Currents In Human Atrial Myocytes Research Articles

P1233Differential effects of five risk variants for atrial fibrillation at the 4q25 region on L-type calcium current and transient inward currents in human atrial myocytes

Abstract Background An increasing number of single nucleotide polymorphisms (SNPs) at the chromosomal region 4q25 have been associated with risk of atrial fibrillation (AF) and we have recently reported that carriers of the rs13143308 risk variant have an increased incidence of spontaneous calcium release-induce transient inward currents (ITI). However, it is not known if different 4q25 variants have similar effects. Purpose This study aimed to compare the effects of five SNPs at 4q25 on L-type calcium current (ICa) and ITI frequency, features that are altered in patients with AF. Methods To avoid confounding effects of AF on calcium homeostasis, atrial samples from 63 patients without AF were genotyped and divided into groups according to the genotype of the SNPs rs1448818, rs6817105, rs13143308, rs6843082, rs3853443 ordered according to their location and identified by the three last digits + an R for risk or N for normal variants. ICa density and ITI frequency were measured with perforated patch clamp technique in atrial myocytes from these patients. Results Three SNPs 818, 308 and 443 segregated independently of the genotype at the other loci. The 105 and 082 loci always co-segregated with 308 but never together. The ICa density was smaller in carriers of 818R and 443N variants (−1.6±0.3pA/pF, p=0.01) or 818N and 443R variants (−1.6±0.4pA/pF, p=0.02) than in patients with 818N and 443N variants (−3.2±0.4pA/pF), independently of the genotype at 105, 308 and 082 (these loci did not affect ICa). In contrast, to this, the ITI frequency was increased only in myocytes from patients carrying 105R, 308R and 082N (1.4±0.2events/min, p<0.001) or 105N, 308R and 082R (1.6±0.5events/min, p=0.002) when compared to patients with 105N, 308N and 082N (0.36±0.09events/min) independently of the genotypes at 818 and 443, or when compared to patients without risk at any of the five loci (0.55±0.30events/min). The table shows schematically the qualitative effects of the different risk variants. Risk variant rs1448818C rs6817105C rs13143308T rs6843082T rs3853445C ICa Decreased Unchanged Unchanged Unchanged Decreased ITI Unchanged Increased Increased Increased Unchanged Conclusion Different SNPs at the chromosomal region 4q25 are associated with differential pathological changes in intracellular calcium homeostasis. Risk variants at rs1448818 or rs3853445 cause loss of ICa without affecting ITI frequency while a risk variant at rs13143308 elevates the ITI frequency without affecting ICa. These findings afford a framework for stratification of pharmacological therapy based on the functional effects of the 4q25 risk variants Acknowledgement/Funding SAF2017-88019; Marato2015-20-30; SGR2017-1769; CIBERCV

Inhibitory effects of hesperetin on Nav1.5 channels stably expressed in HEK 293 cells and on the voltage-gated cardiac sodium current in human atrial myocytes

Voltage-gated sodium channels composed of a pore-forming α subunit and auxiliary β subunits are responsible for the upstroke of the action potential in cardiac myocytes. The pore-forming subunit of the cardiac sodium channel Nav1.5, which is encoded by SCN5A, is the main ion channel that conducts the voltage-gated cardiac sodium current (INa) in cardiac cells. The current study sought to investigate the inhibitory effects of hesperetin on human cardiac Nav1.5 channels stably expressed in human embryonic kidney 293 (HEK 293) cells and on the voltage-gated cardiac sodium current (INa) in human atrial myocytes. The effects of hesperetin on human cardiac Nav1.5 channels expressed in HEK 293 cells and on cardiac Na+ currents in human atrial myocytes were examined through whole-cell patch-clamp techniques. Nav1.5 currents were potently and reversibly suppressed in a concentration- and voltage-dependent manner by hesperetin, which exhibited an IC50 of 62.99 μmol/L. Hesperetin significantly and negatively shifted the voltage-dependent activation and inactivation curves. Hesperetin also markedly decelerated Nav1.5 current inactivation and slowed the recovery from Nav1.5 channel inactivation. The hesperetin-dependent blockage of Nav1.5 currents was frequency-dependent. Hesperetin also potently and reversibly inhibited Na+ current (INa) in human atrial myocytes, consistently with its effects on Nav1.5 currents in HEK 293 cells. Hesperetin is a potent inhibitor of INa in human atrial myocytes and Nav1.5 channels expressed in human embryonic kidney 293 cells. Hesperetin probably functions by blocking the open state and the inactivated state of these channels.

Inhibitory effects of hesperetin on Kv1.5 potassium channels stably expressed in HEK 293 cells and ultra-rapid delayed rectifier K+ current in human atrial myocytes

In the present study, the inhibitory effects of hesperetin (HSP) on human cardiac Kv1.5 channels expressed in HEK 293 cells and the ultra-rapid delayed rectifier K+ current (Ikur) in human atrial myocytes were examined by using the whole-cell configuration of the patch-clamp techniques. We found that hesperetin rapidly and reversibly suppressed human Kv1.5 current in a concentration dependent manner with a half-maximal inhibition (IC50) of 23.15 μΜ with a Hill coefficient of 0.89. The current was maximally diminished about 71.36% at a concentration of 300μM hesperetin. Hesperetin significantly positive shifted the steady-state activation curve of Kv1.5, while negative shifted the steady-state inactivation curve. Hesperetin also accelerated the inactivation and markedly slowed the recovery from the inactivation of Kv1.5 currents. Block of Kv1.5 currents by hesperetin was in a frequency dependent manner. However, inclusion of 30μM hesperetin in pipette solution produced no effect on Kv1.5 channel current, while the current were remarkable and reversibly inhibited by extracellular application of 30μM hesperetin. We also found that hesperetin potently and reversibly inhibited the ultra-repaid delayed K+ current (Ikur) in human atrial myocytes, which is in consistent with the effects of hesperetin on Kv1.5 currents in HEK 293 cells. In conclusion, hesperetin is a potent inhibitor of Ikur (which is encoded by Kv1.5), with blockade probably due to blocking of both open state and inactivated state channels from outside of the cell.

Interaction of DPP10a with Kv4.3 channel complex results in a sustained current component of human transient outward current Ito.

The sustained component of the K(+) outward current in human atrial myocytes is believed to be due to the slowly inactivating ultra-rapid potassium current I Kur and not to the fast inactivating transient outward current Ito. Here we provide evidence for contribution of Ito to this late current due to the effects of dipeptidyl peptidase-like protein (DPP) 10 (DPP10a) interacting with Kv4.3 channels. We studied the late current component of Ito in human atrial myocytes and CHO cells co-expressing Kv4.3 or Kv4.3/KChIP2 (control) and DPP proteins using voltage-clamp technique and a pharmacological approach. A voltage dependent and slowly inactivating late current (43% of peak amplitude) could be observed in atrial myocytes. We found a similar current in CHO cells expressing Kv4.3/KChIP2 + DPP10a, but not in cells co-expressing Kv4.3 + DPP or Kv4.3/KChIP2 + DPP6-S. Assuming that DPP10a influences atrial Ito, we detected DPP10 expression of three alternatively spliced mRNAs, DPP10 protein and colocalization of Kv4.3 and DPP10 proteins in human atrial myocytes. DPP10a did not affect properties of expressed Kv1.5 excluding a contribution to the sustained IKur in atrial cells. To test for the contribution of Kv4-based Ito on sustained K(+) outward currents in human atrial myocytes, we used 4-AP to block IKur, in combination with Heteropoda toxin 2 to block Kv4 channels. We could clearly separate an Ito fraction of about 19% contributing to the late current in atrial myocytes. Thus, the interaction of DPP10a, expressed in human atrium, with Kv4.3 channels generates a sustained current component of Ito, which may affect late repolarization phase of atrial action potentials.

Effects of α1-adrenoceptor agonist phenylephrine on swelling-activated chloride currents in human atrial myocytes.

Swelling-activated chloride currents (ICl.swell) play an important role in cardiac electrophysiology and arrhythmogenesis. However, the regulation of these currents has not been clarified to date. In this research, we focused on the function of phenylephrine, an α1-adrenoceptor agonist, in the regulation of I(Cl.swell) in human atrial myocytes. We recorded I(Cl.swell) evoked by a hypotonic bath solution with the whole-cell patch-clamp technique. We found that I(Cl.swell) increased over time, and it was difficult to achieve absolute steady state. Phenylephrine potentiated I(Cl.swell) from -1.00 ± 0.51 pA/pF at -90 mV and 2.58 ± 1.17 pA/pF at +40 mV to -1.46 ± 0.70 and 3.84 ± 1.67 pA/pF, respectively (P < 0.05, n = 6), and the upward trend in ICl.swell was slowed after washout. This effect was concentration-dependent, and the α1-adrenoceptor antagonist prazosin shifted the dose-effect curve rightward. Addition of prazosin or the protein kinase C (PKC) inhibitor bisindolylmaleimide (BIM) attenuated the effect of phenylephrine. The PKC activator phorbol 12,13-dibutyrate (PDBu) activated I(Cl.swell) from -1.69 ± 1.67 pA/pF at -90 mV and 5.58 ± 6.36 pA/pF at +40 mV to -2.41 ± 1.95 pA/pF and 7.05 ± 6.99 pA/pF, respectively (P < 0.01 at -90 mV and P < 0.05 at +40 mV; n = 6). In conclusion, the α1-adrenoceptor agonist phenylephrine augmented I(Cl.swell), a result that differs from previous reports in other animal species. The effect was attenuated by BIM and mimicked by PDBu, which indicates that phenylephrine might modulate I(Cl,swell) in a PKC-dependent manner.

Src family protein tyrosine kinases modulate L-type calcium current in human atrial myocytes

In the heart, L-type voltage dependent calcium channels (L-VDCC) provide Ca 2+ for the activation of contractile apparatus. The best described pathway for L-type Ca 2+ current (I Ca,L) modulation is the phosphorylation of calcium channels by cAMP-dependent protein kinase A (PKA), the activity of which is predominantly regulated in opposite manner by β-adrenergic (β-ARs) and muscarinic receptors. The role of other kinases is controversial and often depends on tissues and species used in the studies. In different studies the inhibitors of tyrosine kinases have been shown either to stimulate or inhibit, or even have a biphasic effect on I Ca,L. Moreover, there is no clear picture about the route of activation and the site of action of cardiac Src family nonreceptor tyrosine kinases (Src-nPTKs). In the present study we used PP1, a selective inhibitor of Src-nPTKs, alone and together with different activators of I Ca,L, and demonstrated that in human atrial myocytes (HAMs): (i) Src-nPTKs are activated concomitantly with activation of cAMP-signaling cascade; (ii) Src-nPTKs attenuate PKA-dependent stimulation of I Ca,L by inhibiting PKA activity; (iii) Gα s are not involved in the direct activation of Src-nPTKs. In this way, Src-nPTKs may provide a protecting mechanism against myocardial overload under conditions of increased sympathetic activity.

Allitridi inhibits transient outward potassium currents in human atrial myocytes

1. It has been reported that allitridi, an active compound extracted from garlic, has many cardiovascular effects. However, it remains unknown whether allitridi affects major repolarization currents, such as the transient outward K(+) current (I(to) ), ultrarapid delayed rectifier K(+) current (I(Kur)) and the L-type Ca(2+) current (I(Ca)), in human atrial myocytes. 2. In the present study, we investigated the effects of allitridi on I(to), I(Kur), I(Ca) and the action potential in human isolated atrial myocytes using the whole-cell patch recording technique. 3. Allitridi reversibly inhibited I(to), but not I(Kur) and I(Ca), in human atrial myocytes. These effects of allitridi on I(to) were concentration dependent (IC(50) = 44.9 μmol/L). Inactivation of I(to) was accelerated and the voltage-dependent inactivation potential was shifted towards the negative direction. Allitridi (30 μmol/L) significantly prolonged action potential duration in human atrial myocytes. 4. The results of the present study indicate that allitridi inhibits I(to), but not I(Kur) and I(Ca), and prolongs the action potential duration in human atrial myocytes.

Homocysteine modulates sodium channel currents in human atrial myocytes

Hyperhomocysteinemia has been proposed as an important risk factor for cardiac arrhythmias and ischemia worldwide. However, the cellular mechanism underlying toxic effects of homocysteine on hearts remains conjectural. It is well known that aberrant sodium channels can promote the development of cardiac arrhythmias and ischemic injury. So the present study was to investigate toxic effects of homocysteine on sodium currents recorded in human atrial cells. Human atrial myocytes were acutely enzymatically isolated and the whole-cell patch clamp technique was employed to record sodium currents and membrane potential in human atrial cells in the absence and presence of homocysteine. We found that in human atrial myocytes, sodium currents were significantly increased by pathological concentration of homocysteine with the maximum activation potential shifted toward the positive potential. However, physiological concentration of homocysteine did not have any effects on sodium currents. The time constants for time-dependent activation ( τ act) and inactivation ( τ inact) of sodium currents were both markedly shortened by elevated homocysteine levels. The further channel kinetic data showed that elevated homocysteine levels shifted the inactivation curve towards positive potential and accelerated the recovery from inactivation of sodium channel, but did not affect the activation of sodium channel. Additionally, the resting membrane potential of human atrial myocytes was obviously depolarized by elevated homocysteine levels in the current clamp model. Taken together, the data presented in this study first revealed that increased homocysteine levels caused the abnormality of sodium currents in human atrial cells by slowing the inactivation and promote the recovery of sodium channels, which provides a better understanding of hyperhomocysteinemia associated cardiac arrhythmias and ischemia.

Omega-3 polyunsaturated fatty acids inhibit transient outward and ultra-rapid delayed rectifier K+currents and Na+current in human atrial myocytes

The omega-3 (n-3) polyunsaturated fatty acids (omega-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil were recently reported to have an anti-atrial fibrillation effect in humans; however, the ionic mechanisms of this effect are not fully understood. The present study was designed to determine the effects of EPA and DHA on transient outward and ultra-rapid delayed rectifier potassium currents (I(to) and I(Kur)) and the voltage-gated sodium current (I(Na)) in human atrial myocytes. A whole-cell patch voltage clamp technique was employed to record I(to) and I(Kur), and I(Na) in human atrial myocytes. It was found that EPA and DHA inhibited I(to) in a concentration-dependent manner (IC(50): 6.2 microM for EPA; 4.1 microM for DHA) and positively shifted voltage-dependent activation of the current. In addition, I(Kur) was suppressed by 1-50 microM EPA (IC(50): 17.5 microM) and DHA (IC(50): 4.3 microM). Moreover, EPA and DHA reduced I(Na) in human atrial myocytes in a concentration-dependent manner (IC(50): 10.8 microM for EPA; 41.2 microM for DHA) and negatively shifted the potential of I(Na) availability. The I(Na) block by EPA or DHA was use-independent. The present study demonstrates for the first time that EPA and DHA inhibit human atrial I(to), I(Kur), and I(Na) in a concentration-dependent manner; these effects may contribute, at least in part, to the anti-atrial fibrillation of omega-3 PUFAs in humans.

Effects of three metabolites of propiverine on voltage-dependent L-type calcium currents in human atrial myocytes

The non-selective muscarinic receptor antagonist propiverine impairs L-type Ca 2+ currents ( I Ca,L) in human detrusor smooth muscle cells and atrial cardiomyocytes. Here, we have investigated the effects of three metabolites of propiverine on human cardiac I Ca,L. Propiverine reduced I Ca ,L with a − logIC 50 [M] value of 4.1, M-5 only showed minor effect on I Ca ,L at high concentrations, M-6 did not influence I Ca ,L at all. Like the parent compound M-14 also reduced I Ca ,L (− logIC 50 [M] = 4.6). We conclude, that propiverine and M-14 reduce cardiac I Ca ,L at higher concentrations than in detrusor cells and therefore preferentially reduce I Ca ,L in the urinary bladder than in the heart.

Effects of sodium ferulate on the ultrarapid delayed rectifier K + current in human atrial myocytes

Objective To study the effects of sodium ferulate on the ultrarapid delayed rectifier K + current(I Kur) in human atrial myocytes. Methods Human atrial myocytes were isolated by enzyme dispersion method. I Kur in human atrial myocytes were recorded by using the whole cell patch clamp. The changes of I Kur were compared in the absence and the presence of sodium ferulate. Results There was no effect of 0.4 g/L sodium ferulate on I-V relation of I Kur. However, 0.4 g/L sodium ferulate inhibited I Kur to some degrees at each test pulse. The current densities of I Kur at +60 mV decreased from 4.997 ± 0.35 PA/PF to 3.331 ± 0.26 PA/PF( n =6, P < 0.05). The inhibitory effect was concentration-dependent. IC 50 was(0.41 ± 0.03)g/L and the Hill coefficient was 0.95 ± 0.05. Conclusion Sodium ferulate as a potassium channel blocker can inhibit I Kur in human atrial myocytes effectively.

HOMOCYSTEINE INHIBITS POTASSIUM CHANNELS IN HUMAN ATRIAL MYOCYTES

1. A large body of evidence indicates that elevated homocysteine (Hcy) levels portend an increased risk for atrial fibrillation. However, little is known about the electrophysiological effects of Hcy on atrial myocytes. The present study was conducted to investigate the direct effects of Hcy on ion channels in human atria. 2. Whole-cell patch-clamp techniques were used to record potassium currents in human atrial cells. 3. In human atrial myocytes, transient outward potassium currents were significantly decreased by 24.8 +/- 5.9 and 38.4 +/- 10.4% in the presence of 50 and 500 micromol/L Hcy, respectively. The ultrarapid delayed rectifier potassium currents were decreased by approximately 30% when exposed to 500 micromol/L Hcy. The inward rectifier potassium currents were increased by approximately 40% in the presence of 500 micromol/L Hcy. 4. The results of the present study indicate that Hcy, an important risk factor for atrial fibrillation, could cause electrophysiological disturbances of potassium currents in human atrial myocytes.

Raloxifene inhibits transient outward and ultra-rapid delayed rectifier potassium currents in human atrial myocytes

The selective estrogen receptor modulator raloxifene is widely used in the treatment of postmenopausal osteoporosis, and has cardioprotective properties. However, effects of raloxifene on cardiac ion channels are unclear. The present study was designed to investigate the effects of raloxifene and β-estradiol on transient outward and ultra-rapid delayed rectifier potassium currents ( I to1 and I Kur) in human atrial myocytes with a whole cell patch-clamp technique. I to1 was inhibited by raloxifene in a concentration-dependent manner with an IC 50 of 0.9 μM. Raloxifene at 1 μM decreased I to1 by 40.2 ± 1.9% (at + 50 mV, n = 14, P < 0.01 vs control). Time-dependent recovery from inactivation was slowed, and time to peak and time-dependent inactivation of I to1 were significantly accelerated, while steady-state voltage dependent activation and inactivation of I to1 were not affected by raloxifene. In addition, raloxifene remarkably suppressed I Kur (IC 50 = 0.7 μM). Raloxifene at 1 μM decreased I Kur by 57.3 ± 3.3% (at + 50 mV, n = 10, P < 0.01 vs control). However, β-estradiol inhibited I to1 (IC 50 = 10.3 μM) without affecting I Kur. The inhibitory effects of raloxifene and β-estradiol on I to1 and/or I Kur were unaffected by the estrogen receptor antagonist ICI 182,780. Our results indicate that raloxifene directly inhibits the human atrial repolarization potassium currents I to1 and I Kur. Whether raloxifene is beneficial for supraventricular arrhythmias remains to be studied.

Effects of carvedilol on transient outward and ultra-rapid delayed rectifier potassium currents in human atrial myocytes

Carvedilol is a β- and α 1-adrenoceptor antagonist. It is widely used in the treatment of cardiovascular diseases including atrial arrhythmias. However, it is unclear whether carvedilol may affect the repolarization currents, transient outward K + current ( I to) and ultra-rapid delayed rectifier K + current ( I Kur) in the human atrium. The present study evaluated effects of carvedilol on I to and I Kur in isolated human atrial myocytes by whole-cell patch-clamp recording technique. We found that carvedilol reversibly inhibited I to and I Kur in a concentration-dependent manner. Carvedilol (0.3 μM) suppressed I to from 9.2 ± 0.5 pA/pF to 4.8 ± 0.5 pA/pF ( P < 0.01) and I Kur from 3.6 ± 0.5 pA/pF to 1.9 ± 0.3 pA/pF ( P < 0.01) at + 50 mV. I to was inhibited in a voltage-dependent manner, being significantly attenuated at test potentials from + 10 to + 50 mV, whereas the inhibition of I Kur was independent. The concentration giving a 50% inhibition was 0.50 μM for I to and 0.39 μM for I Kur. Voltage-dependence of activation, inactivation and time-dependent recovery from inactivation of I to were not altered by carvedilol. However, time to peak and time-dependent inactivation of I to were significantly accelerated, indicating an open channel blocking action. The findings indicate that carvedilol significantly inhibits the major repolarization K + currents I to and I Kur in human atrial myocytes.

AVE 0118, an Antiarrhythmic Drug with a Novel Action Mechanism: Block of Ikur and Ito Potassium Currents in Human Atrial Myocytes

AVE 0118, an Antiarrhythmic Drug with a Novel Action Mechanism: Block of Ikur and Ito Potassium Currents in Human Atrial Myocytes

Angiotensin II-induced changes of calcium sparks and ionic currents in human atrial myocytes: Potential role for early remodeling in atrial fibrillation

Aims Atrial angiotensin II (ANG II) levels have been shown to be increased in atrial fibrillation (AF). The purpose of the study was to evaluate a potential role of ANG II in the early remodeling and susceptibility to chronicization of AF. Methods and results Isolated human atrial myocytes were incubated in ANG II and/or angiotensin type 1 receptor blocker candesartan. ANG II markedly increased the frequency of spontaneous Ca 2+ sparks, spark full duration, time to peak Ca 2+ fluorescence and decay time measured by confocal imaging. Sarcoplasmic reticulum calcium content estimated by caffeine-evoked calcium release did not differ between ANG II-treated cells and controls. Patch-clamp recordings revealed that ANG II significantly decreased I to and increased I Ca,L current densities. Candesartan blocked these ANG II-mediated alterations. ANG II exhibited no effect on I K1, I Kur and I f current size. Expression of connexin 40 and connexin 43 was not significantly changed by ANG II as assessed by immunohistochemistry and Western blot analysis. Conclusion ANG II-induced alterations of calcium handling and electrophysiological changes in human atrial cells similar to those previously observed in the onset of AF. Prevention of these alterations by candesartan might constitute a useful pharmacological strategy for the treatment of AF.

Carvedilol blocks β2- more than β1-adrenoceptors in human heart

Objective: To understand the basis of the effectiveness of carvedilol in heart failure by determining its specific properties at human heart β1- and β2-adrenoceptors. Methods: The positive inotropic effects of noradrenaline (in the presence of the β2-selective antagonist ICI118551) and adrenaline (in the presence of the β1-selective antagonist CGP20712), mediated through β1- and β2-adrenoceptors, respectively, were investigated in atrial and ventricular trabeculae. The patch-clamp technique was used to investigate effects of noradrenaline and adrenaline on L-type Ca2+ current in human atrial myocytes. Results: Carvedilol was a 13-fold more potent competitive antagonist of the effects of adrenaline at β2-adrenoceptors (−logKB=10.13 ± 0.08) than of noradrenaline at β1-adrenoceptors (−logKB=9.02 ± 0.07) in human right atrium. Chronic carvedilol treatment of patients with non-terminal heart failure reduced the inotropic sensitivity of atrial trabeculae to noradrenaline and adrenaline 5.6-fold and 91.2-fold, respectively, compared to β1-blocker-treated patients, consistent with persistent preferential blockade of β2-adrenoceptors. In terminal heart failure carvedilol treatment reduced 1.8-fold and 25.1-fold the sensitivity of right ventricular trabeculae to noradrenaline and adrenaline, respectively, but metoprolol treatment did not reduce the sensitivity to the catecholamines. Increases of current (ICa,L) produced by noradrenaline and adrenaline were not different in atrial myocytes obtained from non-terminal heart failure patients treated with metoprolol or carvedilol, consistent with dissociation of both β-blockers from the receptors. Conclusions: Carvedilol blocks human cardiac β2-adrenoceptors more than β1-adrenoceptors, thereby conceivably contributing to the beneficial effects in heart failure. The persistent blockade of β-adrenoceptors is attributed to accumulation of carvedilol in cardiac tissue.

566 Clinical parameters associated with the down regulation of the calcium current in human atrial myocytes

566 Clinical parameters associated with the down regulation of the calcium current in human atrial myocytes

The modulation of angiotensin II receptor type 2 on ionic currents in human atrial myocytes

The modulation of angiotensin II receptor type 2 on ionic currents in human atrial myocytes

Effects of diltiazem and nifedipine on transient outward and ultra‐rapid delayed rectifier potassium currents in human atrial myocytes

1. It is unknown whether the widely used L-type Ca(2+) channel antagonists diltiazem and nifedipine would block the repolarization K(+) currents, transient outward current (I(to1)) and ultra-rapid delayed rectifier K(+) current (I(Kur)), in human atrium. The present study was to determine the effects of diltiazem and nifedipine on I(to1) and I(Kur) in human atrial myocytes with whole-cell patch-clamp technique. 2. It was found that diltiazem substantially inhibited I(to1) in a concentration-dependent manner, with an IC(50) of 29.2+/-2.4 microM, and nifedipine showed a similar effect (IC(50)=26.8+/-2.1 muM). The two drugs had no effect on voltage-dependent kinetics of the current; however, they accelerated I(to1) inactivation significantly, suggesting an open channel block. 3. In addition, diltiazem and nifedipine suppressed I(Kur) in a concentration-dependent manner (at +50 mV, IC(50)=11.2+/-0.9 and 8.2+/-0.8 microM, respectively). These results indicate that the Ca(2+) channel blockers diltiazem and nifedipine substantially inhibit I(to1) and I(Kur) in human atrial myocytes.