OBJECTIVETo investigate the effect and potential mechanism of lysophosphatidic acid (LPA) and antiarrhythmic peptide (AAP10) on rabbit ventricular arrhythmia.

METHODSTwenty-four rabbits were randomly divided into three groups (n = 8 each): control group, LPA group and AAP10 + LPA group. Using arterially perfused rabbit ventricular wedge preparations, transmural ECG and action potentials from both endocardium and epicardium were simultaneously recorded in the whole process of all experiments with two separate floating microeletrodes. The incidence of ventricular arrhythmia post S1S2 stimulation was recorded. Protein levels of nonphosphorylated Cx43 and total Cx43 were evaluated by Western blot. The distribution of nonphosphorylated Cx43 was observed by confocal immunofluorescence microscopy.

RESULTSCompared with the control group, the QT interval, endocardial action potential duration, transmural repolarization dispersion (TDR) and incidence of ventricular arrhythmia were significantly increased and nonphosphorylated Cx43 expression was significantly upregulated in the LPA group. Compared with the LPA group, cotreatment with AAP10 can reduce the QT interval, endocardial action potential duration, TDR and incidence of ventricular arrhythmia (25.0% vs 62.5%, P < 0.01) and downregulate nonphosphorylated Cx43.

CONCLUSIONSLPA could promote the arrhythmia possibly by upregulating nonphosphorylated Cx43 and subsequent gap junction transmission inhibition. Gap junction enhancer AAP10 could attenuate the pro-arrhythmic effect of LPA probably by downregulating myocardial nonphosphorylated Cx43 expression.

Animals ; Anti-Arrhythmia Agents ; pharmacology ; Arrhythmias, Cardiac ; chemically induced ; metabolism ; physiopathology ; Connexin 43 ; metabolism ; Lysophospholipids ; adverse effects ; Oligopeptides ; pharmacology ; Rabbits

Under conditions of Na+ channel hyperactivation with aconitine, the changes in action potential duration (APD) and the restitution characteristics have not been well defined in the context of aconitine-induced arrhythmogenesis. Optical mapping of voltage using RH237 was performed with eight extracted rabbit hearts that were perfused using the Langendorff system. The characteristics of APD restitution were assessed using the steady-state pacing protocol at baseline and 0.1 microM aconitine concentration. In addition, pseudo-ECG was analyzed at baseline, and with 0.1 and 1.0 microM of aconitine infusion respectively. Triggered activity was not shown in dose of 0.1 microM aconitine but overtly presented in 1.0 microM of aconitine. The slopes of the dynamic APD restitution curves were significantly steeper with 0.1 microM of aconitine than at baseline. With aconitine administration, the cycle length of initiation of APD alternans was significantly longer than at baseline (287.5 +/- 9.6 vs 247.5 +/- 15.0 msec, P = 0.016). The functional reentry following regional conduction block appears with the progression of APD alternans. Ventricular fibrillation is induced reproducibly at pacing cycle length showing a 2:1 conduction block. Low-dose aconitine produces arrhythmogenesis at an increasing restitution slope with APD alternans as well as regional conduction block that proceeds to functional reentry.
Aconitine/*pharmacology ; Action Potentials/*drug effects ; Animals ; Arrhythmias, Cardiac/*chemically induced/*physiopathology ; Cardiac Pacing, Artificial ; Electrocardiography ; Heart/physiopathology ; Heart Conduction System/physiology ; Myocardium/*pathology ; Rabbits ; Sodium Channels/drug effects/metabolism ; Ventricular Fibrillation/physiopathology

AIMTo clarify mechanisms that the antiarrhythmic effects of matrine and berbamine are weaker than those of amiodarone and RP58866.

METHODSExperimental arrhythmic models were induced by aconitine, coronary artery ligation and electric stimulation in rats and rabbits. Whole-cell patch-clamp techniques were used to record IK1, IKr, IKs and Ito.

RESULTSMatrine and berbamine significantly increased the dose of aconitine for induction of ventricular premature and ventricular tachycardia in rats, decreased the number of arrhythmias induced by coronary artery ligation in rats and increased ventricular fibrillation threshold (VFT) induced by electric stimulation in rabbits, but the anti-arrhythmic potency of matrine and berbamine was lower than that of amiodarone and RP58866. The inhibitory actions of matrine and berbamine on IK1, IKr, IKs, Ito were lower than those of amiodarone and RP58866. The IC50 of matrine for IK1, IKr, IKs, Ito were (46 +/- 3), (32.9 +/- 1.2), (37 +/- 8) and (7.6 +/- 0.5) mol x L(-1), respectively. The IC50 of amiodarone for IK1, IKr, IKs, Ito were (21 +/- 5) , (3.7 +/- 0.7), (5.9 +/- 0.9) and (5.9 +/- 0.6) mol x L(-1), respectively.

CONCLUSIONThe inhibitory actions of matrine and berbamine on IK1, IKr, IKs, Ito were lower than those of amiodarone and RP58866, which might be the reason that the antiarrhythmic effects of matrine and berbamine were weaker than those of amiodarone and RP58866.

Aconitine ; Alkaloids ; pharmacology ; Amiodarone ; pharmacology ; Animals ; Anti-Arrhythmia Agents ; pharmacology ; Arrhythmias, Cardiac ; chemically induced ; physiopathology ; prevention & control ; Benzylisoquinolines ; pharmacology ; Chromans ; pharmacology ; Dogs ; Female ; Guinea Pigs ; Male ; Piperidines ; pharmacology ; Potassium Channels ; drug effects ; Quinolizines ; Rabbits ; Rats

This study is to investigate the effects of phenytoin sodium, lidocaine (sodium channel blockers), propranolol (beta-adrenergic receptor antagonist), amiodarone (drugs prolonging the action potential duration) and verapamil (calcium channel blockers) on arrhythmia of mice induced by Bufonis Venenum (Chansu) and isolated mouse hearts lethal dose of Chansu. Arrhythmia of mice were induced by Chansu and then electrocardiograms (ECGs) were recorded. The changes of P-R interval, QRS complex, Q-T interval, T wave amplitude, heart rate (HR) were observed. Moreover, arrhythmia rate, survival rate and arrhythmia score were counted. Isolated mouse hearts were prefused, and the lethal dose of Chansu was recorded. Compared with control group, after pretreatment with phenytoin sodium, broadening of QRS complex and HR were inhibited, and the incidence of ventricular arrhythmia was reduced dramatically, while survival rate was improved; the isolated mouse hearts lethal dose of Chansu was increased significantly. After pretreatment with lidocaine, the prolongation of P-R interval and broadening of QRS complex were inhibited, and the incidences of ventricular arrhythmia were reduced dramatically, while survival rate was improved; the isolated mouse hearts lethal dose of Chansu was increased significantly. After pretreatment with propranolol, prolongation of P-R interval, broadening of QRS complex, prolongation of Q-T interval and HR were inhibited, and the incidences of both supraventricular and ventricular arrhythmias were reduced dramatically, while survival rate was improved. After pretreatment with amiodarone, HR was inhibited, the incidences of ventricular tachycardia were reduced dramatically. Lastly, after pretreatment with verapamil, the prolongation of P-R interval and Q-T interval were inhibited and the incidences of both supraventricular and ventricular arrhythmias were reduced dramatically; the isolated mouse hearts lethal dose of Chansu was reduced significantly. In in vivo experiments, phenytoin sodium was most effective against the mice arrhythmias induced by Chansu while cautious use of verapamil for Chansu inducing arrhythmia should be noted. It is also concluded that mice ventricular arrhythmias induced by Chansu might be most closely related to sodium channel, supraventricular arrhythmias might be related to beta-adrenergic receptor, and calcium channel plays an important role in conduction block. In in vitro experiments, phenytoin sodium was most effective, followed by lidocaine and propranolol, and amiodarone had no obvious effect and verapamil reduced the lethal dose of Chansu.
Amiodarone ; pharmacology ; Animals ; Anti-Arrhythmia Agents ; pharmacology ; Arrhythmias, Cardiac ; chemically induced ; physiopathology ; Bufanolides ; toxicity ; Electrocardiography ; drug effects ; Female ; Heart Rate ; drug effects ; In Vitro Techniques ; Lethal Dose 50 ; Lidocaine ; pharmacology ; Male ; Mice ; Phenytoin ; pharmacology ; Propranolol ; pharmacology ; Verapamil ; pharmacology

OBJECTIVETo investigate the effect of ethyl acetate extract from Chrysanthemum Morifolium Ramat (CME) on experimental arrhythmia induced by ischemia/reperfusion or aconitine in rats and to explore its underlying mechanisms.

METHODSArrhythmia model in intact rat was induced by aconitine (30 microg/kg body weight, i.v.). In isolated Langendorff perfused rat hearts, regional ischemia and reperfusion was induced by ligation and release of left anterior descending artery. The ventricular fibrillation threshold (VFT), effective refractory period (ERP), and diastolic excitation threshold (DET) in the isolated heart were measured. The action potentials of papillary muscle in rat right ventricle were recorded by conventional glass microelectrode technique.

RESULTSCompared with control group CME significantly decreased the number and duration of ventricular tachycardia (VT); delayed the occurrence of ventricular premature beats (VPB) and VT induced by aconitine. Arrhythmia score of the CME group was lower than that in aconitine-treated group. CME markedly prolonged the ERP and increased the VFT in the isolated perfused rat hearts during ischemia and reperfusion. CME prolonged action potential duration at 50% and 90% repolarization of the right ventricular papillary muscles and decreased the maximal rate of rise of the action potential upstroke, but did not affect the resting potential, amplitude of action potential.

CONCLUSIONCME can reduce myocardial vulnerability and exerts its antiarrhythmic effects induced by aconitine or ischemia/reperfusion, which may be related to its prolongation of action potential duration and effective refractory period that enhance the electrophysiological stability of myocardiaium.

Acetates ; chemistry ; Action Potentials ; drug effects ; Animals ; Anti-Arrhythmia Agents ; isolation & purification ; pharmacology ; Arrhythmias, Cardiac ; chemically induced ; physiopathology ; Chrysanthemum ; chemistry ; Drugs, Chinese Herbal ; pharmacology ; In Vitro Techniques ; Male ; Rats ; Rats, Sprague-Dawley ; Refractory Period, Electrophysiological ; drug effects

OBJECTIVETo explore the possible mechanism of cyclovirobuxine D (CVB-D) in countering and inducing arrhythmia, by way of studying its electro-physiological effect on ventricular papillary muscles of rats in vitro.

METHODSThe transmembrane potential of rat's isolated right ventricular papillary muscles were recorded using conventional glass micro-electrode technique.

RESULTS(1) CVB-D in concentration of 13.3-63.3 micromol/L, showed prolonging effect on the action potential repolarization time, mainly the action potential duration 50 (APD50), APD70 and APD90, in dose-dependent manner, in concentration of 33.3-63.3 micromol/L, it could inhibit the resting potential, action potential amplitude (APA) and maximum depolarization velocity (Vmax) in dose-dependent manner. (2) CVB-D also showed time-dependent effect, the effect initiated 10 min after 20 micromol/L was perfused in ventricular muscle, the APD50, APD70 and APD90 were potentiated gradually along with prolongation of action time and reached the peak at 30-40 min, without any potentiation thereafter. (3) CVB-D could markedly prolong the effective refractory period (ERP) of action potential, increase the ratio of ERP/APD. (4) CVB-D in concentration of 33.3 micromol/L could induce frequent, multifocal spontaneous arrhythmia in some cells when the action time was longer than 45 min.

CONCLUSIONCVB-D has the action of anti-ventricular arrhythmia, the mechanism is correlated with the prolongation of APD and ERP of ventricular muscle as well as the increase of ERP/APD ratio, while it also has the effect of inducing arrhythmia, the mechanism might be concerned with excessive prolongation of APD and the inhibition on RP, APA and Vmax.

Action Potentials ; drug effects ; Animals ; Anti-Arrhythmia Agents ; pharmacology ; Arrhythmias, Cardiac ; chemically induced ; physiopathology ; Drugs, Chinese Herbal ; pharmacology ; Electrophysiologic Techniques, Cardiac ; Heart Ventricles ; drug effects ; In Vitro Techniques ; Male ; Myocytes, Cardiac ; cytology ; Papillary Muscles ; drug effects ; Rats ; Rats, Sprague-Dawley ; Refractory Period, Electrophysiological ; drug effects ; Ventricular Function

OBJECTIVETo study the treatment effect of Wenxin Keli on isoproterenol (ISO) induced heart failure in rats.

METHODSixty six-week old male Wistar rats were randomized into six groups. The rats in control group were only receive distilled water every day. The rats in ISO group also received two subcutaneous injections (85 mg x kg(-1)) of ISO, which were separated by a 24 hour interval and began to receive distilled water 2 weeks later every day. The rats in Wenxin Keli and control group were receive Wenxin Keli (9 mg x kg(-1)) every day. The rats in Wenxin Keli and ISO group received two subcutaneous injections (85 mg x kg(-1)) of ISO, which were separated by a 24 hour interval and began to receive Wenxin Keli (9 mg x kg(-1)) 2 weeks later every day. The rats in valsartan and control group were receive valsartan every day. The rats in valsartan and ISO group received two subcutaneous injections (85 mg x kg(-1)) of ISO, which were separated by a 24 hour interval and began to receive valsartan 30 mg x kg(-1) 2 weeks later every day. Echocardiogram measurement in rats were carried out after 4 weeks and 10 weeks feeding medince of hemodynamic measurement and aconitine induced arrhythmia in rats were carried out after 10 weeks.

RESULTEchocardiogram indicated that left ventricular internal diameter at diastolic phase (LVIDd), left ventricular internal diameter at systolic phase (LVIDs), LV percent fractional shortening (FS) and LV ejection fraction (EF) were decreased in the ISO group. Treatment with valsartan 4 weeks later, FS and EF were increased compared with the ISO group and 10 weeks later, LVIDd, LVIDs, FS, EF were increased. However, treatment with Wenxin Keli 10 weeks later, LVIDs, FS, EF were not changed obviously. Hemodynamic measurement showed that left ventricular end diastolic pressure (LVEDP), left ventricular systolic pressure (LVSP), and dp/dt(max) were improved after 10 weeks of treatment with valsartan. The LVEDP was decreased and dp/dt(max), was increased after 10 weeks of treatment with Wenxin Keli. Aconitine induced arrhythmia in rats in Wenxin Keli and control group were less serious than those in control group, aconitine induced arrhythmia in rats in Wenxin Keli and ISO group were less serious than those in ISO group.

CONCLUSIONWenxin Keli could greatly improve the ISO induced cardiac dysfunction and protect the aconitine-induced arrhythmia in rats.

Animals ; Arrhythmias, Cardiac ; diagnostic imaging ; physiopathology ; prevention & control ; Cardiotonic Agents ; isolation & purification ; pharmacology ; Drug Combinations ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; Echocardiography ; Heart ; drug effects ; physiopathology ; Heart Failure ; chemically induced ; physiopathology ; prevention & control ; Hemodynamics ; drug effects ; Isoproterenol ; Male ; Myocardium ; pathology ; Plants, Medicinal ; chemistry ; Random Allocation ; Rats ; Rats, Wistar ; Ventricular Function, Left ; drug effects

AIMTo study the effect of modified starfish sterol [C03, succinic acid (5-epiandroene-17-one-3beta-ol) diester] on experimental arrhythmias.

METHODSArrhythmias were induced by drugs (Aco, Oua, BaCl2 and adrenalin) i.v., ligating the left anterior descending coronary artery and electricity.

RESULTSC03 71.4 mg x kg(-1) (ig) was shown to increase the dose of Oua inducing VP, VT, VF and CA in guinea pigs (P < 0.01); C03 (26.8, 80.4 mg x kg(-1)) was found to increase the dose of Aco inducing VF and CA in rats (P < 0.01); C03 (8.9, 26.8, 80.4 mg x kg(-1)) increase the dose of barium chloride and delay the onset time of ventricular arrhythmias (P < 0.01); C03 (14.1, 42.3 mg x kg(-10) shorten time of recovering induced by adrenalin in rabbits (P < 0.01); C03 (80.4 mg x kg(-1)) was shown to reduce the number of ventricular arrhythmias induced by coronary artery ligation in rats (P < 0.05), C03 increase VFT induced by electricity in rabbits, VFT of C03 14.1 mg x kg(-1) increased from (5.1 +/- 2.5) V to (11.0 +/- 2.7) V (P < 0.01), 42.3 mg x kg(-1) increased from (6.1 +/- 1.7) V to (15 +/- 5) V (P < 0.01).

CONCLUSIONStarfish sterol has anti-arrhythmic effect.

Aconitine ; Animals ; Anti-Arrhythmia Agents ; therapeutic use ; Arrhythmias, Cardiac ; chemically induced ; physiopathology ; prevention & control ; Barium Compounds ; Cats ; Chlorides ; Epinephrine ; Guinea Pigs ; Materia Medica ; isolation & purification ; therapeutic use ; Mice ; Ouabain ; Rabbits ; Rats ; Starfish ; chemistry ; Sterols ; isolation & purification ; therapeutic use ; Ventricular Fibrillation ; physiopathology

AIMTo search for compounds for the treatment of cardiovascular diseases through prodrug structural modifications of cyclovirobuxine D, a single efficient composition distilled from Box plant in China, which was used to treat angina and myocardial infarction.

METHODSAccording to prodrug design principle, a series of cyclovirobuxine D analogues were prepared, suc as succinate, phosphate and amino acid ester, and their biological activities were tested.

RESULTSSeven new compounds were obtained and confirmed with 1H NMR, MS, and element analysis.

CONCLUSIONIn pharmacology experiment, for treating arrhythmia induced by aconitine, succinate and amino acid ester of cyclovirobuxine D (I and VII) showed better activities than that of cyclovirobuxine D. The normal rhythm of the heart duration of I and VII were ( 11.53 +/- 7.62) min and (12.68 +/- 9.25) min, compared with 0.9% NaCl solution and cyclovirobuxine D, (2.36 +/- 1.68) min and (10.25 +/- 6.59) min (P < 0.01), respectively. Another pharmacology experiment, for treating arrhythmia induced by chloroform, the negative ratio of I and VII were 80% and 82%, compared with 0.9% NaCl solution and cyclovirobuxine D, 43% and 52% (P < 0.05), respectively. The difference between new compounds and cyclovirobuxine D was distinct.

Aconitine ; Animals ; Anti-Arrhythmia Agents ; chemical synthesis ; pharmacology ; Arrhythmias, Cardiac ; chemically induced ; physiopathology ; Buxus ; chemistry ; Chloroform ; Drugs, Chinese Herbal ; chemical synthesis ; pharmacology ; Female ; Heart Rate ; drug effects ; Male ; Mice ; Plants, Medicinal ; chemistry ; Prodrugs ; chemical synthesis ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley

To study the antiarrhythmic effect of the newly developed alpha/beta-blocker TJ0711, a variety of animal models of arrhythmia were induced by CaCl2, ouabain and ischemia/reperfusion. Glass microelectrode technique was used to observe action potentials of right ventricular papillary muscle of guinea pig. The onset time of arrhythmia induced by CaCl2 was significantly prolonged by TJ0711 at 0.75, 1.5 and 3 mg x kg(-1) doses. TJ0711 (1.5 and 3 mg x kg(-1)) can significantly shorten the ventricular tachycardia (VT) and ventricular fibrillation (VF) duration, the incidence of VF and mortality were significantly reduced. On ischemia-reperfusion-induced arrhythmic model, TJ0711 (0.25, 0.5, 1 and 2 mg x kg(-1)) can significantly reduce the ventricular premature contraction (PVC), VT, VF incidence, mortality, arrhythmia score with a dose-dependent manner. At the same time, rats serum lactate dehydrogenase (LDH) and creatine kinase (CK) activities decreased significantly by TJ0711 (1 and 2 mg x kg(-1)). Ouabain could cause arrhythmia in guinea pigs, when TJ0711 (0.375, 0.75, 1.5 and 3 mg x kg(-1)) was given, the doses of ouabain inducing a variety of arrhythmia PVC, VT, VF, cardiac arrest (CA) were significantly increased with a dose-dependent manner. In the TJ0711 0.1-30 micromol x L(-1) concentration range, guinea pig right ventricular papillary muscle action potential RP (rest potential), APA (action potential amplitude) and V(max) (maximum velocity of depolarization) were not significantly affected. APD20, APD50 and APD90 had a shortening trend but no statistical difference with the increase of TJ0711 concentration. TJ0711 has antiarrhythmic effect on the sympathetic nerve excitement and myocardial cell high calcium animal arrhythmia model. Myocardial action potential zero phase conduction velocity and resting membrane potential were not inhibited by TJ0711. APD20, APD50 and APD90 were shortened by TJ0711 at high concentration. Its antiarrhythmic action mechanism may be besides the action of blocking beta1 receptor, may also have a strong selective blocking action on alpha1 receptor and reducing intracellular calcium concentration.
Action Potentials ; drug effects ; Adrenergic alpha-Antagonists ; administration & dosage ; pharmacology ; Adrenergic beta-Antagonists ; administration & dosage ; pharmacology ; Animals ; Anti-Arrhythmia Agents ; administration & dosage ; pharmacology ; Arrhythmias, Cardiac ; blood ; chemically induced ; etiology ; pathology ; physiopathology ; Calcium Chloride ; Creatine Kinase ; blood ; Dose-Response Relationship, Drug ; Female ; Guinea Pigs ; Heart Ventricles ; cytology ; Lactate Dehydrogenases ; blood ; Male ; Myocardial Reperfusion Injury ; complications ; Myocytes, Cardiac ; drug effects ; physiology ; Ouabain ; Papillary Muscles ; cytology ; Phenoxypropanolamines ; administration & dosage ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley