Molecular Mechanisms of Increased Heart Rate in Shenxianshengmai-treated Bradycardia Rabbits / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The molecular mechanisms of Shenxianshengmai (SXSM), a traditional Chinese medicine, on bradycardia have been incompletely understood. The study tried to investigate the gene expression profile and proteomics of bradycardia rabbits' hearts after SXSM treatment.</p><p><b>METHODS</b>Twenty-four adult rabbits were randomly assigned in four groups: sham, model, model plus SXSM treatment, and sham plus SXSM treatment groups. Heart rate was recorded in all rabbits. Then, total RNA of atria and proteins of ventricle were isolated and quantified, respectively. Gene expression profiling was conducted by gene expression chip, and quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) was performed to confirm the results of gene expression chip. We used isobaric tags for elative and absolute quantitation and Western blotting to identify altered proteins after SXSM treatment.</p><p><b>RESULTS</b>There was a constant decrease in the mean heart rate (32%, from 238 ± 6 beats/min to 149 ± 12 beats/min) after six weeks in model compared with that in sham group. This effect was partially reversed by 4-week SXSM treatment. Complementary DNA microarray demonstrated that the increased acetylcholinesterase and reduced nicotinic receptor were take responsibility for the increased heart rate. In addition, proteins involved in calcium handling and signaling were affected by SXSM treatment. Real-time RT-PCR verified the results from gene chip. Results from proteomics demonstrated that SXSM enhanced oxidative phosphorylation and tricarboxylic acid (TCA) cycle in ventricular myocardium to improve ATP generation.</p><p><b>CONCLUSIONS</b>Long-term SXSM stimulates sympathetic transmission by increasing the expression of acetylcholinesterase and reduces the expression of nicotinic receptor to increase heart rate. SXSM also restored the calcium handling genes and altered genes involved in signaling. In addition, SXSM improves the ATP supply of ventricular myocardium by increasing proteins involved in TCA cycle and oxidation-respiratory chain.</p>

The effects of paeoniflorin monomer of a Chinese herb on cardiac ion channels / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Because of the potential proarrhythmic effect of current antiarrhythmic drugs, it is still desirable to find safer antiarrhythmic drugs worldwide. Paeoniflorin is one of the Chinese herb monomers that have different effects on many ion channels. The present study aimed to determine the effects of paeoniflorin on cardiac ion channels.</p><p><b>METHODS</b>Whole-cell patch-clamp technique was used to record ion channel currents. L-type calcium current (I(Ca-L)), inward rectifier potassium current (I(K1)), and transient outward potassium current (I(to1)) were studied in rat ventricular myocytes and sodium current (I(Na)), slow delayed rectifier current (I(Ks)), and HERG current (I(Kr)) were investigated in transfected human embryonic kidney 293 cells.</p><p><b>RESULTS</b>One hundred µmol/L paeoniflorin reduced the peak I(Ca-L) by 40.29% at the test potential of +10 mV (from (-9.78 ± 0.52) pA/pF to (-5.84 ± 0.89) pA/pF, n = 5, P = 0.028). The steady-state activation curve was shifted to more positive potential in the presence of the drug. The half activation potentials were (-11.22 ± 0.27) mV vs. (-5.95 ± 0.84) mV (n = 5, P = 0.007), respectively. However, the steady-state inactivation and the time course of recovery from inactivation were not changed. One hundred µmol/L paeoniflorin completely inhibited the peak I(Na) and the effect was reversible. Moreover, paeoniflorin inhibited the I(K1) by 30.13% at the test potential of -100 mV (from -25.26 ± 8.21) pA/pF to (-17.65 ± 6.52) pA/pF, n = 6, P = 0.015) without effects on the reversal potential and the rectification property. By contrast, 100 µmol/L paeoniflorin had no effects on I(to1), I(Ks) or I(Kr) channels.</p><p><b>CONCLUSIONS</b>The study demonstrated that paeoniflorin blocked I(Ca-L), I(Na), and I(K1) without affecting I(to1), I(Ks), or I(Kr). The multi-channel block effect may account for its antiarrhythmic effects with less proarrhythmic potential.</p>

Clinical characteristics and outcome of 32 patients with long-QT syndrome accompanied with torsade de pointes / 中华心血管病杂志

<p><b>OBJECTIVE</b>To summarize the clinical characteristics and outcome of patients with long-QT syndrome (LQTs) accompanied with torsade de pointes.</p><p><b>METHODS</b>Thirty-two eligible patients were included in this study. Clinical and electrocardiographic data were analyzed and telephone or out-patient follow-up were made in all patients.</p><p><b>RESULTS</b>There were 15 patients with inherited LQTs (h-LQTs) and 17 patients with acquired LQTs (a-LQTs). There are more women (n = 24) than men (n = 8). β blockers, potassium and magnesium supplement were the basic therapy for h-LQTs patients, bivent pacemaker was implanted in 2 patients and implantable cardioverter defibrillator was implanted in 5 patients. Ventricular tachyarrhythmias and syncope occurred in 4 patients during (39.4 ± 25.1) months follow-up. In 17 a-LQTs patients, one patient with dilated cardiomyopathy died suddenly and another patient with implanted cardioverter defibrillator experienced one ventricular tachycardia during (30.9 ± 13.3) months follow-up.</p><p><b>CONCLUSIONS</b>The prognosis in h-LQTs and a-LQTs patients with structure heart disease is poor. ICD or CRT-D therapy is suggestive for a-LQTs patients with structure heart disease.</p>

Effects of Xinjining extract on inward rectifier potassium current in ventricular myocytes of guinea pig / 中国结合医学杂志

<p><b>OBJECTIVE</b>To study the effect of Xinjining extract (, XJN) on inward rectifier potassium current (I(K1)) in ventricular myocyte (VMC) of guinea pigs and its anti-arrhythmic mechanism on ion channel level.</p><p><b>METHODS</b>Single VMC was enzymatically isolated by zymolisis, and whole-cell patch clamp recording technique was used to record the I(k1) in VMC irrigated with XJN of different concentrations (1.25, 2.50, 5.00 g/L; six samples for each). The stable current and conductance of the inward component of I(K1) as well as the outward component of peak I(K1) and conductance of it accordingly was recorded when the test voltage was set on -110 mV.</p><p><b>RESULTS</b>The suppressive rate of XJN on the inward component of I(K1) was 9.54% + or - 5.81%, 34.82% + or - 15.03%, and 59.52% + or - 25.58% with a concentration of 1.25, 2.50, and 5.00 g/L, respectively, and that for the outward component of peak I(K1) was 23.94% + or - 7.45%, 52.98% + or - 19.62%, and 71.42% + or - 23.01%, respectively (all P<0.05). Moreover, different concentrations of XJN also showed effects for reducing I(K1) conductance.</p><p><b>CONCLUSION</b>XJN has inhibitory effect on I(K1) in guinea pig's VMC, and that of the same concentration shows stronger inhibition on outward component than on inward component, which may be one of the mechanisms of its anti-arrhythmic effect.</p>

Electrophysiological effects of Chinese medicine Shen song Yang xin (SSYX) on Chinese miniature swine heart and isolated guinea pig ventricular myocytes / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Shen song Yang xin (SSYX) is a compound of Chinese medicine with the effect of increasing heart rate (HR). This study aimed to evaluate its electrophysiological properties at heart and cellular levels.</p><p><b>METHODS</b>The Chinese miniature swines were randomly assigned to two groups, administered with SSYX or placebo for 4 weeks (n = 8 per group). Cardiac electrophysiological study (EPS) was performed before and after drug administration. The guinea pig ventricular myocytes were enzymatically isolated and whole cell voltage-clamp technique was used to evaluate the effect of SSYX on cardiac action potential (AP).</p><p><b>RESULTS</b>SSYX treatment accelerated the HR from (141.8 +/- 36.0) beats per minute to (163.0 +/- 38.0) beats per minute (P = 0.013) without changing the other parameters in surface electrocardiogram. After blockage of the autonomic nervous system with metoprolol and atropin, SSYX had no effect on intrinsic HR (IHR), but decreased corrected sinus node recovery time (CSNRT) and sinus atrium conducting time (SACT). Intra cardiac EPS showed that SSYX significantly decreased the A-H and A-V intervals as well as shortened the atrial (A), atrioventricular node (AVN) and ventricular (V) effective refractory period (ERP). In isolated guinea pig ventricular myocytes, the most obvious effect of SSYX on action potential was a shortening of the action potential duration (APD) without change in shape of action potential. The shortening rates of APD(30), APD(50) and APD(90) were 19.5%, 17.8% and 15.3%, respectively. The resting potential (Em) and the interval between the end of APD(30) and APD(90) did not significantly change.</p><p><b>CONCLUSIONS</b>The present study demonstrates that SSYX increases the HR and enhances the conducting capacity of the heart in the condition of the intact autonomic nervous system. SSYX homogenously decreases the ERP of the heart and shortens the APD of the myocytes, suggesting its antiarrhythmic effect without proarrhythmia.</p>

Effects of Chinese herbs on multiple ion channels in isolated ventricular myocytes / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Shensong Yangxin (SSYX) is one of the compound recipe of Chinese materia medica. This study was conducted to investigate the effects of SSYX on sodium current (I(Na)), L-type calcium current (I(Ca, L)), transient outward potassium current (I(to)), delayed rectifier current (I(K)), and inward rectifier potassium currents (I(K1)) in isolated ventricular myocytes.</p><p><b>METHODS</b>Whole cell patch-clamp technique was used to study ion channel currents in enzymatically isolated guinea pig or rat ventricular myocytes.</p><p><b>RESULTS</b>SSYX decreased peak I(Na) by (44.84 +/- 7.65)% from 27.21 +/- 5.35 to 14.88 +/- 2.75 pA/pF (n = 5, P < 0.05). The medicine significantly inhibited the I(Ca, L). At concentrations of 0.25, 0.50, and 1.00 g/100 ml, the peak I(Ca, L) was reduced by (19.22 +/- 1.10)%, (44.82 +/- 6.50)% and (50.69 +/- 5.64)%, respectively (n = 5, all P < 0.05). SSYX lifted the I - V curve of both I(Na) and I(Ca, L) without changing the threshold, peak and reversal potentials. At the concentration of 0.5%, the drug blocked the transient component of I(to) by 50.60% at membrane voltage of 60 mV and negatively shifted the inactive curve and delayed the recovery from channel inactivation. The tail current density of I(K) was decreased by (30.77 +/- 1.11)% (n = 5, P < 0.05) at membrane voltage of 50 mV after exposure to the medicine and the time-dependent activity of I(K) was also inhibited. Similar to the effect on I(K), the SSYX inhibited I(K1) by 33.10% at the test potential of -100 mV with little effect on reversal potential and the rectification property.</p><p><b>CONCLUSIONS</b>The experiments revealed that SSYX could block multiple ion channels such as I(Na) I(Ca, L), I(k), I(to) and I(K1), which may change the action potential duration and contribute to some of its antiarrhythmic effects.</p>

Electrophysiological characterization of long QT syndrome associated mutations V630A and N633S / 中华心血管病杂志

<p><b>OBJECTIVE</b>To identify the electrophysiological properties of long-QT syndrome (LQTS) associated missense mutations in the outer mouth of the HERG potassium channel in vitro.</p><p><b>METHODS</b>Mutations V630A and N633S were constructed by Megaprimer PCR method and cRNA were produced by T7 RNA polymerase. The electrophysiological properties of the mutation were investigated in the Xenopus oocyte heterologous expression system.</p><p><b>RESULTS</b>Coexpression of mutant and wild-type HERG subunits caused a dominant-negative effect, and the currents were significantly decreased. Compared with wild-type HERG channels, V630A and N633S mutations were related to decreased time constants for inactivation for V630A/WT and N633S/WT at all potentials, reduced slope conductance and the voltage dependence of steady-state inactivation was shifted to negative potentials for V630A/WT and N633S/WT.</p><p><b>CONCLUSION</b>Present study shows that LQTS associated missense mutations located in the outer mouth of HERG cause a dominant-negative effect and alterations in steady-state voltage dependence of channel gating of heteromultimeric channels suggesting a reduction in expressional current might be one of the pathophysiologic mechanisms of LQTS.</p>