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Results for “Delayed Rectifier Potassium Channels”

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PubMed2006

Temperature acclimation modifies sinoatrial pacemaker mechanism of the rainbow trout heart.

The hypothesis of pacemaker level origin of thermal compensation in heart rate was tested by recording action potentials (AP) in intact sinoatrial tissue and enzymatically isolated pacemaker cells of rainbow trout acclimated at 4 degrees C (cold) and 18 degrees C (warm). With electrophysiological recordings, the primary pacemaker was located at the base of the sinoatrial valve, where a morphologically distinct ring of tissue comprising myocytes and neural elements was found by histological examination. Intrinsic beating rate of this pacemaker was higher in cold-acclimated (46 +/- 6 APs/min) than warm-acclimated trout (38 +/- 3 APs/min; P < 0.05), and a similar difference was seen in beating rate of isolated pacemaker cells (44 +/- 6 vs. 38 +/- 6 APs/min; P < 0.05), supporting the hypothesis that thermal acclimation modifies the intrinsic pacemaker mechanism of fish heart. Inhibition of sarcoplasmic reticulum (SR) with 10 microM ryanodine and 1 microM thapsigargin did not affect heart rate in either warm- or cold-acclimated trout at 11 degrees C but reduced heart rate in warm-acclimated trout from 74 +/- 2 to 42 +/- 6 APs/min (P < 0.05) at 18 degrees C. At 11 degrees C, a half-maximal blockade of the delayed rectifier K+ current (I(Kr)) with 0.1 microM E-4031 reduced heart rate more in warm-acclimated (from 45 +/- 1 to 24 +/- 5 APs/min) than cold-acclimated trout (56 +/- 3 vs. 48 +/- 2 APs/min), whereas I(Kr) density was higher and AP duration less in cold-acclimated trout (P > 0.05). Collectively, these findings suggest that a cold-induced increase in AP discharge frequency is at least partly due to higher density of the I(Kr) in the cold-acclimated trout, whereas contribution of SR Ca2+ release to thermal compensation of heart rate is negligible.

Acclimatization↗

PubMed2001

Safety of antihistamines in children.

The histamine H1 receptor antagonists (antihistamines) are an important class of medications used for the relief of common symptoms associated with hyperhistaminic conditions occurring in children and adults. This group of drugs may be subdivided into 3 classes, or generations, based upon their propensity to induce sedation and cardiotoxicity. The first generation (classical) antihistamines are highly effective in treating hyperhistaminic conditions. However, they frequently induce sedation and may adversely affect a child's learning ability. First generation antihistamine-induced sedation has been described to occur in more than 50% of patients receiving therapeutic dosages. Serious adverse events are unusual following overdoses of first generation antihistamines although life-threatening adverse events have been described. When the so-called 'second generation' antihistamines terfenadine and astemizole were introduced they were widely embraced and quickly used by clinicians of all specialities, including paediatricians, as nonsedating alternatives to the first generation compounds. These new agents were found to be equally or more effective than first generation antihistamines in relieving symptoms associated with hyperhistaminic conditions without the soporific effects of the first generation agents. Unfortunately, after approximately 10 years of widespread clinical use, disturbing reports of potentially life-threatening dysrhythmias, specifically torsades de pointes, were described. Both terfenadine and astemizole have been shown in vitro to inhibit several ion channels, and in particular the delayed outward rectifier potassium channel in the myocardium, predisposing the heart to dysrhythmias. The potential life-threatening cardiotoxicities of the second generation antihistamines led to the search for noncardiotoxic and nonsedating agents. Loratadine, fexofenadine, mizolastine, ebastine, azelastine and cetirizine are the first of the new third generation antihistamines. These drugs have been shown to be efficacious with few adverse events including no clinically relevant cytochrome P450 mediated metabolic-based drug-drug interactions or QT interval prolongation/cardiac dysrhythmias. Appropriate treatment of an antihistamine overdose depends upon which class of compound has been ingested. There is no specific antidote for antihistamine overdose and treatment is supportive particularly for ingestions of first generation compounds. Ingestion of excessive doses of terfenadine or astemizole requires immediate medical attention. Children who accidentally ingest excessive doses of a third generation compound may usually be adequately managed at home. However, patients ingesting large amounts (approximately >3 to 4 times the normal therapeutic daily dose) should receive medical attention. These patients should be monitored for 2 to 3 hours after the ingestion and patients ingesting cetirizine should be advised about the potential for sedation. The availability of newer generation antihistamine compounds has clearly added to the clinical effectiveness and patient tolerance of a widely prescribed class of drugs. These advances have also been accompanied by improved safety profiles, particularly in the case of third generation antihistamine overdose.

Adult↗

PubMed1999

Activation of Ca(2+)-dependent K(+) current by nordihydroguaiaretic acid in porcine coronary arterial smooth muscle cells.

The effects of nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor and an antioxidant, on membrane currents were examined in single smooth muscle cells isolated from porcine coronary artery. Spontaneous transient outward currents (STOCs) recorded at -30 mV were markedly enhanced by NDGA (>/=10 microM). Pretreatment with caffeine and ryanodine abolished STOCs and reduced NDGA-induced increase in outward current at -30 mV by approximately 60%. NDGA showed dual action on an outward current elicited by step depolarization from -60 to 0 mV: inhibition and enhancement at concentrations of 3 and >/=10 microM, respectively. In the presence of Cd(2+), the inhibition of outward current by NDGA disappeared and the enhancement remained. NDGA inhibited both the voltage-dependent Ca(2+) channel current (IC(50) = 2.5 microM) and the delayed rectifier K(+) current (IC(50) = 9.8 microM). The NDGA-induced enhancement of STOCs and outward currents on depolarization was abolished by 100 nM iberiotoxin but was not affected by glibenclamide or apamin. Under current clamp mode, 30 microM NDGA significantly hyperpolarized myocytes. The application of lipoxygenase inhibitors (caffeic acid and esculetin), a cyclooxygenase inhibitor (indomethacin), antioxidants (ascorbic acid and erythorbic acid), and structural-related compounds of NDGA (catechol and dopamine) did not enhance K(+) currents. These results indicate that the opening of the large conductance Ca(2+)-dependent K(+) channel by NDGA, which is independent of its lipoxygenase inhibition or antioxidant effect, results in membrane hyperpolarization.

Animals↗

PubMed2006

CO2 chemosensitivity in Helix aspersa: three potassium currents mediate pH-sensitive neuronal spike timing.

Elevated levels of carbon dioxide increase lung ventilation in Helix aspersa. The hypercapnic response originates from a discrete respiratory chemosensory region in the dorsal subesophageal ganglia that contains CO(2)-sensitive neurons. We tested the hypothesis that pH-dependent inhibition of potassium channels in neurons in this region mediated the chemosensory response to CO(2). Cells isolated from the dorsal subesophageal ganglia retained CO(2) chemosensitivity and exhibited membrane depolarization and/or an increase in input resistance during an acid challenge. Isolated somata expressed two voltage-dependent potassium channels, an A-type and a delayed-rectifier-type channel (I(KA) and I(KDR)). Both conductances were inhibited during hypercapnia. The pattern of voltage dependence indicated that I(KA) was affected by extracellular or intracellular pH, but the activity of I(KDR) was modulated by extracellular pH only. Application of inhibitors of either channel mimicked many of the effects of acidification in isolated cells and neurons in situ. We also detected evidence of a pH-sensitive calcium-activated potassium channel (I(KCa)) in neurons in situ. The results of these studies support the hypothesis that I(KA) initiates the chemosensory response, and I(KDR) and I(KCa) prolong the period of activation of CO(2)-sensitive neurons. Thus multiple potassium channels are inhibited by acidosis, and the combined effect of pH-dependent inhibition of these channels enhances neuronal excitability and mediates CO(2) chemosensory responses in H. aspersa. We did not find a single "chemosensory channel," and the chemosensitive channels that we did find were not unique in any way that we could detect. The protein "machinery" of CO(2) chemosensitivity is probably widespread among neurons, and the selection process whereby a neuron acts or does not act as a respiratory CO(2) chemosensor probably depends on the resting membrane potential and synaptic connectivity.

Action Potentials↗

PubMed2005

Fatty acid responses in taste cells from obesity-prone and -resistant rats.

One of the transduction mechanisms for the chemoreception of fat has been proposed to involve the inhibition of delayed rectifying potassium (DRK) channels by polyunsaturated free fatty acids (PUFAs). In the present study we have compared the responsiveness of fungiform taste receptor cells (TRCs) to fatty acids in obesity-prone (Osborne-Mendel; O-M) and obesity-resistant (S5B/Pl) rat strains using patch clamp recording. TRCs from S5B/Pl rats were markedly more responsive to PUFAs than those from O-M, yet with identical inhibition constants. Moreover, addition of PUFAs to subthreshold concentrations of saccharin enhanced preference for the mixture in two-bottle preference tests compared to the saccharin alone in S5B/Pl but not O-M rats. The correlation between electrophysiological and behavioral effects of PUFAs suggested that differences in fatty acid-sensitive DRK expression may underlie the phenotypic differences between S5B/Pl and O-M rats. Consistent with this hypothesis, O-M rats exhibit a greater DRK current density and express quantitatively more DRK channels as assayed using quantitative real-time PCR. No differences were found when comparing expression of fatty acid activated two pore domain potassium channels. We propose that the ratio of fatty acid-sensitive DRK channels to fatty acid-insensitive DRK channels may be important to contributing to overall peripheral fatty acid sensitivity and in that way influence the strength of the resulting chemosensory response to fat.

Animals↗

PubMed2005

KMUP-1 activates BKCa channels in basilar artery myocytes via cyclic nucleotide-dependent protein kinases.

This study investigated whether KMUP-1, a synthetic xanthine-based derivative, augments the delayed-rectifier potassium (K(DR))- or large-conductance Ca2+-activated potassium (BKCa) channel activity in rat basilar arteries through protein kinase-dependent and -independent mechanisms. Cerebral smooth muscle cells were enzymatically dissociated from rat basilar arteries. Conventional whole cell, perforated and inside-out patch-clamp electrophysiology was used to monitor K+- and Ca2+ channel activities. KMUP-1 (1 microM) had no effect on the K(DR) current but dramatically enhanced BKCa channel activity. This increased BKCa current activity was abolished by charybdotoxin (100 nM) and iberiotoxin (100 nM). Like KMUP-1, the membrane-permeable analogs of cGMP (8-Br-cGMP) and cAMP (8-Br-cAMP) enhanced the BKCa current. BKCa current activation by KMUP-1 was markedly inhibited by a soluble guanylate cyclase inhibitor (ODQ 10 microM), an adenylate cyclase inhibitor (SQ 22536 10 microM), competitive antagonists of cGMP and cAMP (Rp-cGMP, 100 microM and Rp-cAMP, 100 microM), and cGMP- and cAMP-dependent protein kinase inhibitors (KT5823, 300 nM and KT5720, 300 nM). Voltage-dependent L-type Ca2+ current was significantly suppressed by KMUP-1 (1 microM), and nearly abolished by a calcium channel blocker (nifedipine, 1 microM). In conclusion, KMUP-1 stimulates BKCa currents by enhancing the activity of cGMP-dependent protein kinase, and in part this is due to increasing cAMP-dependent protein kinase. Physiologically, this activation would result in the closure of voltage-dependent calcium channels and the relaxation of cerebral arteries.

4-Aminopyridine↗

PubMed2000

D-Sotalol: death by the SWORD or deserving of further consideration for clinical use?

D-Sotalol is the dextro-rotatory isomer of sotalol and a class III anti-arrhythmic. D-Sotalol prolongs cardiac repolarisation by inhibiting the fast component of the delayed outward rectifying potassium channel. In animal studies, D-sotalol has been shown to be more effective in prolonging atrial, rather than ventricular, action potentials, suggesting that D-sotalol may be more effective against supra-ventricular than ventricular arrhythmias. Furthermore, in animal studies, D-sotalol induces after-depolarisations, which are predictors of pro-arrhythmic activity. D-Sotalol shows little or no reverse use dependence in animal and humans and has slow offset kinetics. This suggests that, in addition to being a preventative treatment for arrhythmias, D-sotalol may be effective at the start or during arrhythmia. As D-sotalol does not block the slow component of the delayed outward rectifying potassium channel, which is activated by the sympathetic nervous system, D-sotalol will not protect against sympathetic hyperactivity. D-Sotalol also has no effect on the K(ATP) channel, which is activated in ischaemia to shorten the action potential. Thus D-sotalol is less effective in ischaemia. Anti-arrhythmic activity with D-sotalol has been demonstrated in dog models of ventricular tachycardia and sudden death. Arrhythmias with D-sotalol have been demonstrated in an ischaemic guinea-pig ventricle model in the absence of action potentials. D-Sotalol is a weak beta-adrenoceptor antagonist and may also be a positive inotrope. In humans, D-sotalol has 100% systemic oral bioavailability, a terminal half-life of 7.2 h and is mainly excreted unchanged in the urine. Preliminary, mainly hospital-based, clinical trials showed that D-sotalol was effective in a variety of supraventricular and ventricular arrhythmias. However, a large clinical trial of D-sotalol as a preventative treatment for arrhythmias and sudden death after myocardial infarction, the SWORD trial, was terminated early because of increased mortality with D-sotalol. The group at greatest risk was those with a remote myocardial infarction and relatively good left ventricular function, the group that showed the lowest mortality when untreated. It is assumed that excessive prolongation of the action potential leading to pro-arrhythmia with D-sotalol, underlies the increased risk of death. However, there is little objective evidence in the SWORD trial to support this. Obviously D-sotalol should not be used in humans with a remote myocardial infarction and relatively good left ventricular function. D-Sotalol could still be considered for short-term hospital use in resistant arrhythmias and for longer-term use to prevent atrial fibrillation in those with remote myocardial infarction and poor left ventricular function.

Animals↗

PubMed1999

Beta-cell ion channels: keys to endodermal excitability.

Whereas pancreatic islet cells are not neurons, they are endodermally-derived specialized excitable cells that display many properties of neurons. Multiple ion channels in the pancreatic beta-cell regulate electrical excitability. Our focus for the last several years has been on the delayed rectifier (Kv) K+ channels, in an effort to define the individual roles of specific Kv channel genes in the overall regulation of insulin secretion. The many Kv channel genes, represented by more than 40 mammalian isoforms (termed Kv1 to Kv8), give rise to overlapping functions, primarily regulating repolarization of the plasma membrane. Experiments involving inhibition of Kv channel function have shown the important role Kv channels play in regulating beta-cell calcium oscillations in response to glucose stimulation. From our recent studies, we have concluded that although detectable mRNA for Kv1 family members is present in islets, Kv1 family channels are unlikely to play a significant role in the beta-cell, and we are now focusing on the roles of Kv2 and Kv3 channels.

Delayed Rectifier Potassium Channels↗

PubMed2006

Potassium channel subunit remodeling in rabbits exposed to long-term bradycardia or tachycardia: discrete arrhythmogenic consequences related to differential delayed-rectifier changes.

BACKGROUND: Sustained heart rate abnormalities produce electrical remodeling and susceptibility to arrhythmia. Uncontrolled tachycardia produces heart failure and ventricular tachyarrhythmia susceptibility, whereas bradycardia promotes spontaneous torsade de pointes (TdP). This study compared arrhythmic phenotypes and molecular electrophysiological remodeling produced by tachycardia versus bradycardia in rabbits. METHODS AND RESULTS: We evaluated mRNA and protein expression of subunits underlying rapid (IKr) and slow (IKs) delayed-rectifier and transient-outward K+ currents in ventricular tissues from sinus rhythm control rabbits and rabbits with AV block submitted to 3-week ventricular pacing either at 60 to 90 bpm (bradypaced) or at 350 to 370 bpm (tachypaced). QT intervals at matched ventricular pacing rates were longer in bradypaced than tachypaced rabbits (eg, by approximately 50% at 60 bpm; P<0.01). KvLQT1 and minK mRNA and protein levels were downregulated in both bradypaced and tachypaced rabbits, whereas ERG was significantly downregulated in bradypaced rabbits only. Kv4.3 and Kv1.4 were downregulated by tachypacing only. Patch-clamp experiments showed that IKs was reduced in both but IKr was decreased in bradypaced rabbits only. Continuous monitoring revealed spontaneous TdP in 75% of bradypaced but only isolated ventricular ectopy in tachypaced rabbits. Administration of dofetilide (0.02 mg/kg) to mimic IKr downregulation produced ultimately lethal TdP in all tachypaced rabbits. CONCLUSIONS: Sustained tachycardia and bradycardia downregulate IKs subunits, but bradycardia also suppresses ERG/IKr, causing prominent repolarization delays and spontaneous TdP. Susceptibility of tachycardia/heart failure rabbits to malignant tachyarrhythmias is induced by exposure to IKr blockers. These results point to a crucial role for delayed-rectifier subunit remodeling in TdP susceptibility associated with rate-related cardiac remodeling.

Animals↗

PubMed2005

Apico-basal inhomogeneity in distribution of ion channels in canine and human ventricular myocardium.

OBJECTIVES: The aim of the present study was to compare the apico-basal distribution of ion currents and the underlying ion channel proteins in canine and human ventricular myocardium. METHODS: Ion currents and action potentials were recorded in canine cardiomyocytes, isolated from both apical and basal regions of the heart, using whole-cell voltage clamp techniques. Density of channel proteins in canine and human ventricular myocardium was determined by Western blotting. RESULTS: Action potential duration was shorter and the magnitude of phase-1 repolarization was significantly higher in apical than basal canine myocytes. No differences were observed in other parameters of the action potential or cell capacitance. Amplitude of the transient outward K(+) current (29.6+/-5.7 versus 16.5+/-4.4 pA/pF at +65 mV) and the slow component of the delayed rectifier K(+) current (5.61+/-0.43 versus 2.14+/-0.18 pA/pF at +50 mV) were significantly larger in apical than in basal myocytes. Densities of the inward rectifier K(+) current, rapid delayed rectifier K(+) current, and L-type Ca(2+) current were similar in myocytes of apical and basal origin. Apico-basal differences were found in the expression of only those channel proteins which are involved in mediation of the transient outward K(+) current and the slow delayed rectifier K(+) current: expression of Kv1.4, KChIP2, KvLQT1 and MinK was significantly higher in apical than in basal myocardium in both canine and human hearts. CONCLUSIONS: The results suggest that marked apico-basal electrical inhomogeneity exists in the canine-and probably in the human-ventricular myocardium, which may result in increased dispersion, and therefore, cannot be ignored when interpreting ECG recordings, pathological alterations, or drug effects.

Action Potentials↗

PubMed2006

Diabetes mellitus attenuates the repolarization reserve in mammalian heart.

OBJECTIVE: In diabetes mellitus several cardiac electrophysiological parameters are known to be affected. In rodent experimental diabetes models changes in these parameters were reported, but no such data are available in other mammalian species including the dog. The present study was designed to analyse the effects of experimental type 1 diabetes on ventricular repolarization and its underlying transmembrane ionic currents and channel proteins in canine hearts. METHODS AND RESULTS: Diabetes was induced by a single injection of alloxan, a subgroup of dogs received insulin substitution. After the development of diabetes (8 weeks) electrophysiological studies were performed using conventional microelectrodes, whole cell voltage clamp, and ECG. Expression of ion channel proteins was evaluated by Western blotting. The QTc interval and the ventricular action potential duration in diabetic dogs were moderately prolonged. This was accompanied by significant reduction in the density of the transient outward K+ current (I(to)) and the slow delayed rectifier K+ current (I(Ks)), to 54.6% and 69.3% of control, respectively. No differences were observed in the density of the inward rectifier K+ current (I(K1)), rapid delayed rectifier K+ current (I(Kr)), and L-type Ca2+ current (I(Ca)). Western blot analysis revealed a reduced expression of Kv4.3 and MinK (to 25+/-21% and 48+/-15% of control, respectively) in diabetic dogs, while other channel proteins were unchanged (HERG, MiRP1, alpha(1c)) or increased (Kv1.4, KChIP2, KvLQT1). Insulin substitution fully prevented the diabetes-induced changes in I(Ks), KvLQT1 and MinK, however, the changes in I(to), Kv4.3, and Kv1.4 were only partially diminished by insulin. CONCLUSION: It is concluded that type 1 diabetes mellitus, although only moderately, lengthens ventricular repolarization, attenuates the repolarization reserve by decreasing I(to) and I(Ks) currents, and thereby may markedly enhance the risk of sudden cardiac death.

Action Potentials↗

PubMed2005

Cocaine elicits action potential bursts in a central snail neuron: the role of delayed rectifying K+ current.

The effects of cocaine were studied in an identifiable RP4 neuron of the African snail, Achatina fulica Ferussac, using the two-electrode voltage-clamp method. The RP4 neuron generated spontaneous action potentials and bath application of cocaine (0.3-1 mM) reversibly elicited action potential bursts of the central RP4 neuron in a concentration-dependent manner. The action potential bursts were not blocked when neurons were immersed in high-Mg(2+)solution, Ca(2+)-free solution, nor after continuous perfusion with atropine, d-tubocurarine, propranolol, prazosin, haloperidol, or sulpiride. Similarly, the action potential bursts were not abolished by pretreatment with N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride, (9S,10S,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid hexyl ester or anisomycin. Injection of hyperpolarizing current at an intensity of greater than 2 nA effectively suppressed the cocaine-elicited action potential bursts and no postsynaptic potentials were observed under these conditions. These results suggest that the generation of action potential bursts elicited by cocaine was not due to (1) the synaptic effects of neurotransmitters, (2) the cholinergic, adrenergic or dopaminergic receptors of the excitable membrane, or (3) the cAMP second messengers and new protein synthesis of the RP4 neuron. Notably, the induction of action potential bursts was blocked by pretreatment with 1-[6-[((17beta)-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl]-1H-pyrrole-2,5-dione. Voltage-clamp studies conducted on the RP4 neuron revealed that cocaine at 0.3 mM decreased (1) the Ca(2+) current, (2) the delayed rectifying K(+) current, (3) the fast-inactivating K(+) current and (4) the Ca(2+)-activated K(+) current, but had no remarkable effects on the Na(+) current. Perfusion with Ca(2+)-free solution, which may abolish the Ca(2+) current and Ca(2+)-activated K(+) current, did not cause any bursts of action potentials in control RP4 neurons. Application of 4-aminopyridine, an inhibitor of fast-inactivating K(+) current, and paxilline, an inhibitor of Ca(2+)-activated K(+) current, failed to elicit action potential bursts, whereas tetraethylammonium chloride, a blocker of Ca(2+)-activated K(+) current and delayed rectifying K(+) current, and tacrine, an inhibitor of delayed rectifying K(+) current, successfully elicited action potential bursts. Further, while 1-[6-[((17beta)-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl]-1H-pyrrole-2,5-dione did not affect the delayed rectifying K(+) current of the RP4 neuron, 1-[6-[((17beta)-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl]-1H-pyrrole-2,5-dione decreased the inhibitory effect of cocaine on the delayed rectifying K(+) current. It is concluded that cocaine elicits action potential bursts in the central snail RP4 neuron and that the effect is closely related to the inhibitory effects on the delayed rectifying K(+) current.

Action Potentials↗

PubMed2005

Electrophysiologic characteristics of atrial myocytes in levo-thyroxine-treated rats.

To investigate whether thyroid hormone modulates electrical properties of atrial myocytes, electrocardiogram (ECG), action potentials (APs), and ionic currents were measured. Male Sprague-Dawley rats were randomly divided into control and levo-thyroxine (T4)-treated groups at 6 weeks of age. Levo-thyroxine (500 microg/kg of body weight) was injected daily into the peritoneal cavity for 14 days (T4-treated rats) and the same volume of saline was injected in control rats daily. ECG signals were recorded using apex-base leads. APs, voltage-dependent Na+ and L-type Ca2+ channel current (I(Na) and I(Ca(L))), inwardly rectifying K+ channel current (I(K1)), transient outward K+ channel current (I(to)), and delayed rectifier K+ channel current (I(K(delay))) were measured using patch-clamp techniques. T4 treatment significantly changed electrical properties in rat atrial myocytes, including (1) the increase in heart rate, (2) the increase in cell size, (3) the shortening of action potential duration (APD), (4) the increase in cell membrane capacitance (C(m)), and (5) the decrease in input resistance (R(in)). Although the current densities of I(Na) and I(K1) in T4-treated atrial myocytes did not differ from those in control cells, I(Ca(L)) was significantly decreased and I(K(delay)) was significantly increased in T4-treated rats. Thus, thyrotoxicosis could induce the shortening of APD by alterations in current density of both I(Ca(L)) and I(K(delay)) in rat atrial myocytes.

Action Potentials↗

PubMed2003

Cellular electrophysiology of canine pulmonary vein cardiomyocytes: action potential and ionic current properties.

Pulmonary vein (PV) cardiomyocytes play an important role in atrial fibrillation; however, little is known about their specific cellular electrophysiological properties. We applied standard microelectrode recording and whole-cell patch-clamp to evaluate action potentials and ionic currents in canine PVs and left atrium (LA) free wall. Resting membrane potential (RMP) averaged -66 +/- 1 mV in PVs and -74 +/- 1 mV in LA (P < 0.0001) and action potential amplitude averaged 76 +/- 2 mV in PVs vs. 95 +/- 2 mV in LA (P < 0.0001). PVs had smaller maximum phase 0 upstroke velocity (Vmax: 98 +/- 9 vs. 259 +/- 16 V s(-1), P < 0.0001) and action potential duration (APD): e.g. at 2 Hz, APD to 90% repolarization in PVs was 84 % of LA (P < 0.05). Na+ current density under voltage-clamp conditions was similar in PV and LA, suggesting that smaller Vmax in PVs was due to reduced RMP. Inward rectifier current density in the PV cardiomyocytes was approximately 58% that in the LA, potentially accounting for the less negative RMP in PVs. Slow and rapid delayed rectifier currents were greater in the PV (by approximately 60 and approximately 50 %, respectively), whereas transient outward K+ current and L-type Ca2+ current were significantly smaller (by approximately 25 and approximately 30%, respectively). Na(+)-Ca(2+)-exchange (NCX) current and T-type Ca2+ current were not significantly different. In conclusion, PV cardiomyocytes have a discrete distribution of transmembrane ion currents associated with specific action potential properties, with potential implications for understanding PV electrical activity in cardiac arrhythmias.

Action Potentials↗

PubMed1999

Contribution of L-type Ca2+ current to electrical activity in sinoatrial nodal myocytes of rabbits.

The role of L-type calcium current (ICa,L) in impulse generation was studied in single sinoatrial nodal myocytes of the rabbit, with the use of the amphotericin-perforated patch-clamp technique. Nifedipine, at a concentration of 5 microM, was used to block ICa,L. At this concentration, nifedipine selectively blocked ICa,L for 81% without affecting the T-type calcium current (ICa,T), the fast sodium current, the delayed rectifier current (IK), and the hyperpolarization-activated inward current. Furthermore, we did not observe the sustained inward current. The selective action of nifedipine on ICa,L enabled us to determine the activation threshold of ICa,L, which was around -60 mV. As nifedipine (5 microM) abolished spontaneous activity, we used a combined voltage- and current-clamp protocol to study the effects of ICa,L blockade on repolarization and diastolic depolarization. This protocol mimics the action potential such that the repolarization and subsequent diastolic depolarization are studied in current-clamp conditions. Nifedipine significantly decreased action potential duration at 50% repolarization and reduced diastolic depolarization rate over the entire diastole. Evidence was found that recovery from inactivation of ICa,L occurs during repolarization, which makes ICa,L available already early in diastole. We conclude that ICa,L contributes significantly to the net inward current during diastole and can modulate the entire diastolic depolarization.

Animals↗

PubMed2002

Ionic currents underlying fast action potentials in the obliquely striated muscle cells of the octopus arm.

The octopus arm provides a unique model for neuromuscular systems of flexible appendages. We previously reported the electrical compactness of the arm muscle cells and their rich excitable properties ranging from fast oscillations to overshooting action potentials. Here we characterize the voltage-activated ionic currents in the muscle cell membrane. We found three depolarization-activated ionic currents: 1) a high-voltage-activated L-type Ca(2+) current, which began activating at approximately -35 mV, was eliminated when Ca(2+) was substituted by Mg(2+), was blocked by nifedipine, and showed Ca(2+)-dependent inactivation. This current had very rapid activation kinetics (peaked within milliseconds) and slow inactivation kinetics (tau in the order of 50 ms). 2) A delayed rectifier K(+) current that was totally blocked by 10 mM TEA and partially blocked by 10 mM 4-aminopyridine (4AP). This current exhibited relatively slow activation kinetics (tau in the order of 15 ms) and inactivated only partially with a time constant of ~150 ms. And 3) a transient A-type K(+) current that was totally blocked by 10 mM 4AP and was partially blocked by 10 mM TEA. This current exhibited very fast activation kinetics (peaked within milliseconds) and inactivated with a time constant in the order of 60 ms. Inactivation of the A-type current was almost complete at -40 mV. No voltage-dependent Na(+) current was found in these cells. The octopus arm muscle cells generate fast (~3 ms) overshooting spikes in physiological conditions that are carried by a slowly inactivating L-type Ca(2+) current.

Action Potentials↗

PubMed2000

Effects of experimental heart failure on atrial cellular and ionic electrophysiology.

BACKGROUND: Congestive heart failure (CHF) is frequently associated with atrial fibrillation (AF), but little is known about the effects of CHF on atrial cellular electrophysiology. METHODS AND RESULTS: We studied action potential (AP) properties and ionic currents in atrial myocytes from dogs with CHF induced by ventricular pacing at 220 to 240 bpm for 5 weeks. Atrial myocytes from CHF dogs were hypertrophied (mean+/-SEM capacitance, 89+/-2 pF versus 71+/-2 pF in control, n=160 cells per group, P<0.001). CHF significantly reduced the density of L-type Ca(2+) current (I(Ca)) by approximately 30%, of transient outward K(+) current (I(to)) by approximately 50%, and of slow delayed rectifier current (I(Ks)) by approximately 30% without altering their voltage dependencies or kinetics. The inward rectifier, ultrarapid and rapid delayed rectifier, and T-type Ca(2+) currents were not altered by CHF. CHF increased transient inward Na(+)/Ca(2+) exchanger (NCX) current by approximately 45%. The AP duration of atrial myocytes was not altered by CHF at slow rates but was increased at faster rates, paralleling in vivo refractory changes. CHF created a substrate for AF, prolonging mean AF duration from 8+/-4 to 535+/-82 seconds (P<0.01). CONCLUSIONS: Experimental CHF selectively decreases atrial I(to), I(Ca), and I(Ks), increases NCX current, and leaves other currents unchanged. The cellular electrophysiological remodeling caused by CHF is quite distinct from that caused by atrial tachycardia, highlighting important differences in the cellular milieu characterizing different clinically relevant AF substrates.

Action Potentials↗

PubMed1998

Effects of the diuretic agent indapamide on Na+, transient outward, and delayed rectifier currents in canine atrial myocytes.

The diuretic agent indapamide has been reported to block the slow component of the delayed rectifier K+ current (IKs) without altering the rapid component (IKr) or the inward rectifier current and has been used as a pharmacological probe for IKs; however, the effects of indapamide on Na+ (INa), L-type Ca2+ (ICa), and transient outward K+ (Ito) currents have not been determined. We applied tight-seal, whole-cell, patch-clamp techniques to assess the effects of indapamide on INa, Ito, ICa, and IKs in canine atrial myocytes. Indapamide inhibited INa, Ito, and IKs in a concentration-dependent and reversible way, without altering ICa. Block increased with depolarization, with the 50% blocking concentration (EC50) decreasing from 129 +/- 26 micromol/L (at -60 mV) to 79 +/- 17 micromol/L (at -10 mV) for INa, from 174 +/- 19 micromol/L (at + 10 mV) to 98 +/- 7 micromol/L (at +60 mV) for Ito and from 148 +/- 28 micromol/L (at +10 mV) to 86 +/- 18 micromol/L (at +60 mV) for IKs. Significant inhibition was seen at concentrations as low as 10 micromol/L for all 3 currents. In addition, indapamide effectively inhibited the ultrarapid delayed rectifier current in a voltage-independent way, with an EC50 of 138 +/- 7 micromol/L at +10 mV. Standard microelectrode experiments showed the effects of indapamide on the action potential to be consistent with the ionic actions seen. We conclude that in addition to its well-recognized IKs-blocking action, indapamide also inhibits INa and Ito effectively and with similar potency. Thus, indapamide is not a reliable pharmacological probe with which to study the specific effects of IKs blockade, and INa and Ito block may contribute to the potential profile of cardiac actions of the compound.

Action Potentials↗