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PubMed1997

Differential effect of beta-adrenergic stimulation on the frequency-dependent electrophysiologic actions of the new class III antiarrhythmics dofetilide, ambasilide, and chromanol 293B.

INTRODUCTION: Blockade of the rapid delayed rectifier potassium current (IKr) as an important mechanism for current Class III antiarrhythmics is less effective in action potential prolongation during beta-adrenergic activation. We hypothesized that blockade of the increased slow IK (IKs) current during beta-adrenergic stimulation could improve action potential prolongation and tested this hypothesis by comparison of three different IK blockers: dofetilide, a selective blocker of IKr; ambasilide, a nonselective blocker of IK; and chromanol 293B, a selective blocker of IKs. METHODS AND RESULTS: Transmembrane action potential duration was determined in guinea pig papillary muscles. After equilibration with the potassium channel blockers (dofetilide 10 nM, ambasilide 10 microM, chromanol 293B 10 microM), isoproterenol (10 and 100 nM) was added. The action potential prolonging effect of dofetilide was reduced in the presence of increasing concentrations of isoproterenol whereas the effect of ambasilide was much less reduced. In contrast, the effect of chromanol 293B clearly was increased in the presence of both concentrations of isoproterenol. No afterdepolarizations were observed after application of isoproterenol in control. Following isoproterenol, but not before, dofetilide and chromanol 293B induced early afterdepolarizations in 20% and 17% of the papillary muscles, whereas ambasilide and chromanol 293B induced delayed afterdepolarizations in 27% and 33%, respectively. CONCLUSION: In contrast to dofetilide, the Class III effect of ambasilide is less reduced and the effect of chromanol 293B is enhanced during beta-adrenergic stimulation. Our data support the hypothesis that IKs blockade improves the efficacy of antiarrhythmics in action potential prolongation during beta-adrenergic activation; however, this effect may increase the risk of afterdepolarizations.

Action Potentials↗
PubMed1989

Ionic currents and ion channels of lobster olfactory receptor neurons.

The role of the soma of spiny lobster olfactory receptor cells in generating odor-evoked electrical signals was investigated by studying the ion channels and macroscopic currents of the soma. Four ionic currents; a tetrodotoxin-sensitive Na+ current, a Ca++ current, a Ca(++)-activated K+ current, and a delayed rectifier K+ current, were isolated by application of specific blocking agents. The Na+ and Ca++ currents began to activate at -40 to -30 mV, while the K+ currents began to activate at -30 to -20 mV. The size of the Na+ current was related to the presence of a remnant of a neurite, presumably an axon, and not to the size of the soma. No voltage-dependent inward currents were observed at potentials below those activating the Na+ current, suggesting that receptor potentials spread passively through the soma to generate action potentials in the axon of this cell. Steady-state inactivation of the Na+ current was half-maximal at -40 mV. Recovery from inactivation was a single exponential function that was half-maximal at 1.7 ms at room temperature. The K+ currents were much larger than the inward currents and probably underlie the outward rectification observed in this cell. The delayed rectifier K+ current was reduced by GTP-gamma-S and AIF-4, agents which activate GTP-binding proteins. The channels described were a 215-pS Ca(++)-activated K+ channel, a 9.7-pS delayed rectifier K+ channel, and a 35-pS voltage-independent Cl- channel. The Cl- channel provides a constant leak conductance that may be important in stabilizing the membrane potential of the cell.

Animals↗
PubMed1992

A novel large-conductance Ca(2+)-activated potassium channel and current in nerve terminals of the rat neurohypophysis.

1. Nerve terminals of the rat posterior pituitary were acutely dissociated and identified using a combination of morphological and immunohistochemical techniques. Terminal membrane currents were studied using the 'whole-cell' patch clamp technique and channels were studied using inside-out and outside-out patches. 2. In physiological solutions, but with 7 mM 4-aminopyridine (4-AP), depolarizing voltage clamp steps from different holding potentials (-90 or -50 mV) elicited a fast, inward current followed by a slow, sustained, outward current. This outward current did not appear to show any steady-state inactivation. 3. The threshold for activation of the outward current was -30 mV and the current-voltage relation was 'bell-shaped'. The amplitude increased with increasingly depolarized potential steps. The outward current reversal potential was measured using tail current analysis and was consistent with that of a potassium current. 4. The sustained potassium current was determined to be dependent on the concentration of intracellular calcium. Extracellular Cd2+ (80 microM), a calcium channel blocker, also reversibly abolished the outward current. 5. The current was delayed in onset and was sustained over the length of a 150 ms-duration depolarizing pulse. The outward current reached a peak plateau and then decayed slowly. The decay was fitted by a single exponential with a time constant of 9.0 +/- 2.2 s. The decay constants did not show a dependence on voltage but rather on intracellular Ca2+. The time course of recovery from this decay was complex with full recovery taking > 190 s. 6. 4-AP (7 mM), dendrotoxin (100 nM), apamin (40-80 nM), and charybdotoxin (10-100 nM) had no effect on the sustained outward current. In contrast Ba2+ (200 microM) and tetraethylammonium inhibited the current, the latter in a dose-dependent manner (apparent concentration giving 50% of maximal inhibition (IC50) = 0.51 mM). 7. The neurohypophysial terminal outward current recorded here corresponds most closely to a Ca(2+)-activated K+ current (IK(Ca)) and not to a delayed rectifier or IA-like current. It also has properties different from that of the Ca(2+)-dependent outward current described in the magnocellular neuronal cell bodies of the hypothalamus. 8. A large conductance channel is often observed in isolated rat neurohypophysial nerve terminals. The channel had a unit conductance of 231 pS in symmetrical 150 mM K+.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Functional and molecular evidence for Shaker-like K+ channels in rabbit renal papillary epithelial cell line.

The rabbit papillary epithelial cell line GRB-PAP1 was used to determine the ion transport characteristics of a model of the distal nephron and terminal collecting duct. When grown on permeable supports, monolayers developed a significant electrical resistance and a benzamil-sensitive short-circuit current, indicating that they had the property of electrogenic Na+ transport. Using the whole cell patch-clamp technique, we found that the dominant current in these cells was a slowly inactivating, time- and voltage-dependent K+ current. This current was activated by voltages more positive than -30 mV. At +30 mV, the peak outward currents were > 300 pA. The magnitude of the outward currents and their reversal potentials depended strongly on the extracellular concentration of K+ and not on the extracellular concentration of Cl-. These currents were inhibited by either tetraethylammonium, 4-aminopyridine, charybdotoxin, or dendrotoxin. These characteristics, together with the kinetics of activation and inactivation, are the general characteristics of delayed rectifier channels seen in many muscle and neuronal cells. Because many of these types of channels share sequence homology with the Shaker family of channels cloned from Drosophila, we sought to identify a molecular correlate. Using reverse transcription followed by polymerase chain reaction to amplify Shaker-like sequences, we cloned and sequenced a single 881-bp fragment. The sequence shared identity with a recently reported rabbit Shaker channel that belongs to the subclass Kv 1.2. These data show that this renal papillary epithelial cell line, which has the capability of electrogenic Na+ transport, expresses functional delayed rectifier channels.

4-Aminopyridine↗
PubMed1993

Identification of a specific radioligand for the cardiac rapidly activating delayed rectifier K+ channel.

Class III antiarrhythmic drugs show promise as effective treatments for the suppression of potentially lethal cardiac arrhythmias. Dofetilide (UK-68,798), is a potent class III antiarrhythmic agent that is presently under clinical investigation. The objective of this study was to determine whether [3H]dofetilide could be used as a specific radioligand for the rapidly activating delayed rectifier K+ channel of the heart. We find that [3H]dofetilide binds to high-affinity sites on guinea pig cardiac myocytes. Competition studies using unlabeled dofetilide indicate that binding is characterized by an IC50 of 100 +/- 30 nM (mean +/- SD, n = 13). Scatchard analyses of binding indicate a Kd of 70 +/- 6 nM and a maximal binding capacity of 0.30 +/- 0.02 pmol/mg protein. [3H]Dofetilide is displaced from guinea pig myocytes by dofetilide, clofilium, quinidine, sotalol, and sematilide with a rank order of potency that correlates with functional blockade of the rapidly activating delayed rectifier K+ current (correlation coefficient, 0.951; slope, 0.99 +/- 0.19; p = 0.014). High-affinity [3H]dofetilide binding is not detected in rat myocytes, which are devoid of delayed rectifier K+ current. We conclude that [3H]dofetilide specifically binds to sites associated with the rapidly activating delayed rectifier K+ channel of guinea pig myocardium.

Animals↗
PubMed2005

Prednisolone-induced changes in dystrophic skeletal muscle.

Although glucocorticoids delay the progression of Duchenne muscular dystrophy (DMD) their mechanism of action is unknown. Skeletal muscle gene expression profiles of mdx mice, an animal model of DMD, treated with prednisolone were compared with control mice at 1 and 6 wk. Of the 89 early differentially regulated genes and ESTs, delta-sarcoglycan, myosin Va, FK506-binding protein 51 (FKBP51), the potassium channel regulator potassium inwardly-rectifying channel Isk-like (IRK2) and ADAM 10 were overexpressed, whereas growth hormone-releasing hormone receptor (GHRHR) and Homer-2 were underexpressed. The 58 late differentially overexpressed genes included kallikreins (13, 16, and 26), FKBP51, PI3K alpha regulatory subunit, and IGFBP6, while underexpressed genes included NeuroD and nicotinic cholinergic receptor gamma. At both time points, overexpression of a cohort of genes relating to metabolism and proteolysis was apparent, alongside the differential expression of genes relating to calcium metabolism. Treatment did not increase muscle regeneration, reduce the number of infiltrating macrophages, or alter utrophin expression or localization. However, in the treated mdx soleus muscle, the percentage of slow fibers was significantly lower compared with untreated controls after 6 wk of treatment. These results show that glucocorticoids confer their benefit to dystrophic muscle in a complex fashion, culminating in a switch to a more normal muscle fiber type.

Amyloid Precursor Protein Secretases↗
PubMed2002

Effects of ropivacaine on sodium, calcium, and potassium currents in guinea pig ventricular myocytes.

AIM: To study the effects of ropivacaine (Rop) on sodium current (INa), L-type calcium current (ICa-L), inward rectifier potassium current (IK1), and delayed rectifier potassium current (IK) in isolated guinea pig ventricular myocytes. METHODS: Whole cell patch-clamp techniques were used in our experiment. RESULTS: At potential of -40 mV, Rop 10, 50, and 100 micromol/L decreased sodium current by 8.3 %, 33.3 %, and 62.5 %, respectively and prolonged the time constant of INa inactivation by 8.2 %, 24.7 %, and 64.4 %, respectively (n = 5 cells from 3 animals, P < 0.05). At potential of +10 mV, Rop 50 and 100 micromol/L decreased L-type calcium current by 7.6 % and 22.5 %, and prolonged the slow time constant of ICa-L inactivation by 15.5 % and 33.0 %, respectively (n = 5 cells from 4 animals, P < 0.05). Rop 50 and 100 micromol/L did not markedly change the peak current of delayed rectifier potassium current and inward rectifier potassium current (n = 5 cells from 3 animals, P > 0.05), respectively. CONCLUSION: Rop depressed INa and ICa-L, which may be related to its cardiotoxic effect

Amides↗
PubMed1988

Multiple potassium conductances and their functions in neurons from cat sensorimotor cortex in vitro.

1. Potassium conductances were studied in large layer V neurons using an in vitro slice preparation of cat sensorimotor cortex. The kinetics and pharmacological sensitivity of K+ currents were studied directly using single microelectrode voltage clamp and indirectly by evoking single or multiple spikes and recording the spike repolarization and subsequent afterhyperpolarizations (AHPs). 2. A fast-decaying afterhyperpolarization (fAHP) and a subsequent medium-duration afterhyperpolarization (mAHP) followed a single spike. The amplitude and duration of the mAHP increased when multiple spikes were evoked at a fast rate (e.g., 100 Hz), and a slower afterhyperpolarization (sAHP) appeared only after sustained repetitive firing. 3. All AHPs were reduced by membrane potential hyperpolarization and raised extracellular K+ concentration, suggesting they were caused by an increased K+ conductance. Only the mAHP and sAHP reversed at the estimated value of potassium equilibrium potential (-100 mV), whereas the mean reversal potential of the fAHP was nearly identical to the mean value of resting potential (-71 mV). 4. Mechanisms underlying spike repolarization, the fAHP, and the mAHP were investigated. Two rapidly activating outward currents, a fast-inactivating current and a slowly inactivating delayed rectifier, were detected by voltage clamp. Both currents were reduced rapidly by tetraethylammonium (TEA). The fast transient current was reduced slowly after divalent cations were substituted for Ca2+ (through a mechanism unrelated to blockade of Ca2+ channels), whereas the delayed rectifier was unaffected. 5. Spike duration was increased and the fAHP was abolished only by blocking agents that reduced the fast outward currents. Effects of extracellular and intracellular TEA were similar. Effects of TEA and Ca2+-free perfusate were additive and resembled the effects of intracellular Cs+. The addition of apamin, d-tubocurare, or Cd2+ was ineffective. We conclude that the two fast outward currents reflect pharmacologically and kinetically separate K+ conductances that are primarily responsible for spike repolarization and the fAHP. 6. Voltage-clamp studies revealed two additional outward currents, which were persistent and Ca2+-mediated. Each current activated and deactivated slowly, but the kinetics of one component were approximately 10 times slower than the other. The decay of these currents gave rise to AHPs resembling the mAHP and the early sAHP. 7. Neither the mAHP nor the sAHP was reduced by TEA. The mAHP was reduced when divalent cations were substituted for Ca2+ or when Cd2+, apamin, or d-tubocurare were added.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1982

Identification of gK systems activated by [Ca2+].

Rhythmic caffeine hyperpolarizations generated in bullfrog sympathetic ganglion cells are assumed to be caused by periodic increase in gK due to rise in [Ca2+]i7--9,13. Caffeine-induced outward currents seem to be composed of two different components, which show different pharmacological natures and also different dependencies on membrane potential changes. These two components may be generated by activation of two voltage-dependent K+ currents, namely IK1 (the delayed rectifier K+ current) and IK2 (IM) of ganglion cells. These results suggested that at least two different gK systems were activated by [Ca2+]i in sympathetic ganglion cells.

Acetylcholine↗
PubMed1993

Electrophysiological and morphological properties of granule cells: patch-clamp recordings of newborn rabbit olfactory bulb slices.

Granule cells were investigated by performing whole-cell patch-clamp recordings from thin slices of the olfactory bulb of newborn rabbits. Granule cells were intracellularly stained with Lucifer Yellow in their intact environment. During current-clamp measurements these neurones were characterized by their lack of action potentials upon depolarization. Evidence for a Ca2+ dependent K+ conductance was found. Two types of outward currents were identified in the whole cell mode during voltage clamp; a non-inactivating K+ current that shared some properties of the delayed rectifier K+ current and a non-inactivating K+ current were recorded. No fast inward current was registrated.

Action Potentials↗
PubMed2001

Functional and molecular expression of a voltage-dependent K(+) channel (Kv1.1) in interstitial cells of Cajal.

1. Located within the gastrointestinal (GI) musculature are networks of cells known as interstitial cells of Cajal (ICC). ICC are associated with several functions including pacemaker activity that generates electrical slow waves and neurotransmission regulating GI motility. In this study we identified a voltage-dependent K(+) channel (Kv1.1) expressed in ICC and neurons but not in smooth muscle cells. 2. Transcriptional analyses demonstrated that Kv1.1 was expressed in whole tissue but not in isolated smooth muscle cells. Immunohistochemical co-localization of Kv1.1 with c-kit (a specific marker for ICC) and vimentin (a specific marker of neurons and ICC) indicated that Kv1.1-like immunoreactivity (Kv1.1-LI) was present in ICC and neurons of GI tissues of the dog, guinea-pig and mouse. Kv1.1-LI was not observed in smooth muscle cells of the circular and longitudinal muscle layers. 3. Kv1.1 was cloned from a canine colonic cDNA library and expressed in Xenopus oocytes. Pharmacological investigation of the electrophysiological properties of Kv1.1 demonstrated that the mamba snake toxin dendrotoxin-K (DTX-K) blocked the Kv1.1 outward current when expressed as a homotetrameric complex (EC(50) = 0.34 nM). Other Kv channels were insensitive to DTX-K. When Kv1.1 was expressed as a heterotetrameric complex with Kv1.5, block by DTX-K dominated, indicating that one or more subunits of Kv1.1 rendered the heterotetrameric channel sensitive to DTX-K. 4. In patch-clamp experiments on cultured murine fundus ICC, DTX-K blocked a component of the delayed rectifier outward current. The remaining, DTX-insensitive current (i.e. current in the presence of 10(-8) M DTX-K) was outwardly rectifying, rapidly activating, non-inactivating during 500 ms step depolarizations, and could be blocked by both tetraethylammonium (TEA) and 4-aminopyridine (4-AP). 5. In conclusion, Kv1.1 is expressed by ICC of several species. DTX-K is a specific blocker of Kv1.1 and heterotetrameric channels containing Kv1.1. This information is useful as a means of identifying ICC and in studies of the role of delayed rectifier K(+) currents in ICC functions.

Animals↗
PubMedDate not supplied

GTP-binding proteins couple cardiac muscarinic receptors to a K channel.

Binding of acetylcholine (ACh) to cardiac muscarinic ACh receptors (mAChR) activates a potassium channel that slows pacemaker activity. Although the time course of this activation suggests a multi-step process with intrinsic delays of 30-100 ms, no second-messenger system has been demonstrated to link the mAChR to the channel. Changes in cyclic nucleotide levels (cyclic AMP and cyclic GMP) do not affect this K channel or its response to muscarinic agonists. Indeed, electrophysiological experiments argue against the involvement of any second messenger that diffuses through the cytoplasm. We report here that coupling of the mAChR in embryonic chick atrial cells to this inward rectifying K channel requires intracellular GTP. Furthermore, pretreatment of cells with IAP (islet-activating protein from the bacterium Bordetella pertussis) eliminates the ACh-induced inward rectification. As IAP specifically ADP-ribosylates two GTP-binding proteins, Ni and No, that can interact with mAChRs, we conclude that a guanyl nucleotide-binding protein couples ACh binding to channel activation. This represents the first demonstration that a GTP-binding protein can regulate the function of an ionic channel without acting through cyclic nucleotide second messengers.

Acetylcholine↗
PubMed2000

Effects of potassium channel inhibitors on the relaxation induced by the nitric oxide donor diethylamine nitric oxide in isolated human cerebral arteries.

OBJECT: The goal of this study was to investigate whether K+ channels are involved in nitric oxide (NO)-induced relaxation of isolated human cerebral arteries. METHODS: Successive concentration-response curves relating to the use of the NO donor diethylamine NO (DEA/NO) were established in the absence and presence of different K+ channel inhibitors after mounting human cerebral arteries onto a wire myograph. The arteries were obtained from macroscopically intact tissue that had been removed during brain tumor operations. A high K+ concentration partially inhibited the relaxant effects of DEA/NO. Different K+ channel inhibitors (tetraethylammonium [TEA], 10(-3) M; charybdotoxin, 10(-7) M; glibenclamide, 10(-6) M; 4-aminopyridine [4-AP], 10(-3) M; BaCl2, 5 x 10(-5) M; and apamin, 10(-6) M) alone failed to affect the responses to DEA/NO. However, a combination of TEA, glibenclamide, 4-AP, and BaCl2 partially blocked the relaxant effects of DEA/NO. In addition, the effects of DEA/NO were inhibited by the thromboxane A2 analog U46619 (3 x 10(-7) M). CONCLUSIONS: Inhibitors of the large-conductance or small-conductance Ca++-activated K+ channels, the adenosine triphosphate-sensitive K+ channels, and the delayed-rectifier or inward-rectifier K+ channels failed to alter the effects of DEA/NO when only one K+ channel blocker was used. However, a regimen of a combination of K+ channel blockers that possess selectivity for different channels demonstrated that different K+ channel types are involved; these channels may function in a redundant manner and compensate for each other. Selective thromboxane A2 agonists are capable of inhibiting the relaxant response to the NO donor.

Cerebral Arteries↗
PubMed2006

[Action of AMP579 and adenosine on potassium or sodium ionic channels in isolated rat and guinea pig ventricular myocytes].

AIM: To study the effect of AMP579 and adenosine on potassium ionic (K+) or sodium ionic (Na+) channels and to elucidate ionic mechanisms underlying negative inotropic and antiarrhythmic effects of AMP579 and adenosine. METHODS: Ionic channel currents of rat and guinea pig ventricular myocytes were recorded by patch clamp technique in whole-cell configuration. RESULTS: Adenosine showed a stronger activating effect on transient outward K+ current (I(to)) than AMP579, EC50 of adenosine and AMP579 were 2.33 and 8. 32 micromol x L(-1), respectively (P < 0.05). An adenosine A1 receptor blocker, 1,3-dipropyl-8-cyclopentylxanthine (PD116948), can abolish the effects of AMP579 and adenosine on I(to), demonstrating that the effect is mediated by adenosine A1 receptor. Adenosine exerted a more obvious inhibitory effect on delayed rectifier K+ current (IK) than AMP579. IC50 of adenosine and AMP579 were 1.21 and 2.31 micromol x L(-1), respectively (P < 0.05). AMP579 had a more powerful inhibitory effect on inward rectifier K+ current (IK1) than adenosine. IC50 of AMP579 and adenosine were 4.15 and 20.7 micromol x L(-1), repectively (P < 0.01). AMP579 and adenosine exerted a similar inhibitory effect on fast inward Na+ current (INA), IC50 of AMP579 and adenosine were 9.46 and 6.23 micromol x L(-1), respectively (P > 0.05). CONCLUSION: Adenosine showed a stronger activating effect on I(to) than AMP579, however, the mechanism of AMP579 and adenosine activating I(to) was mediated by adenosine A1 receptor. AMP579 has a more powerful inhibitory effect on IK1, and less inhibitory effect on IK than adenosine. Both drugs have a similar inhibitory effect on INa. The negative inotropic and antiarrhythmic effects are related to these ionic mechanisms.

Adenosine↗
PubMed1995

Putative M-type potassium channels in neuroblastoma-glioma hybrid cells: inhibition by muscarine and bradykinin.

Putative M-type K(+)-channels ('M-channels') were recorded in differentiated NG108-15 neuroblastoma x glioma hybrid cells transformed to express m1 muscarinic acetylcholine receptors using cell-attached patch-electrodes. Channels showed multiple conductances, with peaks at 6-9 and 12-15 pS. Averaged currents showed time-dependent activation during 1 s depolarization steps to around -30 mV. Steady-state Po increased in a voltage-dependent manner when the membrane was depolarized between 10 and 60 mV, with a limiting slope of 5.5 mV/e-fold change in Po. Steady-state kinetics were fit by two open and three shut times: depolarization shortened shut times and lengthened open times. Application of muscarine (10 microM) or bradykinin (10 microM) to the membrane outside the patch reversibly reduced steady-state in-patch channel activity to 38.4 +/- 11.7 and 28.8 +/- 6.1% of control values, respectively. Inhibition was accompanied by a lengthening of channel shut times without significant change in open times or distribution of conductance levels. No effect of muscarine or bradykinin on whole-cell or membrane patch delayed rectifier currents was detected. It is concluded that M-channels in NG108-15 cells are qualitatively similar to, but sparser than, those previously reported in rat sympathetic neurones. Their inhibition by extra-patch acetylcholine and bradykinin suggests that a mobile messenger is involved in the transduction process leading from receptor activation to channel closure.

Animals↗
PubMed1993

A method for rapid exchange of solutions at membrane patches using a 10-microliters microcapsule.

A rapid exchange (less than 2 ms) of the bath solution facing a membrane patch is accomplished by driving the tip of a pipette from the bath through a 100-microns oil layer into a small capsule filled with 10 microliters test solution. The microcapsule method can be applied to both excised patch configurations, inside-out and outside-out patches. On and off reactions of Ca(2+)-activated K+ channel activity have been recorded after changing the intracellular Ca2+ concentration using an inside-out patch. A blockade of these K+ channels by external tetraethylammonium ions is demonstrated with an outside-out patch. The blocking kinetics of delayed-rectifier K+ channels by a purified peptide toxin from snake venom, dendrotoxin, could be measured with our microcapsule method. Using tiny volumes of test solutions this method can be helpful in experiments involving scarce or expensive solutions.

Animals↗
PubMed1996

Ion channel blockers in the treatment of chronic heart failure.

Strategies for pharmacological treatment of chronic congestive heart failure (CHF) are discussed from the viewpoint of cardiac ion channel modulations. It remains controversial as to whether Na channel blockers, which are the most effective drugs to suppress ventricular arrhythmias, can improve the prognosis of chronic CHF. As far as recent knowledge of interactions between the Na channel and its blocker is concerned, lidocaine-like agents such as mexiletine, which inhibit the Na channel current by binding to the channel in the inactivated state, are recommended because they can suppress premature ventricular contractions without prolongation of QRS complexes of sinus beats. To develop a new agent for the treatment of chronic CHF, we extracted the common features of electropharmacologic actions shared by amiodarone and vesnarinone, both of which have been reported to reduce the mortality of patients with chronic CHF. It is concluded that increases in the action potential duration (APD) of ventricular muscle mediated through an inhibition of the delayed rectifier K channel (IK channel) and a reduction of sinus node firing through an inhibition of L type Ca channel in addition to IK channel inhibition, are essential for the treatment of chronic CHF.

Amiodarone↗
PubMed2006

Ginsenoside Re, a main phytosterol of Panax ginseng, activates cardiac potassium channels via a nongenomic pathway of sex hormones.

Ginseng root is one of the most popular herbs throughout the world and is believed to be a panacea and to promote longevity. It has been used as a medicine to protect against cardiac ischemia, a major cause of death in the West. We have previously demonstrated that ginsenoside Re, a main phytosterol of Panax ginseng, inhibits Ca(2+) accumulation in mitochondria during cardiac ischemia/reperfusion, which is attributable to nitric oxide (NO)-induced Ca(2+) channel inhibition and K(+) channel activation in cardiac myocytes. In this study, we provide compelling evidence that ginsenoside Re activates endothelial NO synthase (eNOS) to release NO, resulting in activation of the slowly activating delayed rectifier K(+) current. The eNOS activation occurs via a nongenomic pathway of each of androgen receptor, estrogen receptor-alpha, and progesterone receptor, in which c-Src, phosphoinositide 3-kinase, Akt, and eNOS are sequentially activated. However, ginsenoside Re does not stimulate proliferation of androgen-responsive LNCaP cells and estrogen-responsive MCF-7 cells, implying that ginsenoside Re does not activate a genomic pathway of sex hormone receptors. Fluorescence resonance energy transfer experiments with a probe, SCCoR (single cell coactivator recruitment), indicate that the lack of genomic action is attributable to failure of coactivator recruitment. Thus, ginsenoside Re acts as a specific agonist for the nongenomic pathway of sex steroid receptors, and NO released from activated eNOS underlies cardiac K(+) channel activation and protection against ischemia-reperfusion injury.

Animals↗