Effect of microparticles derived from bone marrow mesenchymal stem cells on cardiomyocyte hypertrophy and its mechanism / 中国生物制品学杂志

@#Objective To investigate the effect of microparticles(MPs)derived from bone marrow mesenchymal stem cells(BMSCs) on myocardial hypertrophy and its mechanism.Methods The osteogenic differentiation and adipogenic differentiation of mesenchymal stem cells(MSCs) were induced. After isolation and purification,the morphological characteristics were observed by transmission electron microscope,and the MPs surface antigen was identified by flow cytometry. Myocardial hypertrophy model was induced by using isoprenaline(ISO)in rats,which were measured for the cardiac structure and function by echocardiography,and then detected for various indexes of the heart and isolated left ventricle. Single ventricular myocytes of rats were acutely isolated and divided into control group(Control group),cardiomyocyte hypertrophy group(ISO group),MPs group(MPs group),and MPs supernatant group(Supernatant group). The mRNA expressions of atrial natriuretic peptide(ANP)and B-type natriuretic peptide(BNP)were detected by qRTPCR. The expression levels of calmodulin-dependent protein kinaseⅡ（CaMKⅡ）and phosphorylated calmodulin-dependent protein kinaseⅡ（p-CaMKⅡ）were detected by ELISA. The L-type calcium current(LCa-L)in single ventricular myocyte of various groups was recorded by whole-cell patch clamp.Results The bone nodules of MSCs osteogenic differentiation turned red after alizarin red staining,and lipid droplets of adipogenic differentiation turned red after oil red O staining;Under transmission electron microscope,MPs membrane had a complete structure,a clear outline and a diameter of about200 nm;The positive rates of CD29 and CD90 on the surface of MPs were(98. 24 ± 0. 82)% and(97. 69 ± 1. 83)%,respectively. Compared with Control group,the left ventricular end diastolic dimension(LVEDD)reduced signifi-cantly(t =5. 065,P < 0. 05),while the interventricular septum end-diastolic dimension(IVSd),left ventricular posterior wall dimension(LVPWd),heart weight to body weight ratio(HW/BW),and heart weight to tibial length ratio(HW/Tibia)significantly increased in ISO group(t = 4. 013,2. 368,4. 392,5. 043 and 6. 120,respectively,each P < 0. 05),indicating that the hypertrophic model was successfully established. The expression levels of ANP and BNP mRNA in hypertrophic cardiomyocytes of rats in ISO group were significantly higher than those in Control group(t = 25. 120 and18. 261,respectively,each P < 0. 01);While the expression levels of ANP and BNP mRNA in MPs group significantly reduced after incubation with 48 μg/mL MPs for 48 h compared with ISO group(t = 12. 110 and 3. 526,respectively,each P < 0. 05);The expression levels of CaMK Ⅱand p-CaMKⅡ in ISO group were significantly higher than those in Control group(t = 3. 278 and 4. 181,respectively,each P < 0. 05),while the expression of p-CaMK Ⅱ in MPs group decreased significantly(t = 5. 420,P < 0. 05);The calcium current density in ISO group was significantly higher than that in Control group(t = 15. 261,P < 0. 01),while that in MPs group was significantly lower than that in ISO group(t =6. 216,P < 0. 05).Conclusion MSC-MPs can significantly inhibit ISO-induced cardiomyocyte hypertrophy in rats,which is related to its down-regulation of cardiomyocyte CaMKⅡ and inhibition of L-type calcium channel.

Change in hippocampal voltage-gated Ⅰ sodium channel of Lithium chloride-Pilocarpine epileptic rat model / 中华实用儿科临床杂志

Objective To research the changes in hippocampal voltage-gated sodium channel of Lithium chloride-Pilocarpine epileptic rat models,including Ⅰ sodium channel α subunit protein (Nav1.1),mRNA of Ⅰ sodium channel alpha subunit protein gene and function of sodium channel.Methods Epileptic rat models of Lithium chloride-Pilocarpine were established.Nav1.1 expression in the hippocampus of experimental rats was detected by immunohistochemical staining method,and the changes in voltage-gated sodium channel function (the current-voltage curves,activation and inactivation curves and the recovery curve) of hippocampus nerve cells were detected by whole cell patch-clamp technique.Results (1) The Lithium chloride-Pilocarpine rat models were successfully reproduced.Three stages of behavior (acute,latent and chronic) of rat models were observed.The blank control group was free of seizure.(2) Immunohistochemistry results:neurons in CA1 and DG regions of hippocampal of epileptic rats were normal,and there was no obvious change in the expression of Nav1.1.In CA3 area,the degeneration and necrosis of neurons were obvious.Staining of Nav1.1 became superficial and even disappeared in these areas,but the normal tissues were enhanced around degenerative and necrotic neurons.Compared with the blank control group,the expression of Nav1.1 in the model group was higher(0.235 ±0.008 vs.O.210 ±0.002),and there was statistically significant difference (t'=-7.426,P ＜ 0.05).(3) The whole-cell patch-clamp technique showed that the sodium current density of the model group increased significantly compared with that of the blank group [(-319.70 ± 28.24) pA/pF vs.(-229.06 ± 26.01) pA/pF,t =8.178,P ＜ 0.05],the threshold value of activation curve decreased (4.15 ± 0.80 vs.4.50 ±0.85,t =11.020,P ＜ 0.05),the threshold value of inactivation curve increased (7.47 ± 0.53 vs.6.24 ±0.31,t =6.940,P ＜ 0.05),and the recovery time after inactivation shortened [(1.36 ± 0.15) ms vs.(1.86 ± 0.21)ms,t =6.712,P ＜ 0.05],and there were all statistically significant differences.Conclusion Repeated seizures can lead to increase Nav1.1 compensatory expression of,and significantly increase sodium channel current density,while the threshold value of activation curve decreases,the threshold value of inactivation curve rises,and the recovery time after inactivation is shortened,which eventually leads to increased neuron excitability and is more likely to cause seizures.

Investigation of effects of monoclonal antibody NCX-3F10against Na+/Ca2+ exchanger on rat cardiac ionic currentsand its suppression on ischemia-reperfusion induced cardiac arrhythmias / 中国药理学通报

Aim To observe the effect of antibody NCX-3F10 on the main ion current of rat ventricular myocytes and its effect on arrhythmias induced by ischemia/reperfusion(I/R).Methods ① The whole-cell patch clamp technique was employed to record the Na+/Ca2+ exchange current(INa/Ca) and other major ion currents in rat ventricular myocytes.② The rat models of arrhythmia induced by ischemia/reperfusion were established by ligating the left coronary artery to in vivo and in vitro.Then the effects of antibody on the arrhythmia were observed.③ The IonOptix ion imaging system was used to observe the effect of antibody on calcium transients in single ventricular myocytes.Results ① The antibody NCX-3F10 dose-dependently inhibited INa/Ca from 5 to 40 mg·L-1.The IC50 for outward and inward currents was 11.15 and 11.69 mg·L-1, and the maximum inhibitory rates were 61% and 62%, respectively.The antibody also had an inhibitory effect on calcium current(ICa-L), and had no significant effect on inward rectifier potassium current(IK1), transient outward potassium current(Ito) and sodium current(INa).② In the isolated rat heart group I/R, 100% rats showed ventricular tachycardia, and 88.89% rats had ventricular fibrillation.After administration of antibody NCX-3F10(10 mg·L-1) 5 min before reperfusion, the incidence of ventricular tachycardia decreased to 44.43%(P<0.05), and the duration of ventricular tachycardia and ventricular fibrillation was also shortened remarkably(P<0.05).③ In the anesthetized rats after administration of antibody NCX-3F10(50 μg·kg-1) 5 min before reperfusion, the incidence and duration of ventricular tachycardia,the incidence and duration of ventricular fibrillation, and total number of ventricular premature beats were significantly decreased(P<0.05).④ From 5 to 40 mg·L-1, NCX-3F10 antibody decreased calcium transient amplitude in rat single ventricular myocytes dose-dependently(P<0.05).Conclusions The NCX-3F10 antibody shows significant arrhythmic effects on ischemia-reperfusion induced arrhythmia in rats both in vitro and in vivo, the underlying mechanism of which is related to NCX and L-type calcium current inhibition and calcium overload reduction by the NCX antibody.

Influence of new baicalin-metal complexes on Kv1.4 and Cav3.2 ion channels / 中国药理学与毒理学杂志

OBJECTIVE To investigate the effect of new baicalin(BC) metal ions(Co2+,Cu2+, and Ni2+)complexes(BMCs)on ion channels Kv1.4 and Cav3.2. METHODS HEK293 or CHO cells loaded with various ion channels(hERG,Kv1.2,Kv1.3,Kv1.4,Kv1.5,Kv1.6,Kv1.7,Kv1.8,Kir1.1, Kir2.1,KCNQ and Cav3.2)were obtained by stable transfection method. Whole-cell patch-clamp tech?nique was used to record current changes of each ion channel induced by BC and BMC in 10μmoL · L-1. The effect of different concentrations(0.3,1,3,10 and 30μmoL · L-1)of BC-Co and BC-Cu on Kv1.4 and Cav3.2 current was detected by whole-cell patch-clamp technique. RESULTS A model of HEK293 cells or CHO cells that stably expressed various ion channels was obtained. BMCs (BC-Co,BC-Cu and BC-Ni)had some impact on various ion channels,especially on Kv1.4 and Cav3.2. The inhibitory rate induced by BC-Co,BC-Cu and BC-Ni(10 μmol · L-1)was 91%,76% and-10%,respectively,for Kv1.4;and 43%,57%and-14%,respectively,for Cav3.2. IC50 of BC-Co was 1.69 and 0.81μmoL·L-1 for Kv1.4 and Cav3.2. IC50 of BC-Cu was 1.66 and 0.58μmoL · L-1 for Kv1.4 and Cav3.2. CONCLUSION BC-Cu and BC-Co concentration-dependently inhibit Kv1.4 and Cav3.2 ion channels.

Protein kinase C enhances the swelling-induced chloride current in human atrial myocytes / 华中科技大学学报（医学）（英德文版）

Swelling-activated chloride currents (ICl.swell) are thought to play a role in several physiologic and pathophysiologic processes and thus represent a target for therapeutic approaches. However, the mechanism of ICl.swell regulation remains unclear. In this study, we used the whole-cell patch-clamp technique to examine the role of protein kinase C (PKC) in the regulation of ICl.swell in human atrial myocytes. Atrial myocytes were isolated from the right atrial appendages of patients undergoing coronary artery bypass and enzymatically dissociated. ICl.swell was evoked in hypotonic solution and recorded using the whole-cell patch-clamp technique. The PKC agonist phorbol dibutyrate (PDBu) enhanced ICl.swell in a concentration-dependent manner, which was reversed in isotonic solution and by a chloride current inhibitor, 9-anthracenecarboxylicacid. Furthermore, the PKC inhibitor bis-indolylmaleimide attenuated the effect and 4α-PDBu, an inactive PDBu analog, had no effect on ICl.swell. These results, obtained using the whole-cell patch-clamp technique, demonstrate the ability of PKC to activate ICl,swell in human atrial myocytes. This observation was consistent with a previous study using a single-channel patch-clamp technique, but differed from some findings in other species.

Cardiac arrhythmia suppression by I K1 channel agonist in isoproterenol-induced myocardial hypertrophic rats and investigation on its mechanism / 中国药理学通报

Aim To investigate the effect of zacopride ( Zac) on cardiac arrhythmia in isoproterenol ( ISO)-in-duced myocardial hypertrophic rats and the underlying electrophysiological mechanisms .Methods ① Fifty-one rats were randomly divided into control group ( n=17 ) , ISO group ( n=17 ) and ISO +Zac group ( n =17 ) .Rat model with cardiac arrhythmia and hypertro-phy was established by intraperitoneal ISO ( 5 mg?kg -1 ) injection.②ECGs were recorded to observe the effects of Zac on arrhythmia in model rats .③ Whole-cell patch clamp was applied to record inwardly rectifi-er potassium current(IK1), resting membrane potential ( RMP ) and amplicated delayed afterdepolarizations (DADs).Results ① Echocardiographic examination showed that , left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic dimension (LVESD) significantly decreased in rats in ISO group compared with control group , whereas left ventricular posterior wall end-diastolic thickness ( LVPWd) and in-terventricular septum end-diastolic thickness ( IVSd ) increased ( P<0.05 ) , suggesting rat model of isoprot-erenol-induced myocardial hypertrophy was successfully established .② ECGs showed that 88.89% of rats in ISO group had ventricular premature beats ( VPBs ) , which significantly decreased to 11.11% after the ap-plication of Zac ( P <0.05 ) .③ Values of RMP de-creased from ( -71.05 ±1.27 ) mV in control group to (-69.38 ±1.21 ) mV in ISO group ( P<0.05 ) . After Zac administration , RMP significantly increased to ( -73.86 ±1.33 ) mV compared with control and ISO group(P<0.05).④DADs and TA incidence sig-nificantly decreased from 88.24% in ISO group to 11.76%in ISO+Zac group ( P<0.05 ) .⑤ Compared with control group , IK1 density was markedly reduced in ISO group, whereas Zac could effectively rescue IK1 suppression to normal level .Conclusions Zac, as a selective IK1 channel agonist , can significantly inhibit cardiac arrhythmia in isoproterenol-induced myocardial hypertrophic rats , which is mainly attributed to in-creased RMP by enhancing IK1 and subsequent suppres-sion of DADs.

Effects of salicylate on voltage-gated calcium channels in rat hippocampal neurons / 中国药理学通报

Aim To provide an electrophysiological basis for hippocampus involved emotional changes caused by tinnitus, the effects of salicylate on electro-physiological characteristics of the voltage-gated calci-um channels in hippocampal neurons were performed. Method The effects of salicylate on voltage-gated cal-cium channels in rat hippocampal neurons were stud-ied, using the whole-cell voltage clamp method. Re-sults Salicylate blocked the voltage-gated calcium channels ( ICa ) in a concentration-dependent manner (0.1~10 mmol · L-1 ) . The half-inhibition concen-tration ( IC50 ) values for the blocking action of salicy-late on ICa were 1.64 mmol·L-1 . With 1 mmol·L-1 salicylate applicalted into bath solution, the steady-state activation curve of calcium channel was shifted by about 9 mV in the hyperpolarizing direction, and its steady-state inactivation curve was not changed. Con-clusion Salicylate inhibits ICa in rat hippocampal neu-rons and significantly affects the activation kinetics of ICa ,which could be related to emotional changes caused by tinnitus.

Effects of taurine-magnesium coordination compound on abnormal calcium current induced by hypoxia-reoxygenation in rat ventricular cardiomyocytes / 中国药理学通报

Aim To investigate the effects of TMCC on abnormal L-type calcium current (ICa,L) in rat ventric-ular cardiomyocytes during hypoxia-reoxygenation to find out the mechanism of antiarrhythmic effect. Methods Whole-cell patch clamp was used to record ICa,L in the ventricular cardiomyocytes during hypoxia-reoxygenation in rat under amiodarone and different concentrations of TMCC. Results In hypoxia-reoxy-genation model, peak ICa,L increased from ( 3. 35 ± 0. 50 ) pA/pF to ( 5. 69 ± 0. 25 ) pA/pF ( n =6 , P 0. 05),(4. 41 ± 0. 22) pA/pF, (3. 82 ± 0. 21)pA/pF(n=6, P<0. 01) by TMCC(100, 200, 400 μmol·L-1 ) and amidodarone 24. 24 μmol·L-1 restored peak ICa,L to(3. 66 ± 0. 27)pA/pF (n=6,P<0. 01 ) . Compared to control group, hypoxia-reoxy-genation turned ICa,L steady-state activation curves to left and inactivation curves to right, which quickened activation and slowed inactivation, TMCC ( 200, 400μmol · L-1 ) and amiodarone could restore the left shift activation curves and right shift inactivation curves. Conclusion TMCC can concentration-de-pendently restore the increase of calcium current due to hypoxia-reoxygenation by promoting inactivation process and inhibiting activation process, and the effect is equal to that of amiodarone. TMCC blocks ICa,L of the ventricular cardiomyocytes, which may be one of its antiarrhythmic mechanisms.

Effects of skeletal muscle denervation on potency of rocuronium.

Background: Rocuronium is an alternative to succinylcholine for rapid tracheal intubation after major thermal injury and other forms of critical illness that cause denervation changes in skeletal muscle. Rocuronium may decrease the potencies of non-depolarizing muscle relaxants. Objectives: Examine whether potency of rocuronium changed during the first month after denervation, and investigate the effects of skeletal muscle denervation on potency of rocuronium. Methods: The denervation mouse model was developed to create denervated individual cells from the flexor digitorum brevis of the hindfoot. The skeletal muscle cells were examined at day 0 in the innervated control and days 1, 4, 7, 14, 21, and 28 in the denervation group. Nicotinic acetylcholine receptors in the cells were activated with 30 M acetylcholine, alone or in combination with various concentrations of rocuronium. Currents were recorded with a whole-cell patch-clamp technique. Results: Rocuronium reversibly inhibited acetylcholine-activated currents in a dose-dependent fashion at different times after denervation. The inhibition concentration for the half-maximal responses of rocuronium increased 1.2- (p >0.05), 1.8-, 2.8-, 2.3-, 2.1-, and 1.9-fold (p<0.01) at day 1, 4, 7, 14, 21, and 28 after denervation, respectively, compared to that at day 0 after denervation. Conclusion: Rocuronium dose required to achieve satisfactory clinical effects changed at different durations after skeletal muscle denervation.

Efffect of TMP on the responses mediated by P2X receptors in rat dorsal root ganglion neurons / 中国药理学通报

Aim To explore the modulaory effect of tetramethylpyrazine(TMP) on the responses mediated by P2X receptors.Methods Whole-cell patch-clamp technique was used to study the effects of TMP on P2X receptor agonists-activated currents in freshly isolated rat dorsal root ganglion(DRG) neurons.Results Extracellular application of ATP of 1 to 1000 ?mol?L~(-1) activated currents in DRG neurons(n=102).The ATP-activated currents showed rapid desensitization or slow desensitization.Preapplication of TMP(0.1～10 mmol?L~(-1))markedly inhibited ATP(100 ?mol?L~(1))-activated currents in the majority of the neurons examined(89.2%,91/102).TMP(1 mmol?L~(-1)) reduced ?,?-meATP(10 ?mol?L~(-1))-activated currents.TMP(1 mmol? L~(-1)) shifted the concentration-response curve of I_(ATP) downward markedly.TMP(1 mmol?L~(-1)) did not alter the reversal potential(0 mV) of ATP-activated currents.TMP(1 mmol?L~(-1)) significantly inhibited ATP(100 ?mol?L~(-1))-activated currents potentiated by PGE_2(100 ?mol?L~(-1))or SP(0.1 ?mol?L~(-1)).Intracellular application of 10 ?mol?L~(-1) H89(which is an inhibitor of PKA) reduced the inhibitory effect of TMP on ATP(100 ?mol?L~(-1))-activated currents.Conclusion The mechanism of TMP action may be the allosteric regulation via acting on PKA system and the large extracellular region of ATP receptor-ion channel complex(P2X receptors) to affect P2X receptor agonists-activated currents in rat DRG neurons.

Substance P inhibits GABA-activated currents in bullfrog primary sensory neurons by protein kinase C / 新乡医学院学报

Objective To research the mechanism or pathway through which Substance P(SP) inhibits r-aminobutyric acid(GABA) activated currents in bullfrog dorsal root ganglion(DRG) neurons.Method The experiment was conducted on freshly isolated bullfrog dorsal root ganglion neurons using a whole-cell patch-clamp technique.Results SP could caused a slow inward current when SP was applied to DRG neurons;SP could inhibits GABA-activated currents;The inhibition could be reduced largely when protein kinase C(PKC) inhibiter,1-(5-isoquinolinesulphorry)-2-methylpiperazine(H-7), was dialyzed in cell body.Conclusion The SP ton inhibit GABA-activated currents through protein kinase C.

Effects of Erythromycin on Voltage-dependent Potassium Current in Hippocampal Neurons of Mice / 中国药房

OBJECTIVE:To study the effect of erythromycin on the voltage-dependent K~+ current in hippocampal neurons of mice.METHODS:Isolation of mice's hippocammal neurons cells and whole-cell patch-clamp techniques were applied to study the change of voltage-dependent K~+ current of hippocampal neurons and the current-voltage curves in mice before and after treatment with erythromycin.RESULTS:Erythromycin inhibited the voltage-dependent K~+ current of mice's hippocampal neurons,and it down-regulated the peak current from(810.67?250.86)pA to(529.96?171.83)pA(P

Effects of taurine magnesium coordination compound on potassium current in guinea pig ventricular cardiomyocytes / 中国药理学通报

Aim To investigate the antiarrhythmic mechanism of taurine magnesium coordination compound(TMC)on the potassium current in single ventricular myocytes of guinea pig.Methods Whole-cell patch clamp was used to record IK,IK1 in single ventricular myocytes of guinea pig.Results In ventricular myocytes of guinea pig,IK was decreased from(8.67?1.04)pA/pF to(6.31?1.16)pA/pF at +70 mV.TMC had no effect on the IK1.Conclusions TMC had inhibitory effect on IK directly and this effect maybe resulted in prolonging the action potential duration(APD)and effective refractory period(ERP).It could be one of the basis of antiarrhythmic effect of TMC.

Inhibition of glycine-activated current by total flavones of epimedium in rat spinal dorsal horn neurons / 中国药理学通报

Aim To investigate total flavones of epimedium (TFE) modulation of glycine-activated current (IGly) in acutely dissociated rat spinal dorsal horn neurons. Method Whole-cell patch-clamp technique was used. Result TFE inhibited IGly reversibly in a concentration-dependent manner. It shifted the concentration-response relationship to the right without altering the maximum response and Hill coefficient of the IGly. TFE did not change the ion selectivity of glycine receptor either. Conclusion These results indicate that TFE directly inhibited the glycine receptor response by decreasing the affinity of glycine to its receptor.

Loureirin B inhibits capsaicin-induced currents in rat dorsal root ganglion neurons / 中国药理学通报

Aim To investigate effects of loureirin B on capsaicin-evoked currents in rat dorsal root ganglion (DRG) neurons. Methods In acutely isolated rat DRG neurons, effects of loureirin B on capsaicin-evoked currents were observed using whole-cell patch-clamp technique. Results ① The holding potential was maintained at -60 mV and VR1 antagonist capsazepine inhibited capsaicin-evoked currents completely; ② Loureirin B concentration-dependently inhibited capsaicin-evoked currents. Loureirin B at the concentrations of 2.0, 4.0, 8.0 and 16.0 ?mol?L-1 reduced capsaicin-evoked currents by 15.36%?2.12%、36.41%?2.43%、76.26%?2.16% and 96.69%?3.21% (n=10, P

Effect of N-n-butyl haloperidol iodide on potassium channel in smooth muscle cells and rings of rat aorta / 中国药理学通报

AIM To investigate the effect of N n butyl haloperidol iodide (F 2) on potassium currents in enzymatically isolated vascular smooth muscle cells (VSMC) from thoracic aortas and the effect of F 2 on aortic rings of rat. METHODS The whole cell patch clamp technique and the contraction of rats thoracic aortic rings were used in experiments. RESULTS The outward currents were observed when holding potential was -40 mV and the cell was depolarized from -30 mV to +100 mV (in 10 mV increase) for 400 ms. At the point of the test potential of +70 mV, solutions of F 2 (0 1,1, 5 ?mol?L -1 ) were added into bath (external) solution, which led to the increase of the outward currents from (229?28)pA,(226?57)pA and(228?42) pA to (354?29) pA ( n =6, P

Effects of taurine-magnesium coordination compound on sodium channel in rat cardiomyocytes of arrhythmia induced by aconitine / 中国药理学通报

Aim To investigate the antiarrhythmic mechanism of taurine-magnesium coordination compound on sodium current in single rat ventricular myocytes of arrhythmia induced by aconitine.Methods Whole-cell patch clamp was used to record INa in normal cardiomyocytes and single rat ventricular cardiomyocytes of arrhythmia induced by aconitine.Results In ventricular cardiomyocytes of rat,INa was blocked by 100~400 ?mol?L-1 TMCC in a concentration-dependent manner.INa was increasd from(45.56?1.96)pA/pF to(59.19?11.49)pA/pF by 1 ?mol?L-1 aconitine,while decreased to(34.23?1.33)pA/pF by 24.24 ?mol?L-1 amiodarone.TMCC(100,200,400 ?mol?L-1)could restore INa to(51.61?5.96)pA/pF,(40.91?6.73)pA/pF,(41.50?5.50)pA/pF respectively.Amiodarone could restore INa to(40.22?1.47)pA/pF.Conclusions TMCC can restore INa,which is increased by aconitine,and the effect is equal to that of amiodarone.TMCC blocks INa of ventricular cardiomyocytes,which may be one of its antiarrhythmic mechanisms.