Effects of catestatin on ventricular arrhythmia in isolated rat hearts with chronic heart failure

AIM:To determine the effects of catestatin (CST) on ventricular arrhythmia (VA) in isolated rat hearts with chronic heart failure (CHF). METHODS:Fifty-one male rats were randomly divided into 2 groups: control (CTL) group (n=17) and CHF group (n=34), which were injected with 0.9% normal saline (1 mL·kg-1·d-1, ip) and isoproterenol (ISO, 5 mg·kg-1·d-1, ip) for 7 d,respectively. The echocardiography was used to assess the cardiac functions 2 weeks after the end of modeling in both groups. The CHF rats were divided into non-treatment group (n=17) and CST treatment group (CST group, n=17). The rats in CST group was given CST (2 nmol·kg-1·d-1, ip) for 3 weeks, while 0.9% normal saline (1 mL·kg-1·d-1, ip) was applied to the rats in non-treatment group. To all the whole Langendorff-perfused hearts, the monophasic action potential (MAP) and the ventricular effective refractory period (VERP) were recorded and measured in left anterior free wall (LAF). The programmed electrical stimulation and burst pacing were used to induce action potential duration (APD) alternans (ALT) and VA in the LAF, respectively. The car-diac myocytes of LAF were enzymatically isolated and the technique of whole-cell patch clamp was used to record L-type Ca2+ current (ICa-L). RESULTS:Compared with CTL group, the peak ICa-L density, 90% of MAP duration (MAPD90), VERP, median of maximum pacing cycle length (PCLmax) inducing APD-ALT and incidence of VA (83.33% vs 1667%) were significantly increased in non-treatment group (all P<0.01). Compared with non-treatment group, the peak ICa-L density, MAPD90, VERP, median of PCLmax inducing APD-ALT and incidence of VA were significantly decreased in CST group (all P<0.05). CONCLUSION: Treatment with CST reduces the incidence of VA in CHF rats, which might be associated with the inhibition of ICa-L.     

Effects of catestatin on calcium handling abnormalities and ventricular arrhythmia after myocardial infarction in rats

AIM: To determine the effects of catestatin (CST) on calcium handling abnormalities and ventri-cular arrhythmia (VA) after myocardial infarction (MI) in rats. METHODS: The adult male SD rats (n=85) were randomly divided into sham group (n=20) and operation group (n=65). MI was induced by ligation of the left anterior descending coronary artery in operation group. The rats in sham group underwent pericardiotomy but without ligating the artery. The rats survived for 1 week after operation were randomly assigned to MI group and CST group. The rats in CST group was treated with CST (30 mg·kg^-1·d^-1, intraperitoneal administration) for 4 weeks, while saline was applied to the rats in sham group and MI group. The calcium imaging study was performed by loading isolated ventricular cardiomyocytes with Fura-2 AM. In the whole Langendorff-perfused hearts, the programmed electrical stimulation was used to induce action potential duration (APD) alternans and VA. The protein levels of ryanodine receptor 2 (RyR2), phosphorylated RyR2 (p-RyR2), calcium/calmodulin-dependent protein kinase II (CaMKII) and phosphorylated CaMKII (p-CAMKII) were determined by Western blot. RESULTS: Compared with sham group, the protein levels of p-RyR2 and p-CaMKII, the diastolic intracellular Ca²⁺ concentrations and the inducibility of VA were significantly increased, whereas the thresholds of Ca²⁺ transient (CaT) and APD alternans and the CaT amplitude were markedly decreased in MI group (P<0.01). Compared with MI group, the protein levels of p-RyR2 and p-CaMKII, the diastolic intracellular Ca²⁺ concentration and the inducibility of VA were significantly decreased, while the thresholds of CaT and APD alternans and the CaT amplitude were markedly increased in CST group (P<0.01). No significant difference of the protein expression of RyR2 and CaMKII among the 3 groups was observed (P>0.05). CONCLUSION: CST reduces the susceptibility to VA after MI via preventing calcium handling abnormalities.     

Characteristics of ventricular electrophysiology in a right ventricular rapid pacing-induced canine heart failure model

AIM: To research the characteristics of ventricular electrophysiology in right ventricular rapid pacing-induced congestive heart failure (CHF) dogs.METHODS: Dogs (n=16) were randomly divided into 2 groups: the control (n=7) and the CHF group (n=9) induced by rapid right ventricular pacing at 240 pulse·min-1 for 4 to 5 weeks.The electrophysiologic parameters were evaluated by the technique of standard electric stimulation and monophasic action potential (MAP) recording.RESULTS: (1) Ventricular effective refractory period (VERP),ventricular MAP duration (MAPD90),ventricular late repolarization duration (VLRD) and intra-ventricular conduction time (IVCT) were prolonged by 26% (P<0.01),43% (P<0.01),318% (P<0.05),and 19% (P<0.01),respectively in CHF group.(2)The ratio of VERP to MAPD₉₀ (VERP/MAPD₉₀) was decreased by 13% (P<0.05) in CHF group.(3) The dispersion of ventricular recovery time (VRT-D) was increased by 185% (P<0.01) in CHF group.(4) The ventricular fibrillation threshold (VFT) was decreased by 48% (P<0.01) in CHF group.CONCLUSION: The abnormal electrophysiological changes in the CHF condition may be contributing factors of lethal ventricular arrhythmias and sudden cardiac deaths in CHF.     

Effects of Shensongyangxin capsule on ventricular electrical properties,structural remodeling and cardiac function in diabetic rats

AIM：To determine the effects of Shensongyangxin capsule (SSYX) on the ventricular electrical properties, structural remodeling and cardiac function in the rats with diabetes mellitus (DM). METHODS：Male SD rats (n=45) were randomly divided into control group (n=15), DM group (n=15) and SSYX group (n=15). The rats in DM group and SSYX group were injected with streptozotocin (60 mg/kg, ip), while the rats in control group were given normal saline (1 mL/kg, ip). The blood samples were collected 72 h after treatment for determining the blood glucose levels in DM group and SSYX group. The model rats in SSYX group were administered with SSYX (1 g·kg-1·d-1, ig) for 6 weeks, while the other rats received normal saline (2 mL·kg-1·d-1, ig). The echocardiography was used to assess the cardiac function, and the lead II electrocardiogram was also recorded in all the animals. The radioimmunoassay and Masson trichrome staining were used to measure the plasma levels of endothelin-1 (ET-1) and the collagen deposition in the ventricles, respectively. A whole Langendorff-perfused heart model was used to conduct the electrophysiologic study. The monophasic action potential (MAP) and the ventricular effective refractory period (VERP) were recorded in the left anterior free wall (LAF), and the burst pacing was used to induce ventricular arrhythmia (VA). RESULTS：Compared with control group, the VERP, action potential duration (APD), QT interval, incidence of VA, degree of myocardial fibrosis and plasma level of ET-1 were increased, while the cardiac function was declined in DM group. Compared with DM group, the VERP, APD, QT interval, incidence of VA, degree of myocardial fibrosis and plasma level of ET-1 were all decreased, while the cardiac function was improved in SSYX group. CONCLUSION：SSYX attenuates the electrical and structural remodeling and improves the cardiac function in DM rats.     

Effects of remifentanil on monophasic action potential and transmural dispersion of repolarization in rabbit myocardium

AIM: To study the effect of remifentanil on monophasic action potential and transmural dispersion of repolarization (TDR) in the 3-layer myocardium of isolated rabbit hearts. METHODS: Adult rabbits (n=18, 2.0 ~ 2.5 kg) were used to isolate the hearts for preparing Langendorff perfusion model. The hearts were randomly divided into 3 groups after perfusion with K-H solution for 15 min: the perfusion in control group (C group) continued for 60 min; the hearts in remifentanil group (R group) were perfused with 12 μg/L remifentanil K-H solution for 60 min; the hearts in remifentanil+aminophylline group (RA group) were given 60-min perfusion of 12 μg/L K-H remifentanil+30 mg/L aminophylline. The HR and 3 layers of myocardial monophasic action potential (MAP) in the left ventricular anterior wall were recorded at time points after balanced infusion for 15 min (T₀), and continued perfusion for 15 min (T₁), 30 min (T₂) and 60 min (T₃). The monophasic action potential duration of repolarization at 90% (MAPD₉₀) and the transmural dispersion of repolarization (TDR) were calculated. The early afterdepolarization, delay afterdepolarization and arrhythmia were also observed. RESULTS: In R group, slower HR and prolonger MAPD₉₀ and TDR at T₁~T₃ were observed as compared with those at T₀ (P<0.05). R group showed slower HR and longer MAPD₉₀ and TDR than C group and RA group (P<0.05). CONCLUSION: Remifentanil slows the HR, extends the MAPD₉₀ and increases the TDR, thus being prone to induce reentry. Aminophylline makes HR faster and MAPD₉₀ shorter, thereby reducing the TDR.     

Effects of mechanical stretch on electrophysiological characteristics of calcium preconditioning myocardium

AIM: To investigate the effects of mechanical stretch under simulated anoxia and reoxygenation conditions on action potential (AP) and effective refractory period (ERP) of calcium preconditioning (CPC) in isolated papillary muscles of guinea pig hearts. METHODS: The intracellular standard glass microelectrode technique was used, and effects of stretch (intensity: 200 mg) on AP and ERP were recorded and observed in CPC papillary muscles. RESULTS: After stretching was implied during anoxia, the reductions of Vmax, RP, APA, APD50, ERP and APD90 in CPC group were less than those in anoxia-reoxygenation (AR) group, and the CT in CPC group was less elongated. Moreover, after the papillary muscles were stretched during reoxygenated reperfusion, the decreases in Vmax, RP, APA, APD50 and ERP in CPC group were less than those in AR group, and the CT and APD90 in CPC group were less extended. Streptomycin inhibited the effect of stretch on AP and ERP in CPC group. CONCLUSIONS: Under simulated anoxia and reoxygenation conditions, papillary muscles in CPC group may have better tolerance to the same stretch than those in the AR. Furthermore, streptomycin (a blockade of stretch-activated ionic channels) may inhibit the effect of mechanical stretch on action potential changes in CPC papillary muscles.     

Effect of captopril on prolongation of action potential duration and reduction Ik in ischemia pig ventricular myocytes

AIM: To evaluate the effect of captopril on action potential duration and outward delayed rectification potassium current (Ik). METHODS: Action potentials were recorded using a conventional glass microelectrode filled with 3 mol/L KCl solution. Membrane patch clamp whole cell recording technique was used to investigate the Ik current maximum in the holding potential -50 mV, lasting time 100 ms, command potential +40 mV. RESULTS: The action potential duration of 30%, 50% repolarization (APD30, APD50) and ERP were significantly prolonged, but APD90 wasn't prolonged significantly when captopril group compared with ischemic group. The amplitude of Ik increased significantly in ischemic group, but significantly decreased in captopril group and in captopril+ischemic group. The shapes of current-voltage relationship were unchanged among groups, but significantly upward in ischemic group and downward in captopril and captopril+ischemic group. CONCLUSION: Captopril exerts electrophysiologic action due to decreasing delay outward rectification potassium current and prolonging action potential duration of APD30, APD50 and ERP.     

Changes of potassium currents in rabbit ventricle with healed myocardial infarction

AIM: To elucidate the mechanism of arrhythmia in healed myocardial infarction (HMI), and to investigate the changes of action potential duration (APD),transient outward potassium current (I_to), delayed rectifier potassium current (I_K) and inward rectifier potassium current (I_K1) of left ventricular myocytes in noninfarcted zone of HMI. METHODS: 12 rabbits were randomly assigned in two groups: HMI group (thoracotomy and ligation of the circumflex coronary); sham-operated group (thoracotomy but no conorary ligation). 3 months after operation, whole cell patch clamp technique was used to record APD, I_to, I_K and I_K1 of ventricular myocytes in non-infarcted zone. RESULTS: Membrane capacitance was larger in HMI group than that in sham-operated group. Action potential duration was lengthened significantly in HMI group and early after depolarization (EAD) appeared in HMI group. The densities of I_to, I_K,tail and I_K1 were reduced significantly in HMI group (P<0.01), from (6.72±0.42) pA/pF, (1.54±0.13) pA/pF and (25.6±2.6) pA/pF in Sham-operated group to (4.03±0.33) pA/pF, (1.14±0.11) pA/pF and (17.6±2.3) pA/pF, respectively. CONCLUSION: The reduced densities of I_to, I_K,tail and I_K1 in ventricular myocytes of non-infarcted zone in HMI are responsible for the prolongation of APD and the presentation of EAD, which play important roles in the malignant arrhythmia of HMI.     

Effect of panax notoginseng saponins on electrophysiological characteristic of atrial cardiomyocytes in guinea pig

AIM: To study the effect of panax notoginseng saponins on the left atrial appendage (LAA) of the guinea pigs. METHODS: Standard microelectrode intracellular recording technique was used to record the LAA action potential (AP) and the effective refractory period (ERP) in the guinea pigs during the pouring with different density of PNS. RESULTS: The effect of PNS in concentration of 0.7, 7, 70, 700 mg/L was significant at 20 min, the APD50 and APD80 of the pouring at 20 min, 30 min, 40 min of the 70 mg/L was longer than the reference group (P<0.05). The rest potential (RP), action potential amplitude (APA) and Vmax kept no change during the pouring at 20 min with 4 difference densities from 0.7 to 700 mg/L. The pouring at 20 min of 7 mg/L and 70 mg/L obviously prolonged the ERP of the atrial cardiomyocytes. compared to the reference group, it prolonged from (127.00±7.26) ms to (153.00±9.19) ms and (161.00±10.21) ms (P<0.01). However, pouring at 10 min with 7 000 mg/L caused the arrhythmias. CONCLUSION: PNS prolongs the APD and ERP in guinea pig atrial cardiomyocytes. It may be the mechanism of PNS against arrhythmias in cellular level, which is similar to amiodarone.     

Effects of Tongxinluo on connexin 43 remodeling and ventricular arrhythmia after myocardial infarction in rats

AIM: To determine the effects of Tongxinluo(TXL) on connexin 43(Cx43) remodeling and ventricular arrhythmia(VA) after myocardial infarction(MI) in rats. METHODS: Male SD rats were randomly divided into sham-operated(sham) group(n=25) and operation group(n=75). The left anterior descending(LAD) was ligated in operated group, while the rats in sham group only underwent pericardiotomy. The rats in operation group which survived for 3 d after operation were randomly assigned to TXL group and MI group. The rats in TXL group was administrated with TXL(2 g·kg^-1·d^-1, intragastric administration) for 4 weeks, while normal saline was applied to the rats in sham group and MI group. The levels of interleukin-1β(IL-1β) and endothelin-1(ET-1) in the tissue from the border zone were measured by ELISA after treatment. The distribution and the mRNA and protein expression of Cx43 were detected by immunohistochemical staining, RT-PCR and Western blotting, respectively. The burst pacing was used to induce ventricular arrhythmia(VA). RESULTS: Compared with sham group, the levels of IL-1β and ET-1 and the incidence of VA were significantly increased, while the mRNA and protein expression of Cx43 was markedly reduced with irregular distribution in MI group(P<0.05). Compared with MI group, the levels of IL-1β and ET-1 and the incidence of VA were significantly reduced, while the expression of Cx43 at mRNA and protein levels was markedly increased with augmented linear distribution in the myocardial cell intercalated disc in TXL group(P<0.05). CONCLUSION: TXL reduces the incidence of VA after MI via inhibiting the Cx43 remodeling.     

Effect of hypercholesterolemia on the ionic currents in cardiac ventricular myocytes of rats

AIM: To determine whether chronic hypercholesterolemia affects ionic currents on cardiac ventricular myocytes of rats. METHODS: Whole-cell patch-clamp technique was used to record the ionic currents in single cardiac myocytes isolated from normal cholesterolemia and hypercholesterolemia rats. RESULTS: In the hypercholesterol group (group Ⅱ), serum total-cholesterol level was significantly higher than that of normal group (group Ⅰ) ［(3.10±0.62)mmol·L-1 vs (1.18±0.37)mmol·L-1, P<0.01, n=20］. The serum triglyceride content of group II was remarkably higher than that of group Ⅰ ［(1.51±0.30)mmol·L-1 vs (0.43±0.15)mmol·L-1, P<0.01, n=20］. In ventricular myocytes of rats, 50% repolarization of action potential duration (APD50) prolonged from (70.86±8.12)ms (group Ⅰ) to (116.16±6.90)ms (group Ⅱ) (n=10 in each group, P<0.01); APD90 prolonged from (95.10±7.27)ms (group Ⅰ) to (144.04±7.39)ms (group Ⅱ) (n=10 in each group, P<0.01); at the test potential of -120 mV, Ik1 increased from (-16.98±4.54) pA/pF(group Ⅰ) to (-19.92±4.08) pA/pF (group Ⅱ) (n=12 in each group, P<0.05); at the test potential of 0 mV, ICa-L decreased from (-8.56±1.29) pA/pF (group Ⅰ) to (-5.24±0.90) pA/pF (group Ⅱ) (n=10 in each group, P<0.01); at the test potential of +60 mV, Ito decreased from (13.20±1.97) pA/pF (group Ⅰ) to (10.30±1.97) pA/pF (group Ⅱ) (n=8 in each group, P<0.05). CONCLUSION: Hypercholesterolemia affects the ionic currents on cardiomyocytes of rats greatly, which may be the ionic mechanism of cardiac toxicity induced by hypercholesterolemia.     

Electrophysiological effects of amiodarone on pacemaker cells in guinea-pig left ventricular outflow tract under conditions of hypoxia,acidosis and treatment with epinephrine

AIM: To study the electrophysiological effects of amiodarone on the pacemaker cells in guinea-pig left ventricular outflow tract under the conditions of hypoxia, acidosis and treatment with epinephrine.METHODS: The action potentials of the pacemaker cells in guinea-pig left ventricular outflow tract were recorded by conventional intracellular microelectrode technique. The effects of amiodarone on the spontaneous slow response potentials were investigated under the conditions of hypoxia, acidosis and treatment with epinephrine.RESULTS: (1) Amiodarone at concentration of 0.1 μmol/L markedly decreased the rate of pacemaker firing (RPF) and maximal diastolic potential (MDP), lengthened 80% of the duration of action potential (APD80). Amiodarone at concentration of 1 μmol/L significantly decreased the velocity of diastolic depolarization (VDD) and RPF, the maximal rate of depolarization (Vmax), MDP and amplitude of action potential (APA), lengthened 50% of the duration of action potential (APD50) and APD80. Amiodarone at concentration of 10 μmol/L led to a significant decrease in VDD and RPF, Vmax, MDP and APA, a notable lengthening in APD50 and APD80 was also observed. (2) Under the condition of hypoxia and perfusion with deprived glucose content for 15 min, VDD, RPF, MDP, Vmax and APA decreased significantly, APD50 was shortened notably. Under the condition of hypoxia, amiodarone at concentration of 1 μmol/L significantly decreased VDD, RPF and Vmax, increased MDP, lengthened APD50 and APD80 as compared to the cells treated with hypoxia only. (3) Perfusion with pH 6.8 solution for 10 min, VDD and RPF significantly decreased, Vmax and APA notably reduced, APD80 was markedly shortened. Under the condition of acidosis for 10 min, amiodarone significantly decreased VDD, RPF, MDP and APA, lengthened APD50 and APD80 as compared to the cells under the condition of acidosis only. (4) Perfusion of epinephrine at concentration of 10 μmol/L for 10 min resulted in a significant increase in VDD, RPF, Vmax, MDP and APA, a notable shorting in APD50 and APD80 was also observed. Compared to 10 μmol/L epinephrine group, 1 μmol/L amiodarone+10 μmol/L epinephrine significantly reduced VDD, RPF, Vmax, MDP and APA, lengthened APD50 and APD80.CONCLUSION: Amiodarone markedly decreases the autorhythmicity of the pacemaker cells in guinea-pig left ventricular outflow tract. This electrophysiological effects were significantly influenced by hypoxia, acidosis and epinephrine.     

Effects of arachidonic acid on action potential and L-type calcium current in rabbit cardiomyocytes

AIM:To study the influence of arachidonic acid (AA) on the action potential and L-type calcium current in rabbit cardiomyocytes. METHODS:Single ventricular myocyte was isolated using enzyme dispersion method. Whole-cell clamp-patch technique was used to record action potential and L-type calcium current. RESULTS: ① AA shortened action potential duration obviously, without marked effect on the resting potential and action potential amplitude. ② AA reduced the current densities from (10.21±3.15)PA/PF to (6.53±2.17)PA/PF (n=6, P<0.05), and up-shifted the I-V curves of ICa-L without changes of their active, peak and reverse potentials. CONCLUSION:AA inhibits L-type calcium current and shortens action potential duration, which may contribute to its cardiovascular effect.     

Dexamethasone pretreatment attenuates reperfusion arrhythmia in rats

AIM: To investigate the effect of dexamethasone (DEX) preconditioning on reperfusion arrhythmia. METHODS: 46 Sprague-Dawley rats were divided randomly into DEX and control (CON) group, the rats were pretreated with DEX or sodium chloride before their hearts were separated for Langendorff perfusion and for ischemia/reperfusion. The reperfusion arrhythmias were observed dynamically after 60 min reperfusion following 30 min ischemia. The expression of HSP72 in myocardium was examined by Western blotting and immunohistochemistry at reperfusion 60 min. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and the activities of Na+-K+-ATP ase, Ca2+-Mg2+-ATPase on myocardial plasma membrane were detected. RESULTS: Compared with control group, the accumulated points and persistence time of ventricular arrhythmia were reduced significantly in DEX group (P<0.05), the expression of HSP72 was significant upregulated (P<0.05), the level of MDA was reduced significantly, the activities of SOD, CAT, GSH-Px and Na+-K+-ATPase were significantly higher (P<0.05). CONCLUSION: Dexamethasone pretreatment markedly reduces the reperfusion ventricular arrhythmias in rats, which may be attributed to upregulation of HSP72, SOD, CAT, GSH-Px , Na+-K+-ATPase and inhibition of lipid peroxidation.     

Recent advance in cardiac ion channel remodeling in diabetes

Occurrence of lethal cardiac arrhythmia, which is associated with prolongation of the QT interval in electrocardiogram(ECG), is related to increased mortality in the patients with diabetes mellitus (DM). Increased QT interval reflects the prolonged cardiac action potential duration (APD). APD abnormality is based on by cardiac ion channel remodeling induced by DM-related pathological changes. As DM is becoming an important risk factor for atrial fibrillation, the most clinically common arrhythmia, this review mainly summarizes the alterations of ion channel currents and relevant protein expression in diabetic ventricular myocytes to explore the underlying mechanisms of arrhythmia, and also discusses some research achievements from investigating the atrial myocytes in DM.     

Relationship between QT dispersion and autonomic nerve of heart

QT dispersion (QTd, equals maximal minus minimal QT interval on a standard ECG) has been shown to reflect inhomogeneity of myocardial repolarization and cardial electrical instability, hence, been proposed to be associated with ventricular arrhythmias.But the intrinsical mechanism of QTd is incompletely understood. Contributing to QTd are differences of action potential duration (APD) in the three-dimensional structure of ventricular myocardium, which is identified to own three cell subtypes: endocardial, midmyocardial (M cells) and epicardial cells. And findings suggest that regional differences in the duration of the M cell action potential may lead transmural and spatial dispersion of repolarization. Autonomic nerves by combining receptors on the myocardial cells, especially M cells affect significantly the APD. Concordance between heterogeneity of ventricular myocardium and heterogeneity of autonomic innervation in heart provide support for the role of autonomic nerve in the generat ion of the QT dispersion.     

Signal pathways involved in reverse remodeling of the hypertrophic heart in rat after pressure unloading

AIM: Heterotopic transplantation of rat hypertrophic hearts has been shown to reverse chamber enlargement and regress cardiac myocyte hypertrophy. The purpose of this study was to gain a better understanding of molecular changes associated with the beneficial reverse remodeling after pressure unloading of hypertrophic heart. METHODS: Stable cardiac hypertrophy was induced by abdominal aortic constriction (AAC) in Lewis rats (6 weeks). Left ventricular (LV) pressure unloading was induced by heterotopic transplantation of hypertrophic hearts (AAC-HT) and/or normal hearts (NL-HT) (2 weeks). We measured heart weight (HW) and LV weight (LVW) of all groups. Cross-sectional area of cardiomyocyte was assessed by hematoxylin/eosin staining. We further analyzed the regulation of prohypertrophic signaling pathways of mitogen-activated protein kinases (MAPKs), Akt/GSK3β and NF-κB in both transplanted groups by Western blotting. RESULTS: The HW and LVW in AAC hearts were higher (P<0.05) than those in normal controls, but the transplanted hearts in AAC-HT group showed a significant reduction in HW and LVW compared to the AAC hearts. Pressure unloading induced a decrease in cardiomyocyte size in AAC-HT and NL-HT hearts. A significant decrease in phosphorylation of p44/p42 MAP kinases (ERK), Akt, GSK3β and NF-κB was detected in AAC-HT hearts, but the phosphorylation of p38 MAP kinase and Jun-N-terminal kinase (JNK) were not changed compared to AAC hearts. The phosphorylation of MAPKs, Akt/GSK3β and NF-κB showed no difference between NL-HT hearts and normal controls. CONCLUSION: Pressure unloading of the hypertrophic heart caused a reverse remodeling through regulating the ERK, Akt/GSK3β, and NF-κB signal pathways which act as potential target pathways for reversal of LV hypertrophy.     

Mechanism of gender difference in sotalol-induced torsade de pointes

AIM: To investigate the mechanism of gender difference in sotalol-induced torsade de pointes (TdP) in rabbits in vitro. METHODS: 40 rabbits of both sexes were divided into two groups: low concentration (1×10-5 mol/L d-sotalol) group and high concentration (1×10-4 mol/L d-sotalol) group. With the monophasic action potential (MAP) recording technique, MAP of epicardium, midmyocardium and endocardium were simultaneously recorded by specially designed plunge-needle electrodes across the left ventricular free wall of rabbit hearts purfused by Langendorff method. TdP was induced by bradycardia, d-sotalol and low-K+, Mg2+ tyrode solution. RESULTS: d-sotalol prolonged the duration of 90% repolarization (MAPD90) of epicardium, midmyocardium and endocardium in a concentration-dependent manner and the effect on midmyocardium was the most obvious. In low concentration group, MAPD90 of midmyocardium of male rabbit heart increased from (222±11) ms to (230±10) ms and that of female rabbit heart increased from (263±12) ms to (281±12) ms. In high concentration group, MAPD90 of midmyocardium of male rabbit heart increased from (217±10) ms to (296±18) ms and that of female rabbit heart increased from (258±10) ms to (368±19) ms. There was no difference in TDR between male and female rabbit hearts before perfusion with d-sotalol. D-sotalol prolonged TDR in a concentration-dependent manner. In low concentration group, TDR of male and female rabbit hearts was (20.0±5.1) ms and (28.0±5.6) ms. In high concentration group, TDR of male and female rabbit hearts was (38.0±4.8) ms and (55.0±7.7) ms, respectively. There was EAD in 6 female hearts while no EAD developed in male heart and no TdP developed in low concentration group. In high concentration group, 10 female, 9 male hearts developed EAD, 9 female and 3 male hearts developed TdP. CONCLUSION: The greater TDR induced by d-sotalol in female may be responsible for the higher incidence of TdP of female rabbit heart.     

Zacopride enhances inward rectifier potassium current (IK1) to antagonize arrhythmias

AIM: To investigate the effects of zacopride on aconitine or BaCl2-induced arrhythmias and involved ionic mechanisms. METHODS: The whole-cell patch-clamp technique was used to record the inward rectifier K+ current (IK1), Ca+ current (ICa-L), Na+ current (INa), transient outward K+ current (Ito), the resting membrane potential (RMP) and action potential (AP) in the single cell of rat ventricular myocardium. Two arrhythmic models were elicited by injection of 30 μg/kg aconitine or 4 mg/kg BaCl2 intravenously. Zacopride at dose of 15 μg/kg was administered immediately after the development of first sinus rhythm disorders to observe its effects on arrhythmias. The ECGs were recorded simultaneously. RESULTS: In voltage clamp mode, 0.1-10.0 μmol/L zacopride dose-dependently enhanced IK1 with no significant effects on ICa-L, INa and Ito (P>0.05). Zacopride at concentration of 1.0 μmol/L showed the most potent activity on IK1 with approximately 30% increment both in inward current and outward current (P<0.01). Correspondingly, 0.1-10.0 μmol/L zacopride hyperpolarized RMP and shortened the action potential duration (APD) in a concentration-dependent manner (P<0.01). Furthermore, 1.0 μmol/L zacopride abolished aconitine-induced delayed afterdepolarization (DAD) and triggered activity (TA). In vivo, zacopride (15 μg/kg) significantly shortened the duration of arrhythmias elicited by aconitine ［from (57.58±3.21) min to (38.25±2.59) min］ or BaCl2 ［from (49.31±2.46) min to (30.94±1.73) min］. CONCLUSION: As an agonist of IK1, zacopride enhanced IK1, hyperpolarized RMP and shortened APD, which may be the fundamental mechanisms underlying its antiarrhythmic effect. Enhancing IK1 might be a new antiarrhythmic strategy.     

Effect of platelet activating factor on the action potential and potassium currents in guinea-pig ventricular myocytes

AIM: To investigate the effects of platelet activating factor (PAF) on the action potential and potassium currents in guinea-pig ventricular myocytes. METHODS: By using whole-cell patch clamp technique, the effects of PAF on APD₉₀, I_K1 and I_K were investigated in enzymatically dispersed single guinea-pig ventricular myocytes. RESULTS: With 5 mmol/L ATP in the pipette electrode, 1 μmol/L PAF increased APD₉₀ from (225.8±23.3) ms to (352.8±29.8) ms (n=5, P<0.05), decreased I_K1 and I_K tail currents from (-6.1±1.3) nA to (-5.6±1.1) nA (n=5, P<0.05) at -120 mV and from (173.5±16.7) pA to (152.1±11.5) pA (P<0.05, n=4) at +30 mV, respectively. In contract, without ATP in the pipette electrode, 1 μmol/L PAF shortened APD₉₀ from (153.0±24.6) ms to (88.2±19.4) ms (n=5, P<0.01). Incubation of myocytes with 1 μmol/L glibenclamide, a blocker of I_KATP restored prolongation of APD induced by PAF. CONCLUSION: In guinea-pig ventricular myocytes, with 5 mmol/L ATP in the pipette, PAF prolonged APD partly due to the inhibition of I_K and I_K1, while with 0 mmol/L ATP in the pipette, PAF induced an activation of I_KATP, hence a decrease in APD was observed. Therefore, PAF might amplify the heterogeneity between ischemia and normal cardiac myocytes during ischemic reperfusion, which might play a vital role in the pathogenesis of the arrhythmias induced by ischemia/reperfusion.