli.

Animals↗
PubMed1994

Potassium channel block by cytoplasmic polyamines as the mechanism of intrinsic rectification.

Inwardly rectifying potassium channels conduct ions more readily in the inward than the outward direction, an essential property for normal electrical activity. Although voltage-dependent block by internal magnesium ions may underlie inward rectification in some channels, an intrinsic voltage-dependent closure of the channel plays a contributory, or even exclusive, role in others. Here we report that, rather than being intrinsic to the channel protein, so-called intrinsic rectification of strong inward rectifiers requires soluble factors that are not Mg2+ and can be released from Xenopus oocytes and other cells. Biochemical and biophysical characterization identifies these factors as polyamines (spermine, spermidine, putrescine and cadaverine). The results suggest that intrinsic rectification results from voltage-dependent block of the channel pore by polyamines, not from a voltage sensor intrinsic to the channel protein.

Animals↗
PubMed1990

Potassium channel blockade differentially affects the relative refractory period of frog afferent terminals and axons.

1. The effects of potassium channel blockade on afferent axons and terminal regions in frog dorsal roots and spinal cords, respectively, were investigated in vitro. 2. A condition-test (C-T) protocol was used to assess the population relative refractory period. Characteristics of main axons were evaluated by stimulation at the proximal end of transected dorsal roots (DR). Characteristics of terminal regions were tested by stimulation at the base of the dorsal horn (DH). 3. DH recovery of excitability was delayed by low concentrations of 4-aminopyridine (4-AP) and tetraethylammonium (TEA) alone or combined. The same treatments did not affect recovery to DR stimulation. 4. DH recovery of excitability was not delayed by solutions suppressing terminal calcium influx. 5. We conclude that sensitivity of the relative refractory period to potassium channel blocking agents differs between main axons and axon terminal regions. This may indicate differences between axon terminals and main axons in the mechanism of action potential repolarization. 6. We hypothesize that rapid action potential repolarization by pharmacologically sensitive potassium channels in presynaptic terminal regions keeps terminal action potentials short. Terminal action potential brevity would limit calcium influx, thus preventing terminal calcium overload but contributing to transmission failures at spinal synapses.

4-Aminopyridine↗
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↗
PubMed2003

Enhanced cardioprotection of the rat heart during hypothermic storage with combined Na+ - H+ exchange inhibition and ATP-dependent potassium channel activation.

BACKGROUND: We investigated the ability of mitochondrial adenosine triphosphate-dependent potassium-channel activation to augment the protection of Na(+)-H(+) exchanger inhibition in isolated working rat hearts after 6 hours of hypothermic storage in an extracellular-based cardioplegic solution. METHODS: We treated hearts with the potassium-channel openers diazoxide (100 micromol/liter) or BMS-180448 (10 micromol/liter) or with the Na(+)-H(+) exchanger inhibitor cariporide (10 micromol/liter). Cariporide also was administered in combination with either diazoxide or BMS-180448 in 2 other treatment groups. All hearts were arrested and stored at 2 to 3 degrees C. After storage, we reperfused hearts for 10 minutes before performing work for a further 15 minutes, and then we measured and assessed cardiac function using a 2-way analysis of variance model. RESULTS: Neither diazoxide nor BMS-180448 significantly improved recovery of cardiac output. Cariporide therapy significantly improved cardiac output compared with control. However, we obtained the greatest recovery of cardiac output when we combined cariporide with either diazoxide or BMS-180448. CONCLUSIONS: Cariporide is more cardioprotective than the potassium-channel openers diazoxide and BMS-180448 after prolonged hypothermic storage. Co-administration of diazoxide or BMS-180448 with cariporide results in additive cardioprotection, with significantly improved cardiac function when compared with either treatment given alone. Such a combination could be used to improve the functional recovery of hearts stored for cardiac transplantation.

Animals↗
PubMed2001

Spermine mediates inward rectification in potassium channels of turtle retinal Müller cells.

Retinal Müller cells are highly permeable to potassium as a consequence of their intrinsic membrane properties. Therefore these cells are able to play an important role in maintaining potassium homeostasis in the vertebrate retina during light-induced neuronal activity. Polyamines and other factors present in Müller cells have the potential to modulate the rectifying properties of potassium channels and alter the Müller cells capacity to siphon potassium from the extracellular space. In this study, the properties of potassium currents in turtle Müller cells were investigated using whole cell voltage-clamp recordings from isolated cells. Overall, the currents were inwardly rectifying. Depolarization elicited an outward current characterized by a fast transient that slowly recovered to a steady level along a double exponential time course. On hyperpolarization the evoked inward current was characterized by an instantaneous onset (or step) followed by a slowly developing sustained inward current. The kinetics of the time-dependent components (block of the transient outward current and slowly developing inward current) were dependent on holding potential and changes in the intracellular levels of magnesium ions and polyamines. In contrast, the instantaneous inward and the sustained outward currents were ohmic in character and remained relatively unaltered with changes in holding potential and concentration of applied spermine (0.5--2 mM). Our data suggest that cellular regulation in vivo of polyamine levels can differentially alter specific aspects of potassium siphoning by Müller cells in the turtle retina by modulating potassium channel function.

Animals↗
PubMed1991

Analysis of anesthetic action on the potassium channels of the Shaker mutant of Drosophila.

Recent evidence suggest that exposure to volatile anesthetic agents causes a change in conductance through an undelineated potassium channel. With recently developed genetic and molecular techniques the Drosophila melanogaster (D.m.) genome can be manipulated to study the role that potassium ion channel function plays in anesthetic action. The IA potassium channel is encoded by the Shaker (Sh) locus on the X chromosome of D.m. Because this channel may be one of those involved in volatile anesthetic action, we tested the sensitivity to isoflurane in three Shaker strains with different degrees of dysfunctional IA conductance (Shnull greater than ShKS133 greater than Sh5). Anesthetic sensitivity was also examined in mutant strains of D.m. which express abnormalities either in other potassium channel conductances (eag, slo) or other ion conductances (para). The normally conducting wild type served as the control. Two-day-old adult D.m. were stimulated with a heat source during exposure to the volatile anesthetic isoflurane, and the number moving in response to the noxious stimulus was noted. After testing the Shaker and control strains at no fewer than 13 concentrations, the IC50S (isoflurane concentration in percent vol/vol at which 50% of the flies did not respond to the heat stimulus) were derived. The IC50 values for Sh 5 (0.89), Sh133 (1.29), and Shnull (1.37) were significantly different from the wild type (0.56). The rank order of insensitivity of these Shaker mutants corresponded to the extent of the alteration in IA conductance as established by previous studies in these mutants. Neither eag (0.66), para (0.48), nor slo (0.63) differed significantly from the wild type. These data suggest that the IA potassium channel plays a role in volatile anesthetic action.

Animals↗
PubMed2001

Potassium channels: the importance of transport signals.

The number, type and distribution of ion channels on a neuron's surface determine its electrical response to stimulation. One way that a cell determines how many molecules of each channel type are sent to the surface has been eludicated in a recent study of intrinsic protein transport signals within potassium channels.

Animals↗
PubMed2001

Hypercholesterolemia alters vascular functions and gene expression of potassium channels in rat aortic smooth muscle cells.

AIM: To investigate the effects of hypercholesterolemia on functions of rat aorta and on gene expression of inward rectifier and ATP-sensitive potassium channels in aortic smooth muscle. METHODS: Rats were treated with high-cholesterol emulsion ig for 2 weeks; the aortic rings with and without endothelium were prepared to examine the aortic contractile and relaxation responses; RT-PCR was used to observe the gene expression of inward rectifier and ATP-sensitive potassium channels. RESULTS: Hypercholesterolemia damaged the endothelium-dependent vascular functions severely, but did not affect the endothelium-independent vascular functions; Kir6.2 mRNA expression was upregulated (P < 0.05) and Kir3.1 mRNA expression was downregulated markedly (P < 0.05) in hypercholesterolemic smooth muscle. CONCLUSION: Hypercholesterolemia altered the vascular functions and regulated gene expression levels of specific inward rectifier and ATP-sensitive potassium channel subtypes.

Animals↗
PubMed1990

Hypoxic dilation of coronary arteries is mediated by ATP-sensitive potassium channels.

The function of the heart depends critically on an adequate oxygen supply through the coronary arteries. Coronary arteries dilate when the intravascular oxygen tension decreases. Hypoxic vasodilation in isolated, perfused guinea pig hearts can be prevented by glibenclamide, a blocker of adenosine triphosphate (ATP)-sensitive potassium channels, and can be mimicked by cromakalim, which opens ATP-sensitive potassium channels. Opening of potassium channels in coronary smooth muscle cells and the subsequent drop in intracellular calcium is probably the major cause of hypoxic and ischemic vasodilation in the mammalian heart.

Adenosine Triphosphate↗