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PubMed2006

Comparison of four rate-correction algorithms for the ventricular repolarization period in assessing net effects of IKr blockers in dogs.

The utility of corrected and uncorrected QT interval changes for assessing net repolarization delay by I(Kr) (a rapid component of delayed rectifier K(+) currents) blockers was assessed in halothane-anesthetized dogs using the electrocardiogram and monophasic action potential (MAP) recordings with electrical ventricular pacing. Intravenous administration of dl-sotalol (0.2 - 2 mg/kg) prolonged the MAP duration and RR interval, while terfenadine (3 mg/kg) increased the MAP duration but transiently shortened RR interval. The order of correlation coefficient between the MAP duration at a pacing cycle length of 400 ms and MAP duration itself or that with arithmetical correction was uncorrected > Van de Water = Matsunaga > Fridericia > Bazett. These results suggest that Matsunaga's and Van de Water's formulae would better predict the net repolarization delay in the in vivo canine model. Also, the risk of drug candidates that may prolong the QT interval should be judged by change in uncorrected QT interval as well as corrected QT interval.

Action Potentials↗
PubMed2006

Single transmembrane domain insulin-like growth factor-II/mannose-6-phosphate receptor regulates central cholinergic function by activating a G-protein-sensitive, protein kinase C-dependent pathway.

The insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor is a single-pass transmembrane glycoprotein that plays an important role in the intracellular trafficking of lysosomal enzymes and endocytosis-mediated degradation of IGF-II. However, its role in signal transduction after IGF-II binding remains unclear. In the present study, we report that IGF-II/M6P receptor in the rat brain is coupled to a G-protein and that its activation by Leu27IGF-II, an analog that binds rather selectively to the IGF-II/M6P receptor, potentiates endogenous acetylcholine release from the rat hippocampal formation. This effect is mediated by a pertussis toxin (PTX)-sensitive GTP-binding protein and is dependent on protein kinase Calpha (PKCalpha)-induced phosphorylation of downstream substrates, myristoylated alanine-rich C kinase substrate, and growth associated protein-43. Additionally, treatment with Leu27IGF-II causes a reduction in whole-cell currents and depolarization of cholinergic basal forebrain neurons. This effect, which is blocked by an antibody against the IGF-II/M6P receptor, is also sensitive to PTX and is mediated via activation of a PKC-dependent pathway. These results together revealed for the first time that the single transmembrane domain IGF-II/M6P receptor expressed in the brain is G-protein coupled and is involved in the regulation of central cholinergic function via the activation of specific intracellular signaling cascades.

Acetylcholine↗
PubMed2003

Pacemaker mechanism of porcine sino-atrial node cells.

In cardiac sino-atrial node (SAN) cells, time- and voltage-dependent changes in the gating of various ionic currents provide spontaneous, stable and repetitive firing of action potentials. To address the ionic nature of the species-dependent heart rate, action potentials and membrane currents were recorded in single cells dissociated from the porcine SAN, and compared with those from SAN cells of rabbits, guinea-pigs and mice. The porcine SAN cells exhibited spontaneous activity with a frequency of 60-80 min(-1), which was much slower than that of rabbit SAN cells. Under voltage clamp conditions, depolarization activated the L-type Ca2+ current (I(CaL)) followed by a gradual activation of the delayed rectifier K+ current (I(K)) while hyperpolarization activated the hyperpolarization-activated cation current (I(h)). It was found that the major component of I(K) in porcine SAN is the slowly activating I(K) (I(Ks)), in contrast to SAN cells of the rabbit and other species in which the rapid I(K) (I(Kr)) plays an active role in repolarization and the subsequent pacemaker depolarization. Replacement of rabbit I(Kr) with porcine I(Ks) and a slight modification in the gating parameters and amplitudes of other current systems in the 'Kyoto Model' gave an adequate reconstruction of spontaneous action potentials as well as of the voltage clamp recordings. We conclude that the density and the kinetics of I(K) contribute, in part, to the different heart rates of various species.

Action Potentials↗
PubMed2005

Azimilide dihydrochloride.

Azimilide dihydrochloride is an antiarrhythmic drug with Vaughn Williams class III properties, which blocks both fast (IKr) and slow (IKs) components of the delayed rectifier cardiac potassium channel. The drug slows the heart rate slightly and, like other class III antiarrhythmic drugs, prolongs ventricular repolarization and thus, the QT interval. Unlike sotalol, another class III antiarrhythmic drug, azimilide does not exhibit reverse-use dependence, that is, its binding characteristics and effectiveness are not related to the heart rate. Azimilide is 85% bioavailable, reaches peak blood concentrations in 6-8 h and has a long elimination half-life of 114 h. Clinical trials have utilized once-daily dosing. These trials have tested the use of the drug for patients with supraventricular and ventricular arrhythmias.

Anti-Arrhythmia Agents↗
PubMed1999

E 4031.

Explore the source record for details and available documents.

Animals↗
PubMed2004

Pharmacological modulation of I(Ks): potential for antiarrhythmic therapy.

The slowly (I(Ks)) and rapidly (I(Kr)) activating delayed rectifier K(+) currents play important roles in cardiac ventricular repolarization. Compared with I(Kr), however, I(Ks) has important distinguishing characteristics, including beta-adrenergic receptor stimulation and accumulation at rapid rates that may impart significant therapeutic relevance. Therefore, development of selective I(Ks) inhibitors has been pursued as a strategy for providing potentially safer and more effective Class III antiarrhythmic agents and pharmacological tools for elucidating the normal physiological and potential pathological role of I(Ks) in cardiac repolarization. We have identified a series of 3-Acylamino-1,4 benzodiazepines that are very potent and selective inhibitors of I(Ks). A representative compound, L-768,673 (1) (IC(50)~8nM), has been extensively characterized for its pharmacologic activity. L-768,673 concentration-dependently prolongs action potential duration in a frequency-independent manner in vitro, but decreases transmural dispersion of refractoriness, a risk factor for arrhythmia induction. In conscious dogs, L 768,673 administered IV (0.3-100 micro g/kg) and PO (0.03-1 mg/kg) elicits consistent but limited (5-15%) QT(c) prolongation, and increases ventricular refractory period more at fast than at slow pacing rates, indicating a "forward" rate-dependence in vivo. In an anesthetized canine model of anterior myocardial infarction, I(Ks) blockers suppress the development of ischemic ventricular fibrillation at intravenous doses that minimally prolong the QT interval. I(Ks) blockers display an interesting and intriguing profile of effects on cardiac electrophysiologic parameters that differ in remarkable ways from other selective Class III agents such as I(Kr) blockers. It remains to be determined if these properties can be exploited clinically to provide more effective and safer treatment of cardiac arrhythmias.

Acetamides↗
PubMed2004

Novel antiarrhythmic compounds with combined class IB and class III mode of action.

Cardiac arrhythmias represent a major area of cardiovascular research, and for drug therapy, a large choice of antiarrhythmic agents have been available. However, clinical trials with antiarrhythmic drugs have recently indicated that serious side effects may considerably limit the use of various antiarrhythmic agents, in particular, for preventing arrhythmia-related mortality. Amiodarone with its complex mode of action, while exerting a strong and favorable antiarrhythmic action, posseses extracardiac untoward side effects originating from its chemical structure. In this paper, we report on our attempt to develop conceptually new, therapeutically valuable antiarrhythmic compounds, in which Class I/B and Class III features were combined into single molecules bearing no structural resemblance to amiodarone. Synthesis and pharmacological screening of series of N-(phenylalkyl)-N-(phenoxyalkyl)amines led us to discover some new promising compounds with the required dual mode of action. GYKI-16638, selected for further investigation, was also found to possess a remarkable in vivo antiarrhythmic effect, and it is now considered as a safe new antiarrhythmic drug candidate.

Action Potentials↗
PubMed2004

Profile of I(Ks) during the action potential questions the therapeutic value of I(Ks) blockade.

The goal of this paper is two fold. First, we attempt to review the reports available on the role of I(Ks) in myocardial repolarization. Based on theoretical considerations and experimental results, it seems reasonable to assume that I(Ks)blockade will lengthen the action potential. However, results obtained with I(Ks) blockers, like chromanol 293B or L-735,821, are conflicting, since from slight lengthening to marked prolongation of action potentials were equally obtained. Although these contradictory results were explained by interspecies or regional differences, the role of I(Ks) in repolarization is a matter of growing dispute. In the second part of this study, we simulated the performance of I(Ks) during cardiac action potentials. We compared the profile of the predicted current in three mathematical models in order to determine the relative role of the current in repolarization. We studied the effect of the cycle length, action potential duration and height of the plateau on the profile of I(Ks) in epicardiac, endocardiac and midmyocardiac ventricular action potentials. The results indicate that the height of the plateau is the most important parameter to control activation of I(Ks)in cardiac tissues, and accordingly, the interspecies and regional differences observed in the efficacy of I(Ks) blockers are likely due to the known differences in action potential morphology. We conclude also that I(Ks)blockade may have unpredictable effects on the length of the action potential in a diseased heart, questioning the possible therapeutic value of drugs blocking I(Ks).

Action Potentials↗
PubMed2007

The effect of C-type natriuretic peptide on delayed rectifier potassium currents in gastric antral circular myocytes of the guinea-pig.

C-type natriuretic peptides (CNP) play an inhibitory role in smooth muscle motility of the gastrointestinal tract, but the effect of CNP on delayed rectifier potassium currents is still unclear. This study was designed to investigate the effect of CNP on delayed rectifier potassium currents and its mechanism by using conventional whole-cell patch-clamp technique in guinea-pig gastric myocytes isolated by collagenase. CNP significantly inhibited delayed rectifier potassium currents [I(K (V))] in dose-dependent manner, and CNP inhibited the peak current elicited by depolarized step pulse to 86.1+/-1.6 % (n=7, P<0.05), 78.4+/-2.6 % (n=10, P<0.01) and 67.7+/-2.3 % (n=14, P<0.01), at concentrations of 0.01 micromol/l, 0.1 micromol/l and 1 micromol/l, respectively, at +60 mV. When the cells were preincubated with 0.1 micromol/l LY83583, a guanylate cyclase inhibitor, the 1 ?micromol/l CNP-induced inhibition of I(K (V)) was significantly impaired but when the cells were preincubated with 0.1 micromol/l zaprinast, a cGMP-sensitive phosphodiesterase inhibitor, the 0.01 micromol/l CNP-induced inhibition of I(K (V)) was significantly potentiated. 8-Br-cGMP, a membrane permeable cGMP analogue mimicked inhibitory effect of CNP on I(K (V)). CNP-induced inhibition of I(K (V)) was completely blocked by KT5823, an inhibitor of cGMP-dependent protein kinase (PKG). The results suggest that CNP inhibits the delayed rectifier potassium currents via cGMP-PKG signal pathway in the gastric antral circular myocytes of the guinea-pig.

Animals↗
PubMed1999

Electrophysiologic effects of chronic amiodarone therapy and hypothyroidism, alone and in combination, on guinea pig ventricular myocytes.

Amiodarone is a widely used antiarrhythmic drug, the mechanisms of action of which remain incompletely understood. Indirect evidence suggests that the class III properties of amiodarone may be mediated by cardiac antithyroid effects. We sought to determine whether the effects of chronic amiodarone on repolarization in guinea pig hearts can be attributed to an antithyroid action by studying the changes in dofetilide-sensitive rapid (IKr) and dofetilide-resistant slow (IKs) delayed rectifier currents, inward rectifier K+ current (IK1), and action potentials of ventricular myocytes from five groups of guinea pigs: control, hypothyroid, amiodarone-treated for 7 days, hypothyroid plus amiodarone, and vehicle (dimethyl sulfoxide) treated. IKs was reduced by amiodarone (to 61% of control, P <.05, at 50 mV) but was more strongly reduced by hypothyroidism (to 35% of control, P <.01, 50 mV). Amiodarone significantly reduced IKr and IK1 (by 55 and 64% at 10 mV and -50 mV, respectively), which were unaffected by hypothyroidism. Amiodarone alone and hypothyroidism alone had similar action potential-prolonging actions. Hypothyroid animals treated with amiodarone showed a combination of ionic effects (strong IKs reduction, similar to hypothyroidism alone; reduced IKr and IK1, similar to amiodarone alone), along with action potential prolongation significantly greater than that caused by either intervention alone. We conclude that chronic amiodarone and hypothyroidism have different effects on ionic currents and that their combination prolongs action potential duration to a greater extent than either alone in guinea pig hearts, suggesting that the class III actions of amiodarone are not mediated by a cardiac hypothyroid state.

Action Potentials↗
PubMed1999

Effects of verapamil, zatebradine, and E-4031 on the pacemaker location and rate in response to sympathetic stimulation in dog hearts.

To investigate whether slow inward Ca2+ current (ICa), hyperpolarization-activated inward current (If), and a rapid type of delayed rectifier K+ current (IKr) similarly act on the pacemaker location, sinoatrial node region, and subsidiary superior and inferior pacemaker regions, we studied the effects of verapamil, zatebradine, and E-4031 on the atrial rate and the 3-ms earliest activation region (EAR) determined from the isochronal activation sequence map in the autonomically decentralized heart of the anesthetized dog. Three blockers decreased atrial rate similarly. Verapamil shifted the EAR from the SA node region to the inferior pacemaker region. The EAR induced by zatebradine was variable, but the EAR induced by E-4031 tended to shift to the inferior pacemaker region. Sympathetic nerve stimulation increased atrial rate and shifted the EAR to the superior pacemaker region. Verapamil attenuated the increased atrial rate by 28%, and it shifted the EAR to the lower pacemaker regions consistently. Zatebradine also attenuated the increased rate by 53% and shifted the EAR from the anterior to the posterior-superior right atrium. On the other hand, E-4031 affected neither the rate nor the EAR in response to sympathetic stimulation. These results suggest that ICa, If, and IKr inhibitors differentially influence the pacemaker activity among three pacemaker regions when sympathetic tone is absent or present and that the role of ICa, If, and IKr of the pacemaker cells distributed in the atrial pacemaker complex is different in the dog heart in situ.

Animals↗
PubMed1998

Effects of barium on delayed rectifier potassium current in bullfrog sympathetic neurons pretreated with wortmannin.

The effect of barium (1 mM) on a delayed rectifier-type potassium current was examined in bullfrog sympathetic neurons. An M-type potassium current was eliminated by pretreatment of the cells with a microbial product, wortmannin (10 microM). An A-type potassium current was continuously inactivated by setting a holding potential at -65 mV. In treated cells (n = 10), the delayed rectifier at 0 mV averaged 2200 +/- 107 pA in the presence of barium (1 mM) as compared to 2308 +/- 110 pA in the controls, and 2085 +/- 103 pA after washing out the barium. It is concluded that the delayed rectifier is insensitive to barium blockage in amphibian autonomic neurons.

Androstadienes↗
PubMed1999

Non-muscarinic and non-nicotinic inhibition by the acetylcholine analogue carbachol of the delayed rectifier potassium current, iK, in rabbit isolated sino-atrial node cells.

The effect of carbachol, an analogue of acetylcholine, on the delayed rectifier potassium current, iK, was investigated in rabbit isolated sino-atrial node cells using the whole cell patch clamp technique with amphotericin-permeabilized patches. In the presence of 500 nM atropine and 500 nM hexamethonium to block muscarinic and nicotinic receptors, respectively, 500 nM carbachol decreased the amplitude and rate of deactivation of iK without, however, affecting the slope of the iK activation curve. The same concentration of carbachol decreased the pacemaking rate of spontaneously active sino-atrial node cells by more than 13%. Thus, there is a non-muscarinic and non-nicotinic pathway for cholinergically induced reduction in the amplitude and rate of deactivation of iK that would appear to contribute to negative chronotropy in rabbit sinoatrial node pacemaker cells.

Amphotericin B↗
PubMed2000

Modulation of delayed rectifier potassium current, iK, by isoprenaline in rabbit isolated pacemaker cells.

Permeabilized patch whole-cell voltage clamp methods were used to investigate the effects of isoprenaline (ISO) on total delayed rectifier potassium current, iK, in rabbit sino-atrial (SA) node pacemaker cells; total iK is composed of the rapidly activating iKr and the slowly activating iKs, but predominantly iKr in this species. ISO (20 nM) increased the amplitude of total iK and caused a negative shift of approximately 10 mV in the activation curve for iK, both in the absence and in the presence of 300 nM nisoldipine to block the L-type Ca2+ current, iCa,L. The same concentration (20 nM) of ISO increased the spontaneous pacemaker rate of SA node pacemaker cells by 16%. In addition to increasing the amplitude of iK, ISO (20-50 nM) also increased the rate of deactivation of this current. The stimulation of iK by ISO was reversed by 10 microM H-89, a selective protein kinase A inhibitor, but not by 200 nM bisindolymaleimide I, a selective protein kinase C inhibitor. It therefore appears that the mechanisms by which -adrenoceptor agonists increase pacemaking rate in sinoatrial node pacemaker cells include an increase in the rate of deactivation of iK in addition to the well-documented augmentation of iCa,L and the positive shift of the activation curve for the hyperpolarization-activated inward current, if. The observations are also consistent with a role for protein kinase A in the stimulation of iK by ISO in SA node cells.

Adrenergic beta-Agonists↗
PubMed2000

[The expression of arrhythmic related genes on Xenopus oocytes for evaluation of class III antiarrhythmic drugs from ocean active material].

By techniques of gene clone, microinjection and patch-clamp, human arrhythmic related gene Kv1.5 and Kv4.2 are translated mRNA, and injected into Xenopus Oocytes, respectively. A pure and single K+ current of ultrarapid delayed rectifier K+ current (Ikur) or transient outward K+ current (Ito) is respectively expressed on Xenopus Oocytes. This is a modern pharmacological model for evaluation class III antiarrhythmic drugs, overcomes many defects such as lacking human fresh cardiac muscle cells as material and co-expression of many currents on cell membrane. A new compound A1998 from Ocean material is evaluated in this model for class III antiarrhythmic functions.

Animals↗
PubMed2001

Increment of calcium-activated and delayed rectifier potassium current by hyposmotic swelling in gastric antral circular myocytes of guinea pig.

AIM: To observe the effect of hyposmotic swelling on calcium-activated potassium current [IKCa] and delayed rectifier potassium current [IKV] in gastric antral circular myocytes of guinea pig. METHODS: The whole cell patch-clamp technique was used, and the myocytes were isolated by collagenase. Cells were swelled by the hyposmotic solution (200 Osmmol/kg). RESULTS: The hyposmotic solution markedly increased IKCa and IKV. The increase of IKCa was markedly inhibited by tetrathylammonium (TEA) 4 mmol/L and charybdotoxin (ChTX) 200 nmol/L. The increase of IKV was incompletely blocked by TEA and completely blocked by 4-aminopyridine (4-AP) 10 mmol/L. There was no significant difference between the amplitudes of the increase of IKCa and IKV (P < 0.05). IKCa increased (17.0 +/- 4.8) s after the cells were perfused with the hyposmotic solution, whereas IKV increased (30.7 +/- 13.7) s after the cells exposed to the hyposmotic solution. There was significant difference between the latency of IKCa and IKV (P < 0.05). CONCLUSION: Hyposmotic swelling increased both IKCa and IKV, and the increment was likely related to the cell volume regulation.

4-Aminopyridine↗
PubMed2002

Effects of benzyltetrahydropalmatine on the rapidly activating component of delayed rectifier potassium current in guinea pig ventricular myocytes.

AIM: To investigate the effect of benzyltetrahydropalmatine (BTHP) on the rapidly activating component of delayed rectifier K+ current (Ikr) in single guinea pig ventricular myocytes. METHODS: Whole-cell patch clamp technique was used to record Ikr. RESULTS: Ikr was blocked by 1-100 mumol.L-1 BTHP in concentration-, voltage-, and specifically frequency-dependent fashion, with IC50 of 13.5 mumol.L-1 (95% confidence range: 11.2-15.8 mumol.L-1). 30 mumol.L-1 BTHP reduced Ikr and Ikr.tail by (31 +/- 4)% and (36 +/- 5)% (n = 6, P < 0.01), respectively. The time constant for deactivation (tau') of the tail current was decreased by 30 mumol.L-1 BTHP from (238 +/- 16) ms to (196 +/- 14) ms, while drug had no any effect on the time constant for activation (tau) of Ikr,tail. CONCLUSION: BTHP inhibited Ikr in a frequency-dependent fashion.

Animals↗
PubMed2002

[Effects of donepezil on the delayed rectifier-like potassium current in pyramidal neurons of rat hippocampus and neocortex].

AIM: To investigat the effects of donepezil on delayed rectifier-like potassium currents (IK) in rat hippocampus and neocortex. METHODS: Whole cell configuration of the patch-clamp techniques were used to characterize IK in acutely isolated rat hippocampal and neocortical pyramidal neurons. RESULTS: The slowly inactivating outward currents (IK) were recorded in all cells under investigation. Donepezil in micromolar concentrations were shown to supress the IK of all cells in a dose-dependent and voltage-dependent manner. The steady-state activation curves of IK were characterized by half-activation potentials of -15.5 mV in hippocampal and -4.1 mV in neocortical pyramidal neurons and were changed to -26.2 mV and -18.6 mV, respectively, after perfusion with donepezil (10 mumol.L-1). CONCLUSION: At concentrations as low as 1 mumol.L-1, donepezil was found to block the IK in a voltage-dependent manner in hippocampus and neocortex. This effect may be synergistic with the anticholinesterase activity of donepezil to increase its therapeutic effectiveness.

Animals↗