tetrodotoxin and Arrhythmias--Cardiac

This review presents the roles of cardiac sodium channel NaV1.5 late current (late INa) in generation of arrhythmic activity. The assumption of the authors is that proper Na(+) channel function is necessary to the maintenance of the transmembrane electrochemical gradient of Na(+) and regulation of cardiac electrical activity. Myocyte Na(+) channels' openings during the brief action potential upstroke contribute to peak INa and initiate excitation-contraction coupling. Openings of Na(+) channels outside the upstroke contribute to late INa, a depolarizing current that persists throughout the action potential plateau. The small, physiological late INa does not appear to be critical for normal electrical or contractile function in the heart. Late INa does, however, reduce the net repolarizing current, prolongs action potential duration, and increases cellular Na(+) loading. An increase of late INa, due to acquired conditions (e.g. heart failure) or inherited Na(+) channelopathies, facilitates the formation of early and delayed afterpolarizations and triggered arrhythmias, spontaneous diastolic depolarization, and cellular Ca(2+) loading. These in turn increase the spatial and temporal dispersion of repolarization time and may lead to reentrant arrhythmias.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Calcium; Homeostasis; Humans; Myocytes, Cardiac; NAV1.5 Voltage-Gated Sodium Channel; Sodium; Tetrodotoxin

Alterations in microscopic conduction could contribute to microreentry and arrhythmogenesis in pathological settings. This chapter reviews microconduction in the ventricular myocardium. Gap junctions play a significant role in longitudinal and transverse propagation of the action potential wavefront in the ventricle. Studies of microscopic conduction in patterned cultures of neonatal rodent myocytes have provided novel insights into the role of gap junctions, the effects of uncoupling versus altered excitability, and the contribution of discontinuities and branching. Decreased gap junctional coupling can contribute to slowing of conduction and development of unidirectional block. However, in the setting of structural inhomogeneities and unbalanced current source and load, decreased coupling can, at times, improve conduction and be 'anti-arrhythmic,' attesting to the complexity of intercellular coupling as a therapeutic target. Genetically engineered mouse models of Cx43 depletion demonstrate slow conduction and arrhythmogenesis that appears to be reentrant in nature. Studies in these models provide novel insights into the contribution of gap junctions to impulse propagation and arrhythmogenesis in the intact heart. Overall, gap junction expression, distribution and heterogeneity are important contributors to microscopic conduction, and alterations in any of these can contribute to the development of an arrhythmogenic substrate in pathological states.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Cells, Cultured; Connexins; Fatty Acids, Monounsaturated; Gap Junctions; Gene Deletion; Heart; Humans; Mice; Mice, Knockout; Tetrodotoxin

Late sodium current in cardiac cells is very small compared with the fast component, but as it flows throughout the action potential it may make a substantial contribution to sodium loading during each cardiac cycle. Late sodium current may contribute to triggering arrhythmia in two ways: by causing repolarisation failure (early after depolarisations); and by triggering late after depolarisations attributable to calcium oscillations in sodium-calcium overload conditions. Reduction of late sodium current would therefore be expected to have therapeutic benefits, particularly in disease states such as ischaemia in which sodium-calcium overload is a major feature.

Topics: Arrhythmias, Cardiac; Calcium; Calcium Channels; Humans; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Sodium; Sodium Channels; Sodium-Calcium Exchanger; Tetrodotoxin

Calcium channels are critical to normal cardiac function. They are involved in the generation and conduction of the action potential and in contraction. Three surface membrane channels have been identified. The L-type Ca channel is most abundant and is responsible for Ca entry into the cell that triggers contraction. T-type Ca channels are most prevalent in the conduction system and are probably involved in automaticity. A newly described TTX-sensitive calcium current may be important in "boosting" or enhancing conduction and contraction. The main intracellular Ca channel resides in the sarcoplasmic reticulum and is responsible for the release of the Ca that activates contraction. Oscillatory behavior of this channel influences the sarcolemmal membrane, causing delayed aftercontractions and arrhythmias such as those seen in digoxin toxicity. The on-going molecular characterization of these channels will enhance our knowledge of their normal function and dysfunction in disease states, leading to the development of new therapeutic agents to treat arrhythmias and contractile dysfunction.

Topics: Adrenergic beta-Agonists; Animals; Arrhythmias, Cardiac; Calcium; Calcium Channels, L-Type; Calcium Channels, T-Type; Calcium Signaling; Humans; Inositol 1,4,5-Trisphosphate; Magnesium; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Structure-Activity Relationship; Terminology as Topic; Tetrodotoxin

Topics: Animals; Arrhythmias, Cardiac; Heart Transplantation; Humans; Myocardial Infarction; Myocardial Ischemia; Rats; Sodium Channels; Sympathetic Nervous System; Tetrodotoxin

The effects of antiarrhythmic agents, including Classes I and IV and 3-10 mM Mg2+ on aconitine-induced arrhythmias were examined using a conventional microelectrode and patch clamp method in Langendorff-perfused rabbit hearts and isolated guinea-pig ventricular myocytes. Intracoronary application of 0.1 microM aconitine induced polymorphic ventricular tachycardia (PVT) which continued for more than 60 minutes. Application of aconitine to ventricular myocytes caused a prolonged action potential duration (APD) and the appearance of early afterdepolarization (EAD) together with the occurrence of an inward hump of the I-V curve around -60 to -40 mV and increased outward current at positive voltages. Application of 10 microM TTX and 5 mM or higher Mg2+ restored aconitine-induced PVT to sinus rhythm in Langendorff-perfused preparations and also shortened the prolonged APD, demonstrating the abolishment of EAD by aconitine in ventricular myocytes. However, antiarrhythmic agents did not exert such effects. In conclusion, the antiarrhythmic actions of Mg2+ and TTX in aconitine-induced arrhythmia are to abolish EAD and shorten the prolonged APD by suppression of the inward Na+ current around -60 to -40 mV.

Topics: Aconitine; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Guinea Pigs; In Vitro Techniques; Magnesium; Membrane Potentials; Myocardium; Patch-Clamp Techniques; Rabbits; Tachycardia, Ventricular; Tetrodotoxin

Calcium antagonists (slow channel blocking agents) are a very heterogeneous group of agents with dissimilar structural, electrophysiologic and pharmacologic properties. Nifedipine is a potent, long-acting vasodilator that has proved highly efficacious in relieving anginal symptoms caused by coronary vasospasm. In vivo, it exerts no myocardial depressant effects and has no antiarrhythmic properties. Treatment with nifedipine can safely be combined with administration of a beta receptor blocking agent. VErapamil prolongs atrioventricular (A-V) conduction (A-H interval) in a dose-dependent manner. It is the drug of choice for the treatment of reentrant supraventricular arrhythmias, irrespective of whether reentry occurs within the A-V node or through an accessory pathway (the Wolff-Parkinson-White syndrome). Verapamil is only moderately effective as an antianginal agent. Diltiazem is efficacious for the treatment of angiospastic angina, but its value as an antiarrhythmic agent remains to be delineated.

Topics: Angina Pectoris; Angina Pectoris, Variant; Animals; Arrhythmias, Cardiac; Benzazepines; Calcium; Cardiovascular System; Diltiazem; Dogs; Electrophysiology; Humans; Hypertension; Ion Channels; Kinetics; Muscle, Smooth, Vascular; Myocardial Contraction; Myocardial Infarction; Nifedipine; Pyridines; Sheep; Tetrodotoxin; Vasodilator Agents; Verapamil

Arsenic trioxide (As(2)O (3)) is a new promising regimen for patients with a relapse of acute promyelocytic leukemia (APL), but causes life-threatening arrhythmias. This study aimed to investigate the incidence and mechanism of arrythmogenesis caused by As(2)O(3).. Standard 12-lead ECGs were monitored throughout As(2)O(3) therapy in 20 APL patients. As(2)O (3) (0.15 mg/kg) significantly prolonged the corrected QT interval (QTc: 445+/-7 to 517+/-17 ms, means+/-SE, p<0.01), and also increased the QTc dispersion and transmural dispersion of repolarization. Non-sustained ventricular tachycardias and torsades de pointes occurred in 4 and 1 patients, respectively. The action potentials and isometric contraction were measured in guinea pig papillary muscles during As(2)O (3) perfusion (350 micromol/L). The action potential duration was prolonged (APD(90): 150+/-11 to 195+/-12 ms at 60 min, p<0.01, n=5) and perfusion of As(2)O(3) in a low K(+) solution with a low stimulation rate augmented the prolongation of APD, and provoked early after-depolarizations and triggered activities. The prolonged exposure to As(2)O(3) induced muscle contracture, aftercontractions, triggered activities and electromechanical alternans. Tetrodotoxin or butylated hydroxytoluene partially prevented the As(2)O(3)-induced prolongation of APD.. The prolonged QTc and spatial heterogeneity are responsible for the As(2)O(3)-induced ventricular tachyarrhythmias. In addition to prolongation of the APD, cellular Ca(2+) overload and lipid peroxidation might contribute to the electrophysiological abnormalities caused by As(2)O(3).

Topics: Action Potentials; Animals; Antineoplastic Agents; Antioxidants; Arrhythmias, Cardiac; Arsenic Trioxide; Arsenicals; Butylated Hydroxytoluene; Electrocardiography; Electrophysiology; Guinea Pigs; Humans; Leukemia, Promyelocytic, Acute; Lipid Peroxidation; Long QT Syndrome; Myocardial Contraction; Oxides; Papillary Muscles; Poisons; Reactive Oxygen Species; Tetrodotoxin

Topics: 4-Aminopyridine; Action Potentials; Aging; Animals; Arrhythmias, Cardiac; Isoproterenol; Male; Myocytes, Cardiac; Rats; Sodium; Tetrodotoxin; Ventricular Fibrillation

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used for the assessment of drug proarrhythmic potential through multielectrode array (MEA). HiPSC-CM cultures beat spontaneously with a wide range of frequencies, however, which could affect drug-induced changes in repolarization. Pacing hiPSC-CMs at a physiological heart rate more closely resembles the state of in vivo ventricular myocytes and permits the standardization of test conditions to improve consistency. In this study, we systematically investigated the time window of stable ion currents in high-purity hiPSC-derived ventricular cardiomyocytes (hiPSC-vCMs) and confirmed that these cells could be used to correctly predict the proarrhythmic risk of Comprehensive In Vitro Proarrhythmia Assay (CiPA) reference compounds. To evaluate drug proarrhythmic potentials at a physiological beating rate, we used a MEA to electrically pace hiPSC-vCMs, and we recorded regular field potential waveforms in hiPSC-vCMs treated with DMSO and 10 CiPA reference drugs. Prolongation of field potential duration was detected in cells after exposure to high- and intermediate-risk drugs; in addition, drug-induced arrhythmia-like events were observed. The results of this study provide a simple and feasible method to investigate drug proarrhythmic potentials in hiPSC-CMs at a physiological beating rate.

Topics: Action Potentials; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium; Cations, Divalent; Cell Differentiation; Humans; Induced Pluripotent Stem Cells; Ion Transport; Microelectrodes; Models, Biological; Myocardial Contraction; Myocytes, Cardiac; Nifedipine; Patch-Clamp Techniques; Phenethylamines; Primary Cell Culture; Quinidine; Sotalol; Sulfonamides; Tetrodotoxin; Verapamil

Severe arrhythmias-such as ventricular arrhythmias-can be fatal, but treatment options are limited. The effects of a combined formulation of tetrodotoxin (TTX) and lidocaine (LID) on severe arrhythmias were studied. Patch clamp recording data showed that the combination of LID and TTX had a stronger inhibitory effect on voltage-gated sodium channel 1.5 (Nav1.5) than that of either TTX or LID alone. LID + TTX formulations were prepared with optimal stability containing 1 μg of TTX, 5 mg of LID, 6 mg of mannitol, and 4 mg of dextran-40 and then freeze dried. This formulation significantly delayed the onset and shortened the duration of arrhythmia induced by aconitine in rats. Arrhythmia-originated death was avoided by the combined formulation, with a decrease in the mortality rate from 64% to 0%. The data also suggests that the anti-arrhythmic effect of the combination was greater than that of either TTX or LID alone. This paper offers new approaches to develop effective medications against arrhythmias.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Disease Models, Animal; Drug Combinations; Drug Stability; Excipients; Female; Freeze Drying; Lidocaine; Male; NAV1.5 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Tetrodotoxin; Voltage-Gated Sodium Channel Blockers

The physiological role of cardiac late Na

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Pacing, Artificial; Disease Models, Animal; Female; Heart Rate; Heart Ventricles; In Vitro Techniques; Isolated Heart Preparation; Kinetics; Myocytes, Cardiac; Piperidines; Pyridines; Rabbits; Sodium Channel Blockers; Sodium Channels; Tetrodotoxin; Triazoles

Topics: Arrhythmias, Cardiac; Heart Ventricles; Humans; Sodium; Tetrodotoxin

Cardiac arrhythmias associated with intracellular calcium inhomeostasis are refractory to antiarrhythmic therapy. We hypothesized that late sodium current (I

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Arrhythmias, Cardiac; Calcium; Calcium Channel Agonists; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Disease Models, Animal; Male; Muscle Contraction; Oxazepines; Phosphorylation; Rabbits; Sodium Channels; Tetrodotoxin

Na(+) current (INa) results from the integrated function of a molecular aggregate (the voltage-gated Na(+) channel complex) that includes the β subunit family. Mutations or rare variants in Scn1b (encoding the β1 and β1B subunits) have been associated with various inherited arrhythmogenic syndromes, including Brugada syndrome and sudden unexpected death in patients with epilepsy. We used Scn1b null mice to understand better the relation between Scn1b expression, and cardiac electrical function. Loss of Scn1b caused, among other effects, increased amplitude of tetrodotoxin-sensitive INa, delayed after-depolarizations, triggered beats, delayed Ca(2+) transients, frequent spontaneous calcium release events and increased susceptibility to polymorphic ventricular arrhythmias. Most alterations in Ca(2+) homeostasis were prevented by 100 nM tetrodotoxin. We propose that life-threatening arrhythmias in patients with mutations in Scn1b, a gene classically defined as ancillary to the Na(+) channel α subunit, can be partly consequent to disrupted intracellular Ca(2+) homeostasis.. Na(+) current (INa) is determined not only by the properties of the pore-forming voltage-gated Na(+) channel (VGSC) α subunit, but also by the integrated function of a molecular aggregate (the VGSC complex) that includes the VGSC β subunit family. Mutations or rare variants in Scn1b (encoding the β1 and β1B subunits) have been associated with various inherited arrhythmogenic syndromes, including cases of Brugada syndrome and sudden unexpected death in patients with epilepsy. Here, we have used Scn1b null mouse models to understand better the relation between Scn1b expression, and cardiac electrical function. Using a combination of macropatch and scanning ion conductance microscopy we show that loss of Scn1b in juvenile null animals resulted in increased tetrodotoxin-sensitive INa but only in the cell midsection, even before full T-tubule formation; the latter occurred concurrent with increased message abundance for the neuronal Scn3a mRNA, suggesting increased abundance of tetrodotoxin-sensitive NaV 1.3 protein and yet its exclusion from the region of the intercalated disc. Ventricular myocytes from cardiac-specific adult Scn1b null animals showed increased Scn3a message, prolonged action potential repolarization, presence of delayed after-depolarizations and triggered beats, delayed Ca(2+) transients and frequent spontaneous Ca(2+) release events and at the whole heart level, increased susceptibility to polymorphic ventricular arrhythmias. Most alterations in Ca(2+) homeostasis were prevented by 100 nM tetrodotoxin. Our results suggest that life-threatening arrhythmias in patients with mutations in Scn1b, a gene classically defined as ancillary to the Na(+) channel α subunit, can be partly consequent to disrupted intracellular Ca(2+) homeostasis in ventricular myocytes.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Calcium Signaling; Cells, Cultured; Gene Deletion; Mice; Myocytes, Cardiac; Sodium Channel Blockers; Tetrodotoxin; Voltage-Gated Sodium Channel beta-1 Subunit

The aim of the study was to determine the characteristics of the late Na current (INaL) and its arrhythmogenic potential in the progression of pressure-induced heart disease. Transverse aortic constriction (TAC) was used to induce pressure overload in mice. After one week the hearts developed isolated hypertrophy with preserved systolic contractility. In patch-clamp experiments both, INaL and the action potential duration (APD90) were unchanged. In contrast, after five weeks animals developed heart failure with prolonged APDs and slowed INaL decay time which could be normalized by addition of the INaL inhibitor ranolazine (Ran) or by the Ca/calmodulin-dependent protein kinase II (CaMKII) inhibitor AIP. Accordingly the APD90 could be significantly abbreviated by Ran, tetrodotoxin and the CaMKII inhibitor AIP. Isoproterenol increased the number of delayed afterdepolarizations (DAD) in myocytes from failing but not sham hearts. Application of either Ran or AIP prevented the occurrence of DADs. Moreover, the incidence of triggered activity was significantly increased in TAC myocytes and was largely prevented by Ran and AIP. Western blot analyses indicate that increased CaMKII activity and a hyperphosphorylation of the Nav1.5 at the CaMKII phosphorylation site (Ser571) paralleled our functional observations five weeks after TAC surgery. In pressure overload-induced heart failure a CaMKII-dependent augmentation of INaL plays a crucial role in the AP prolongation and generation of cellular arrhythmogenic triggers, which cannot be found in early and still compensated hypertrophy. Inhibition of INaL and CaMKII exerts potent antiarrhythmic effects and might therefore be of potential therapeutic interest. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes".

Topics: Acetanilides; Action Potentials; Animals; Arrhythmias, Cardiac; Blood Pressure; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cardiomegaly; Cells, Cultured; Female; Heart Failure; Heart Ventricles; Mice; Mice, Inbred C57BL; NAV1.1 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Peptides; Piperazines; Ranolazine; Sodium; Sodium Channel Blockers; Tetrodotoxin

Dravet syndrome is a severe form of intractable pediatric epilepsy with a high incidence of SUDEP: Sudden Unexpected Death in epilepsy. Cardiac arrhythmias are a proposed cause for some cases of SUDEP, yet the susceptibility and potential mechanism of arrhythmogenesis in Dravet syndrome remain unknown. The majority of Dravet syndrome patients have de novo mutations in SCN1A, resulting in haploinsufficiency. We propose that, in addition to neuronal hyperexcitability, SCN1A haploinsufficiency alters cardiac electrical function and produces arrhythmias, providing a potential mechanism for SUDEP.. Postnatal day 15-21 heterozygous SCN1A-R1407X knock-in mice, expressing a human Dravet syndrome mutation, were used to investigate a possible cardiac phenotype. A combination of single cell electrophysiology and in vivo electrocardiogram (ECG) recordings were performed.. We observed a 2-fold increase in both transient and persistent Na(+) current density in isolated Dravet syndrome ventricular myocytes that resulted from increased activity of a tetrodotoxin-resistant Na(+) current, likely Nav1.5. Dravet syndrome myocytes exhibited increased excitability, action potential duration prolongation, and triggered activity. Continuous radiotelemetric ECG recordings showed QT prolongation, ventricular ectopic foci, idioventricular rhythms, beat-to-beat variability, ventricular fibrillation, and focal bradycardia. Spontaneous deaths were recorded in 2 DS mice, and a third became moribund and required euthanasia.. These data from single cell and whole animal experiments suggest that altered cardiac electrical function in Dravet syndrome may contribute to the susceptibility for arrhythmogenesis and SUDEP. These mechanistic insights may lead to critical risk assessment and intervention in human patients.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Cardiac Electrophysiology; Death, Sudden, Cardiac; Disease Models, Animal; Epilepsies, Myoclonic; Heart Rate; Humans; Ion Channel Gating; Mice; Mice, Inbred C57BL; Mutation; Myocytes, Cardiac; NAV1.5 Voltage-Gated Sodium Channel; Pentylenetetrazole; Protein Biosynthesis; Telemetry; Tetrodotoxin; Transcription, Genetic

Aconitine, well-known for its high cardiotoxicity, causes severe arrhythmias, such as ventricular tachycardia and ventricular fibrillation, by opening membrane sodium channels. Tetrodotoxin, a membrane sodium-channel blocker, is thought to antagonize aconitine activity. Tetrodotoxin is a potent blocker of the skeletal muscle sodium-channel isoform Na(v)1.4 (IC50 10 nM), but micromolar concentrations of tetrodotoxin are required to inhibit the primary cardiac isoform Na(v)1.5. This suggests that substantial concentrations of tetrodotoxin are required to alleviate the cardiac toxicity caused by aconitine. To elucidate the interaction between aconitine and tetrodotoxin in the cardiovascular and respiratory systems, mixtures of aconitine and tetrodotoxin were simultaneously administered to mice, and the effects on electrocardiograms, breathing rates, and arterial oxygen saturation were examined. Compared with mice treated with aconitine alone, some mice treated with aconitine-tetrodotoxin mixtures showed lower mortality rates and delayed appearance of arrhythmia. The decreased breathing rates and arterial oxygen saturation observed in mice receiving aconitine alone were alleviated in mice that survived after receiving the aconitine-tetrodotoxin mixture; this result suggests that tetrodotoxin is antagonistic to aconitine. When the tetrodotoxin dose is greater than the dose that can block tetrodotoxin-sensitive sodium channels, which are excessively activated by aconitine, tetrodotoxin toxicity becomes prominent, and the mortality rate increases because of the respiratory effects of tetrodotoxin. In terms of cardiotoxicity, mice receiving the aconitine-tetrodotoxin mixture showed minor and shorter periods of change on electrocardiography. This finding can be explained by the recent discovery of tetrodotoxin-sensitive sodium-channel cardiac isoforms (Na(v)1.1, 1.2, 1.3, 1.4 and 1.6).

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Biomarkers; Disease Models, Animal; Electrocardiography; Heart Rate; Male; Mice; Mice, Inbred ICR; Myocardium; Oxygen; Respiratory Rate; Sodium Channel Blockers; Tetrodotoxin; Time Factors; Voltage-Gated Sodium Channels

Many studies indicate that an increase in late sodium current (I(Na.L)) of cardiomyocytes causes intracellular Na overload and subsequently raises the reverse Na/Ca exchanger current (INCX), ultimately resulting in intracellular Ca overload. Therefore, using drugs to inhibit the increased INa.L under various pathological conditions can lower intracellular Ca overload. This study was intended to explore the effect of sophocarpine (SOP) on the increase in INa.L, INCX, calcium transient and contraction in rabbit ventricular myocytes induced by Anemonia sulcata toxin II (ATX II), an opener of sodium channel, with the application of whole-cell patch-clamp techniques, the video-based motion edge detection system, and the intracellular calcium concentration determination system. The results indicate that tetrodotoxin (TTX, 4 μM ) obviously decreased INa.L and INCX enlarged by ATX II (30 nM), and SOP (20, 40, and 80 μM) also inhibited both the parameters concentration dependently in rabbit ventricular myocytes. However, transient sodium current remained unaffected by the above-mentioned concentrations of ATX II, TTX, and SOP. In addition, SOP also reversed diastolic calcium concentration, calcium transient amplitude, and ventricular muscle contractility augmented by ATX II. Its effects were similar to those of TTX, a specific inhibitor of the sodium channel. In conclusion, SOP inhibits INa.L, INCX, diastolic Ca concentration, and contractility in rabbit ventricular myocytes, which suggests that relief of intracellular Ca overload through inhibiting INa.L is likely to become a new therapeutic mechanism of SOP against arrhythmia and myocyte damage associated with intracellular Ca overload.

Topics: Alkaloids; Animals; Arrhythmias, Cardiac; Calcium; Cnidarian Venoms; Dose-Response Relationship, Drug; Female; Heart Ventricles; Male; Myocardial Contraction; Myocytes, Cardiac; Patch-Clamp Techniques; Rabbits; Sodium; Sodium Channels; Sodium-Calcium Exchanger; Tetrodotoxin

Resveratrol has been demonstrated to be protective in the cardiovascular system. The aim of this study was to assess the effects of resveratrol on hydrogen peroxide (H(2)O(2))-induced increase in late sodium current (I(Na.L)) which augmented the reverse Na(+)-Ca(2+) exchanger current (I(NCX)), and the diastolic intracellular Ca(2+) concentration in ventricular myocytes.. I(Na.L), I(NCX,) L-type Ca(2+) current (I(Ca.L)) and intracellular Ca(2+) properties were determined using whole-cell patch-clamp techniques and dual-excitation fluorescence photomultiplier system (IonOptix), respectively, in rabbit ventricular myocytes.. Resveratrol (10, 20, 40 and 80 µM) decreased I(Na.L) in myocytes both in the absence and presence of H(2)O(2) (300 µM) in a concentration dependent manner. Ranolazine (3-9 µM) and tetrodotoxin (TTX, 4 µM), I(Na.L) inhibitors, decreased I(Na.L) in cardiomyocytes in the presence of 300 µM H(2)O(2). H(2)O(2) (300 µM) increased the reverse I(NCX) and this increase was significantly attenuated by either 20 µM resveratrol or 4 µM ranolazine or 4 µM TTX. In addition, 10 µM resveratrol and 2 µM TTX significantly depressed the increase by 150 µM H(2)O(2) of the diastolic intracellular Ca(2+) fura-2 fluorescence intensity (FFI), fura-fluorescence intensity change (△FFI), maximal velocity of intracellular Ca(2+) transient rise and decay. As expected, 2 µM TTX had no effect on I(Ca.L).. Resveratrol protects the cardiomyocytes by inhibiting the H(2)O(2)-induced augmentation of I(Na.L.)and may contribute to the reduction of ischemia-induced lethal arrhythmias.

Topics: Acetanilides; Animals; Antioxidants; Arrhythmias, Cardiac; Calcium; Diastole; Dose-Response Relationship, Drug; Electrophysiology; Female; Heart Ventricles; Hydrogen Peroxide; Ischemia; Male; Muscle Cells; Patch-Clamp Techniques; Piperazines; Rabbits; Ranolazine; Resveratrol; Sodium; Stilbenes; Temperature; Tetrodotoxin

Left ventricular hypertrophy (LVH) is frequently associated with clinical atrial arrhythmias, but little is known about how it causes those arrhythmias. Our previous studies have shown that LVH increases the late sodium current (I(Na-L)) that plays an important role in the genesis of ventricular arrhythmias. We hypothesize that LVH may also induce an upregulation of the I(Na-L) in atrial myocytes, leading to atrial electrical abnormalities. The renovascular hypertension model was used to induce LVH in rabbits. Action potential and membrane current recordings were performed in single myocytes. At a pacing cycle length of 2,000 ms, spontaneous phase-2 early afterdepolarizations (EADs) could be recorded from the left atrial myocytes in 10 of 12 LVH rabbits, whereas no EADs could be elicited in right atrial myocytes of LVH rabbits or atrial myocytes from any of the 12 control rabbits. Spontaneous automaticity (SA) from left atrial myocytes was observed in 9 out of 12 LVH rabbits, but none in right atrial myocytes of LVH rabbits or control rabbits, at a pacing rate of 8,000 ms. The left atrial myocytes of LVH rabbits had a significantly higher density of the I(Na-L) compared with those of control rabbits (0.90 +/- 0.12 in LVH vs. 0.50 +/- 0.08 pA/pF in control, n = 8, P < 0.01). Tetrodotoxin, an I(Na-L) blocker, abolished all atrial EADs and SA at 10 microM. Our results demonstrate that LVH induction results in a significant increase of I(Na-L) in the left atrial myocytes that may render these cells susceptible to the genesis of EADs and SA. The I(Na-L) may serve as a potentially useful ionic target for antiarrhythmic drugs for the treatment of atrial arrhythmias in the setting of LVH.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Calcium Channel Blockers; Cell Separation; Electrophysiology; Heart Atria; Hypertrophy, Left Ventricular; In Vitro Techniques; Male; Membrane Potentials; Myocytes, Cardiac; Organ Size; Rabbits; Ryanodine; Sodium Channel Blockers; Sodium Channels; Tetrodotoxin

Reentrant arrhythmias often develop in the setting of myocardial infarction and ensuing slow propagation. Increased Na(+) channel expression could prevent or disrupt reentrant circuits by speeding conduction if channel availability is not limited by membrane depolarization within the diseased myocardium. We therefore asked if, in the setting of membrane depolarization, action potential (AP) upstroke and normal conduction can be better preserved by the expression of a Na(+) channel isoform with altered biophysical properties compared to the native cardiac Na(+) channel isoform, namely having a positively shifted, voltage-dependent inactivation.. The skeletal Na(+) channel isoform (SkM1) and the cardiac Na(+) channel isoform (Nav1.5) were expressed in newborn rat ventricular myocyte cultures with a point mutation introduced in Nav1.5 to increase tetrodotoxin (TTX) sensitivity so native and expressed currents could be distinguished. External K(+) was increased from 5.4 to 10 mmol/L to induce membrane depolarization. APs, Na(+) currents, and conduction velocity (CV) were measured. In control cultures, elevated K(+) significantly reduced AP upstroke ( approximately 75%) and CV ( approximately 25%). Expression of Nav1.5 did not protect AP upstroke from K(+) depolarization. In contrast, in SkM1 expressing cultures, high K(+) reduced AP upstroke <50% and conduction was not significantly reduced. In a simulated anatomical reentry setting (using a void), the angular velocity (AV) of induced reentry was faster and the excitable gap shorter in SkM1 cultures compared to control for both normal and high K(+).. Expression of SkM1 but not Nav1.5 preserves AP upstroke and CV in a K(+)-depolarized syncytium. The higher AV and shorter excitable gap observed during reentry excitation around a void in SkM1 cultures would be expected to facilitate reentry self-termination. SkM1 Na(+) channel expression represents a novel gene therapy for the treatment of reentrant arrhythmias.

Topics: Action Potentials; Animals; Animals, Newborn; Arrhythmias, Cardiac; Cells, Cultured; Gene Transfer Techniques; Genetic Therapy; Heart Ventricles; Humans; Muscle Proteins; Muscle, Skeletal; Mutagenesis, Site-Directed; Myocytes, Cardiac; NAV1.5 Voltage-Gated Sodium Channel; Point Mutation; Potassium; Rats; Sodium Channel Blockers; Sodium Channels; Tetrodotoxin; Time Factors

A voltage-gated calcium channel containing Cav2.3e (alpha1Ee) as the ion conducting pore has recently been detected in rat heart. Functional evidence for this Ca2+ channel to be involved in the regulation of heart beating, besides L- and T-type channels, was derived from murine embryos where the gene for Cav1.2 had been ablated. The remaining "L-type like" current component was not related to recombinant splice variants of Cav1.3 containing channels. As recombinant Cav2.3 channels from rat were reported to be weakly dihydropyridine sensitive, the spontaneous activity of the prenatal hearts from Cav2.3(-|-) mice was compared to that of Cav2.3(+|+) control animals to investigate if Cav2.3 could represent such a L-type like Ca(2+) channel. The spontaneous activity of murine embryonic hearts was recorded by using a multielectrode array. Between day 9.5 p.c. to 12.5 p.c., the beating frequency of isolated embryonic hearts from Cav2.3-deficient mice did not differ significantly from control mice but the coefficient of variation within individual episodes was more than four-fold increased in Cav2.3-deficient mice indicating arrhythmia. In isolated hearts from wild type mice, arrhythmia was induced by superfusion with a solution containing 200 nM SNX-482, a blocker of some R-type voltage gated Ca2+ channels, suggesting that R-type channels containing the splice variant Cav2.3e as ion conducting pore stabilize a more regular heart beat in prenatal mice.

Topics: Alternative Splicing; Animals; Arrhythmias, Cardiac; Calcium Channel Blockers; Calcium Channels; Calcium Channels, L-Type; Calcium Channels, R-Type; Cation Transport Proteins; Heart; In Vitro Techniques; Isradipine; Mice; Mice, Knockout; Patch-Clamp Techniques; Protein Subunits; Sodium Channel Blockers; Spider Venoms; Tetrodotoxin

Variant 3 of the congenital long-QT syndrome (LQTS-3) is caused by mutations in the gene encoding the alpha subunit of the cardiac Na(+) channel. In the present study, we report a novel LQTS-3 mutation, E1295K (EK), and describe its functional consequences when expressed in HEK293 cells. The clinical phenotype of the proband indicated QT interval prolongation in the absence of T-wave morphological abnormalities and a steep QT/R-R relationship, consistent with an LQTS-3 lesion. However, biophysical analysis of mutant channels indicates that the EK mutation changes channel activity in a manner that is distinct from previously investigated LQTS-3 mutations. The EK mutation causes significant positive shifts in the half-maximal voltage (V(1/2)) of steady-state inactivation and activation (+5.2 and +3.4 mV, respectively). These gating changes shift the window of voltages over which Na(+) channels do not completely inactivate without altering the magnitude of these currents. The change in voltage dependence of window currents suggests that this alteration in the voltage dependence of Na(+) channel gating may cause marked changes in action potential duration because of the unique voltage-dependent rectifying properties of cardiac K(+) channels that underlie the plateau and terminal repolarization phases of the action potential. Na(+) channel window current is likely to have a greater effect on net membrane current at more positive potentials (EK channels) where total K(+) channel conductance is low than at more negative potentials (wild-type channels), where total K(+) channel conductance is high. These findings suggest a fundamentally distinct mechanism of arrhythmogenesis for congenital LQTS-3.

Topics: Adolescent; Amino Acid Substitution; Arrhythmias, Cardiac; Cell Line; Conserved Sequence; DNA Mutational Analysis; Electrocardiography; Heart; Humans; Ion Channel Gating; Kidney; Long QT Syndrome; Male; Mutation; NAV1.5 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Phenotype; Sodium; Sodium Channels; Tetrodotoxin; Transfection

Left ventricular remodeling after myocardial infarction is accompanied by electrical abnormalities that might predispose to rhythm disturbances. To get insight into the ionic mechanisms involved, we studied myocytes isolated from four different regions of the rat ventricles, 4-6 months after ligation of the left coronary artery. Using the whole-cell patch-clamp technique, we never observed T-type Ca(2+)current in both diseased and control hearts. In contrast, in 41 out of 78 cells isolated from 16 post-myocardial infarcted rats, analysed in the presence of 30 m m Na(+)ions, we found a tetrodotoxin (TTX)-resistant Na(+)current with quite variable amplitude in every investigated region. Albeit being resistant to 100 microM TTX, this Na(+)-dependent current was highly sensitive to lidocaine since 3 microM lidocaine induced about 65% tonic block. It was also inhibited by 5 microM nifedipine and 2 m m Co(2+), but was insensitive to 100 microM Ni(2+). The TTX-resistant Na(+)channel availability was shifted rightward by 25-30 mV with respect to TTX-sensitive Na(+)current; therefore, a large "window current" might flow in the voltage range from -70 to -20 mV. In conclusion, in late post-myocardial infarction, a Na(+)current with specific kinetics and pharmacology may provide inward charges in a critical range of membrane voltages that are able to alter action potential time course and trigger ventricular arrhythmia. These apparent new characteristics of the Na(+)channel might result in part from environmental changes during heart remodeling.

Topics: Animals; Arrhythmias, Cardiac; Cells, Cultured; Ions; Kinetics; Male; Myocardial Infarction; Myocardium; Patch-Clamp Techniques; Rats; Rats, Wistar; Sodium; Tetrodotoxin; Time Factors

Pulmonary veins are important foci of ectopic beats to initiate paroxysmal atrial fibrillation. The purpose of this study were to investigate the electrophysiological characteristics of excitable cells in canine pulmonary veins obtained from healthy and chronic rapid atrial pacing dogs and their responses to cardioactive agents.. Transmembrane action potentials (APs) were recorded from multiple sites of pulmonary veins isolated from 17 healthy dogs and 14 dogs with chronic (6-8 weeks) rapid atrial pacing (780 bpm).. In normal superfusate, several types of electrical activities were identified, including silent electrical activity, fast response APs driven by electrical stimulation, and spontaneous fast or slow response APs (with or without early afterdepolarizations). The incidences of AP with an early afterdepolarization (93% versus 41%) was greater in chronic pacing dogs. The spontaneous activities were depressed by beta-adrenoceptor blocker, calcium channel blocker, adenosine and acetylcholine. High frequency (>8 Hz) irregular rhythms occurred spontaneously or were induced by cardioactive agents or electrical stimuli. The incidence of spontaneously occurring tachyarrhythmias was much higher in preparations from chronic pacing dogs (93%) than from control (12%). The tachyarrhythmias were suppressed by sodium channel blocker, potassium channel blocker or magnesium.. Pulmonary veins have arrhythmogenic ability through spontaneous activities or high-frequency irregular rhythms. The higher incidence of spontaneously occurring high-frequency irregular rhythms in chronic rapid atrial pacing dogs may account for the increased risk of atrial fibrillation in these dogs.

Topics: Acetylcholine; Action Potentials; Adenosine; Adrenergic beta-Antagonists; Animals; Arrhythmias, Cardiac; Atrial Fibrillation; Calcium Channel Blockers; Cardiac Pacing, Artificial; Dogs; Isoproterenol; Muscle, Smooth, Vascular; Myocardium; Potassium Channel Blockers; Propranolol; Pulmonary Veins; Sodium Channels; Sotalol; Tetrodotoxin

Because the role of sodium channels in the initiation and maintenance of VF is not fully elucidated, we studied the significance of sodium channel activity in VF using sodium channel blockers. In nonischemic isolated feline hearts, the following electrophysiologic parameters were measured before and after application of tetrodotoxin (5 x 10(-7) M, n = 6) or lidocaine (1 x 10(-5) M, n = 8): (a) during pacing, epicardial conduction time; refractoriness; the fastest rate for 1:1 pacing/response capture, and all tissue resistivity, indirectly reflecting intercellular electrical resistance; (b) during 8 min of electrically induced tachyarrhythmias, all tissue resistivity; peak frequency (to measure average frequency based on fast-Fourier transformation analysis); and normalized entropy (to measure the degree of arrhythmia organization). In nonischemic isolated rabbit hearts (n = 4), three-dimensional mapping was performed before and after application of lidocaine (1 x 10(-5) M). In feline hearts, lidocaine and tetrodotoxin application resulted in: (a) more spontaneous arrhythmia termination (63-67%) than in nontreated hearts (7%); (b) transformation from mainly VF into ventricular tachycardia with increased organization; and (c) prolongation of conduction time (155-248%) (p < 0.01 for all parameters). The ventricular refractory period was slightly prolonged by tetrodotoxin in the right ventricle and exhibited rate-dependent shortening in control and with lidocaine. Tetrodotoxin and lidocaine reduced the pacing rate for 1:1 pacing/response capture, and all tissue resistivity was not significantly affected. Peak frequency was decreased by tetrodotoxin and lidocaine mainly in the left ventricle (p < 0.01). In nontreated left ventricles, peak frequency was increased over time but was attenuated by lidocaine. In isolated rabbit hearts, several simultaneous wave fronts were detected during VF in nontreated hearts and were reduced to only one or two major wavefronts after application of lidocaine. Suppression of sodium channel activity that primarily slowed conduction time and had little or no effect on ventricular refractory period and all tissue resistivity resulted in less stable and more organized arrhythmias and reduced tachyarrhythmia rate compared with nontreated hearts. These results suggest an active role for sodium channels in the maintenance of ventricular fibrillation.

Topics: Anesthetics, Local; Animals; Arrhythmias, Cardiac; Cats; Echocardiography, Three-Dimensional; Electrocardiography; Electrophysiology; Female; Fourier Analysis; Heart; Heart Conduction System; In Vitro Techniques; Lidocaine; Male; Models, Biological; Rabbits; Sodium Channels; Tetrodotoxin; Ventricular Fibrillation

Topics: Adult; Animals; Arrhythmias, Cardiac; Diagnosis, Differential; Electrocardiography; Foodborne Diseases; Humans; Japan; Male; Takifugu; Tetrodotoxin

Effects of various agents on reoxygenation-induced arrhythmias, action potentials, and tension of guinea pig papillary muscles were recorded to investigate the site of action. Triggered activities due to delayed afterdepolarizations (DADs) and aftercontractions were elicited on reoxygenation after 60-min substrate-free hypoxia. Low extracellular Ca2+ (0.1 mM) abolished arrhythmias, and high Ca2+ (4.9 mM) increased the amplitudes of DADs and aftercontractions. D-600 at the high concentration (20 microM) decreased the incidence of arrhythmias (p < 0.05 vs. no drug) and decreased the recovery of developed tension after reoxygenation (p < 0.001). Ryanodine (1 microM) abolished aftercontractions and arrhythmias but did not affect the recovery of developed tension. Tetrodotoxin (TTX 3 microM) and nicorandil (100 microM) decreased the incidence of arrhythmias (p < 0.05), but did not affect the recovery of developed tension or the amplitudes of aftercontractions. TTX caused only a slight decrease in Ca2+ transients in a fluo-3-loaded guinea pig ventricular myocyte. The Ca2+ entry through the Ca2+ channels apparently synchronized Ca2+ release from the sarcoplasmic reticulum, and D-600 at the high concentration apparently decreased the incidence of arrhythmias. TTX and nicorandil decreased arrhythmias, probably by decreasing the Na+ current or by increasing the ATP-sensitive K+ current, respectively.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium; Gallopamil; Guinea Pigs; In Vitro Techniques; Myocardial Reperfusion Injury; Niacinamide; Nicorandil; Papillary Muscles; Tetrodotoxin

Both ischemia and reperfusion are associated with ventricular arrhythmias. In both instances, neutrophils migrate into the ischemic zone, are activated by locally released factors, and bind to myocytes. The activated neutrophils liberate platelet activating factor (PAF). We have studied the arrhythmogenic actions of PAF on transmembrane potentials of isolated canine cardiac myocytes.. Cardiac myocytes were prepared from normal canine hearts by standard methods and studied in vitro by recording transmembrane potentials under control conditions and during exposure to graded doses of PAF, usually 0.25 to 1.25 micrograms (0.25 to 1.2 microM). Myocytes were superfused with Tyrode's solution (2.0 mL/min), paced at a cycle length of 1000 msec, and maintained at a temperature between 36 degrees and 38 degrees C. PAF caused a consistent and dose-dependent set of alterations in the transmembrane potential, including increased action potential duration, runs of early afterdepolarizations (EADs), and transient arrest of repolarization (PA). In addition, in some myocytes PAF caused intermittent small depolarizations both at the plateau voltage and resting potential. The effects of PAF were transient: only some residual action potential prolongation was noted after Tyrode's washout for 5 minutes. Effects of PAF were blocked in a dose-dependent manner by the PAF receptor antagonist, CV-6209. Both tetrodotoxin (1.2 x 10(-6) M) and xylocaine (5 x 10(-5) M) antagonized the ability of PAF to cause EADs and PA.. PAF consistently exerts arrhythmogenic effects on the membrane of ventricular myocytes. Since PAF is liberated by activated neutrophils and since activated neutrophils migrate into ischemic myocardium on reperfusion, we judge that PAF liberated by such neutrophils is an important arrhythmogenic factor for reperfusion arrhythmias. The same mechanism may be a cause of arrhythmias during the evolution of infarction.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dogs; Dose-Response Relationship, Drug; Female; Lidocaine; Male; Membrane Potentials; Patch-Clamp Techniques; Platelet Activating Factor; Platelet Membrane Glycoproteins; Pyridinium Compounds; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Tetrodotoxin

The aim was to examine under abnormal conditions the flow of currents across junctional (J-) cells found between Purkinje fibre cells and ventricular muscle cells, and determine whether these currents play a role in increasing the excitation rate of ventricular muscle.. Canine Purkinje fibre and papillary muscle preparations were mapped to locate the Purkinje fibre-ventricular muscle cell junction (PVJ). Using standard techniques, action potentials from Purkinje fibres, J-cells, and ventricular muscle cells and extracellular electrograms were simultaneously recorded at the PVJ. The tissue was then superfused with Tyrode solution plus 4.5-5.0 mmol of ethylenediamine tetra-acetate (EDTA).. EDTA prolonged the action potential duration mainly in Purkinje fibres. Secondary plateaus were recorded at membrane potentials of -63.5(SD 7.6) mV (n = 16) in J-cells, and at membrane potentials of -74.9(4.3) mV (n = 9) in ventricular muscle cells. Triggered activations appeared on both secondary plateaus with the earliest site of activation at J-cells (n = 12), at ventricular muscle cells (n = 4), or in both (n = 6). Tetrodotoxin (3-9 x 10(-7) M) and verapamil (1 x 10(-6)-10(-5) M) suppressed triggered activations.. The PVJ zone appears to be an important site for the generation of triggered activations. Interventions suggest that triggered activations originating in the J-cell depend on delayed repolarisations which trigger the activation of sodium and/or calcium channels.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Dogs; Edetic Acid; Female; Heart Ventricles; Lidocaine; Male; Membrane Potentials; Myocardium; Purkinje Fibers; Tetrodotoxin; Verapamil

Cooling induces electromechanical changes in the heart. The aim of the study was to examine how the calcium channel blocker, nisoldipine (NIS), altered these changes compared to those induced by other drugs that shorten action potential duration such as tetrodotoxin and nicorandil.. Guinea pig papillary muscle action potentials and developed force were recorded using the conventional microelectrode technique and a force transducer. Restitution of action potential duration was determined by introducing extrastimuli at progressively longer diastolic intervals from 40 to 9000 ms. Preparations were divided into four groups: (1) no drug (control); (2) 1 microM tetrodotoxin, a sodium channel blocker; (3) 1 mM nicorandil, an ATP sensitive potassium channel activator; and (4) 1 microM nisoldipine (n = 6 in each group). Action potential duration and developed force were recorded after addition of drug at 37 degrees C, and at each 1 degree C change in temperature during cooling to 27 degrees C. The restitution protocol was performed at 37 degrees C and 27 degrees C.. Tetrodotoxin had no effect on action potential duration at 90% of repolarisation (APD90) while nisoldipine and nicorandil greatly shortened APD90. Cooling from 37 degrees to 27 degrees C with nisoldipine produced less hypothermia induced lengthening in APD90 than in the other group. Developed force did not increase with reduction in temperature in the presence of nisoldipine. The range of premature action potential durations was defined as the difference in APD90 at diastolic interval of 40 and 100 ms. This range decreased with nisoldipine in contrast to the marked increases that occurred in the other groups during cooling.. Increased intracellular Ca2+ might be responsible for the hypothermia induced increase in APD90, developed force, and range of premature action potential durations, since calcium channel blockade, which prevents an increase in intracellular Ca2+, greatly reduced these changes. The reduced range of premature action potential durations may reduce dispersion of ventricular refractoriness, and hence be expected to decrease hypothermia induced arrhythmias.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Calcium; Calcium Channel Blockers; Cold Temperature; Guinea Pigs; Heart; Niacinamide; Nicorandil; Nisoldipine; Tetrodotoxin; Time Factors; Vasodilator Agents

1. Effects of caffeine on the automaticity in spontaneously beating rabbit sino-atrial node cells were examined. 2. Caffeine (0.5-2 mM) caused only a positive chronotropic effect. At over 5 mM, caffeine caused an initial positive and subsequently a negative chronotropic effect. Both were not modified by pindolol (1 microM) and atropine (1 microM). 3. At 10 mM, a dysrhythmia occurred in all 9 preparations. The effects were reversible, and dysrhythmia also disappeared after washout. 4. When extracellular K+ was increased from 2.7 to 8 mM, the dysrhythmia induced by caffeine (10 mM) was abolished, and the sinus rate was increased. 5. Addition of tetrodotoxin (TTX) (10(-7) M) in the presence of caffeine (10 mM) also abolished the dysrhythmia and increased the sinus rate. 6. In addition, a decrease in extracellular Ca2+ ([Ca]o) to 0.5 mM abolished the dysrhythmia and increased the sinus rate, whereas increasing [Ca]o to 7.4 mM potentiated the negative chronotropic effect and failed to inhibit the dysrhythmia. 7. These results indicate that the positive chronotropic effect is due to the stimulatory effect of caffeine, and the negative effect is directly and indirectly due to development of cellular calcium overload.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Biological Clocks; Caffeine; Calcium; Heart Rate; In Vitro Techniques; Potassium; Rabbits; Sinoatrial Node; Tetrodotoxin

Several studies have suggested a central role for Na+/Ca2+ in the pathogenesis of ouabain-induced cardiac arrhythmias. To test this hypothesis, the effects on ouabain-induced arrhythmias of i.v. pretreatment with R 56,865, a Na+ and Ca2+ overload inhibitor, were compared with those of lidocaine, verapamil and tetrodotoxin in anesthetized guinea-pigs. Cardiac arrhythmias were induced by i.v. infusion of ouabain (10 micrograms/kg per min). All nine guinea-pigs pretreated with saline developed ventricular premature beats at an ouabain dose of 159 +/- 9 micrograms/kg (mean +/- S.E.M.), ventricular tachycardia at a dose of 190 +/- 10 micrograms/kg, ventricular fibrillation at a dose of 253 +/- 18 micrograms/kg and died at a dose of 269 +/- 16 micrograms/kg; none of the animals developed heart block or asystole. Pretreatment with R 56,865 (1.25 mg/kg, n = 6) significantly increased the ouabain doses required to induce ventricular premature beats, ventricular tachycardia, ventricular fibrillation and death relative to those for the saline group. Pretreatment with a Ca2+ entry blocker verapamil (0.32 mg/kg, n = 6) also significantly increased the ouabain doses required to provoke ventricular arrhythmias and death; this medication was associated with second or third degree heart block during ouabain infusion in four out of six animals. Pretreatment with lidocaine (10 mg/kg, n = 6) caused a significant increase in the dose of ouabain needed to initiate cardiac arrhythmias and to cause death. Pretreatment with a selective Na+ channel blocker tetrodotoxin (4 micrograms/kg, n = 6) also significantly increased the ouabain doses required to provoke ventricular premature beats, ventricular tachycardia, ventricular fibrillation, and death.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arrhythmias, Cardiac; Benzothiazoles; Blood Pressure; Calcium; Electrocardiography; Guinea Pigs; Heart Rate; Lidocaine; Male; Ouabain; Piperidines; Sodium; Tetrodotoxin; Thiazoles; Verapamil

Early afterdepolarizations (EADs) are a type of triggered activity found in heart muscle. We used voltage-clamped sheep cardiac Purkinje fibers to examine the mechanism underlying EADs induced near action potential plateau voltages with the Ca2+ current agonist Bay K 8644 and the effect of several interventions known to suppress or enhance these EADs. Bay K 8644 produced an inward shift of the steady-state current-voltage relation near plateau voltages. Tetrodotoxin, lidocaine, verapamil, nitrendipine, and raising [K]o abolish EADs and shift the steady-state current-voltage relations outwardly. Using a two-pulse voltage-clamp protocol, an inward current transient was present at voltages where EADs were induced. The voltage-dependence of availability of the inward current transient and of EAD induction were similar. The time-dependence of recovery from inactivation of the inward current transient and of EAD amplitude were nearly identical. Without recovery of the inward current transient, EADs could not be elicited. The inward current transient was enhanced with Bay K 8644 and blocked by nitrendipine, but was not abolished by tetrodotoxin or replacement of [Na]o with an impermeant cation. These results support a hypothesis that the induction of EADs near action potential plateau voltages requires 1) a conditioning phase controlled by the sum of membrane currents present near the action potential plateau and characterized by lengthening and flattening of the plateau within a voltage range where, 2) recovery from inactivation and reactivation of L-type Ca2+ channels to carry the depolarizing charge can occur. Our results suggest an essential role for the L-type Ca2+ "window" current and provide a framework for understanding the role of several membrane currents in the induction and block of EADs.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Action Potentials; Animals; Arrhythmias, Cardiac; Calcium; Calcium Channels; Heart Conduction System; Nitrendipine; Purkinje Fibers; Sheep; Tetrodotoxin

Ciguatoxin, the toxin present in fish responsible for ciguatera, at doses equal or above the maximum positive inotropic dose in atria (greater than 0.15 mouse units/ml) induced arrhythmias in atria and papillary muscles stimulated at 1 Hz and dose-dependent negative inotropy in atria. Negative inotropy was enhanced by ouabain or by an increase in stimulation to 3 Hz, little affected by procaine or increasing Ringer [Ca2+] and reversed by lidocaine and tetrodotoxin (TTX). Ciguatoxin caused negative inotropy associated with cell depolarisation in 1.2 mM Ca2+-Ringer and additionally caused signs of Ca overload in 3.2 mM Ca2+-Ringer. Ciguatoxin induced transient after-contractions and contracture in atria which were common in 3.2 mM but not 1.2 mM Ca2+-Ringer and which were enhanced by ouabain. TTX and lidocaine abolished after-contractions and contracture while procaine was less effective. Extrasystoles consisting of short bursts of 1-2 extra contractions per sec were seen in atria and papillary muscles within 45 min of ciguatoxin being added. The effect was observed in 3.2 mM but seldom in 1.2 mM Ca2+-Ringer and was absent when low doses of propranolol or TTX were added prior to ciguatoxin. Flutter was observed in a few papillary muscles after ciguatoxin. These results suggest that the toxic effects of ciguatoxin stem from its direct action of opening myocardial Na+ channels. Extrasystoles appeared to result mainly from its effect on neural Na+ channels causing an increased release of noradrenaline from the nerves associated with the myocardium.

Topics: Animals; Arrhythmias, Cardiac; Calcium; Cardiac Complexes, Premature; Ciguatoxins; Depression, Chemical; Dose-Response Relationship, Drug; Female; Guinea Pigs; In Vitro Techniques; Lidocaine; Male; Marine Toxins; Membrane Potentials; Myocardial Contraction; Papillary Muscles; Sodium Channels; Tetrodotoxin

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Vessels; Heart Rate; Hexamethonium; Hexamethonium Compounds; Ion Channels; Nitroprusside; Rats; Reference Values; Sodium; Tetrodotoxin

Aconitine will induce arrhythmias after the fiber has been completely repolarized. This arrhythmia is generally facilitated in the presence of high Ca2+ solution, yet the aconitine-induced arrhythmia occurs even in the presence of low Ca2+ solutions. We studied aconitine-induced arrhythmia (particularly the amplitude of delayed afterdepolarization) in the frog atrium or guinea-pig papillary muscles in Ca2+-free solution, in the presence or absence of Ca2+ channel blocking agents. In Ca2+-free solution, aconitine (10(-5) g/ml) decreased the resting potential, overshoot, Vmax, and shortened the duration of the 90% action potential, before the onset of delayed afterdepolarization in frog atrial preparations. Tetrodotoxin (TTX) (2 X 10(-7) g/ml) blocked these aconitine-induced electrical changes. Verapamil (10(-6) g/ml) in nominally Ca2+-free solution blocked neither the generation of delayed afterdepolarization nor the triggered activity, while LaCl3 (0.5 mM) or TTX halted it. Delayed afterdepolarization appeared following the aconitine-induced transient increase in twitch tension. This transient increase in twitch tension was blocked by LaCl3 and TTX but not by verapamil. Delayed afterdepolarization in Ca2+-free solution demonstrated the voltage dependence of a U shape between -40 and -80 mV and was inhibited by low Na+ and high K+. Under the influence of aconitine in the guinea pig papillary muscle exposed to the Ca2+-free solution, depolarizing clamp pulses produced a transient inward current, and here the sigmoid time- and voltage-dependent characteristics were similar to those seen in the case of digitalis intoxication. These results suggest that intracellular Na+ loading plays an important role in the aconitine-induced delayed afterdepolarization and transient inward currents in low Ca2+ solution.

Topics: Aconitine; Aconitum; Action Potentials; Animals; Arrhythmias, Cardiac; Calcium; Calcium Channel Blockers; Guinea Pigs; Heart; Heart Atria; Membrane Potentials; Myocardium; Rana catesbeiana; Tetrodotoxin

This paper describes the interaction of several polypeptide neurotoxins isolated from sea anemone toxins and scorpion venom with the tetrodotoxin-resistant Na+ channel of rat cardiac cells. The 22Na+ flux and tension development were measured to examine in parallel the cardiotonic and cardiotoxic effects of these polypeptides. Inotropic effects and arrhythmias were seen in the concentration range in which an action of the toxins on the Na+ channel was observed. The maximal inotropic effect was systematically observed at toxin concentrations below the concentration value observed for half-maximal stimulation of 22Na+ flux through the Na+ channel. Arrhythmias began at concentrations near the value for half-maximal stimulation of 22Na+ flux by the toxins. Toxins extracted from the sea anemones Anemonia sulcata and Anthopleura xanthogrammica were more active than scorpion toxins and sea anemone Radianthus paumotensis toxins. The most interesting among all the toxins tested for potential use in cardiotherapy was toxin II from Anthopleura xanthogrammica.

Topics: Animals; Arrhythmias, Cardiac; Cells, Cultured; Cnidarian Venoms; In Vitro Techniques; Ion Channels; Myocardial Contraction; Myocardium; Neurotoxins; Rats; Scorpion Venoms; Sea Anemones; Tetrodotoxin

Microelectrode techniques were used to study the electrophysiological properties of pacemaker fibers in isolated atrioventricular valves of the rabbit heart. In spontaneously beating tricuspid and mitral valve preparations superfused with normal Tyrode solution, leading pacemaker activity was generated by fibers located on the valve leaflet. Impulse conduction from the automatic focus to atrial myocardium was slow, and in approximately 50% of preparations, exit block occurred. Valve pacemaker fibers had significantly different action potential characteristics compared with the primary pacemaker cells of the sinoatrial node. However, the activity of both pacemaker types was largely insensitive to tetrodotoxin but readily suppressed by verapamil. Endogenous neurotransmitters, released from postganglionic nerve endings in the vicinity of valve pacemaker fibers, exerted profound chrono- and dromotropic effects. Brief cholinergic stimuli strongly influenced valve pacemaker cycle length in a phase-dependent manner, qualitatively similar to that in the sinoatrial node. During overdrive of valve pacemaker fibers with external bipolar stimuli, locally released neurotransmitters modified automaticity and conduction which, under certain conditions, favored pacemaker escape. These data demonstrate that the atrioventricular valve leaflets contain cardiac fibers capable of generating spontaneous impulses and that intrinsic autonomic nerves may play a role in precipitating premature extrasystoles.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Electrophysiology; Epinephrine; Heart Conduction System; Heart Valves; Nerve Fibers; Neurotransmitter Agents; Rabbits; Sinoatrial Node; Tetrodotoxin; Verapamil

Intracellular recordings were obtained from spheroidal aggregates of 7-day embryonic chick heart cells after 3 days in gyratory culture. Three types of perturbations in the membrane potential were observed under experimental conditions expected to increase intracellular calcium: 1) multiple oscillations (of 5-20 mV peak-to-peak amplitude) during diastole in aggregates exposed to 10-15 mM Ca, 5 microM strophanthidin, or K-free solutions; 2) less periodic spontaneous voltage fluctuations (of less than 1.5 mV peak-to-peak amplitude) in aggregates exposed to solutions containing 22% of the normal [Na], and 3) depolarizing afterpotentials (DAPs), following repolarization of the action potential, in aggregates treated with 20-50 microM A23187, a Ca ionophore, or 5-10 mM caffeine. The oscillations were reduced markedly by 0.03-3.0 microM tetrodotoxin (TTX) and were blocked by 5-10 mM caffeine. Spontaneous voltage fluctuations were increased by raising external Ca, were unaffected by 30 microM TTX, and were blocked by 5 mM caffeine. DAPs were not blocked by 5 mM caffeine or by 0.1 microM TTX and 1 microgram/ml D 600, concentrations that greatly reduced the action potential upstroke velocity and plateau, respectively. Two intracellular electrodes were employed to test for electrotonic coupling between cells within an aggregate. An electrotonic response in one cell could be recorded when current was injected into another cell during recordings of each of the perturbations but was somewhat less during spontaneous voltage fluctuations. Possible ionic mechanisms for the perturbations and for concomitant changes in the configuration of the action potential are discussed.

Topics: Animals; Arrhythmias, Cardiac; Caffeine; Calcimycin; Calcium; Cells, Cultured; Chick Embryo; Diastole; Electrophysiology; Gallopamil; Heart; Ion Channels; Membrane Potentials; Myocardium; Sodium; Strophanthidin; Tetrodotoxin

Brevetoxin-B (GbTX-B), a cyclic polyether purified from the marine dinoflagellate Gymnodinium breve, produced positive inotropic and arrhythmogenic effects on isolated rat and guinea pig cardiac preparations at concentrations between 1.25 X 10(-8) and 1.87 X 10(-7) M. The toxin (10(-7) M) transiently increased left ventricular +dP/dt, hydraulic work, and oxygen consumption of paced working rat hearts, then reduced these variables during continuous exposure. Brevetoxin-B exerted a much smaller positive inotropic effect on working guinea pig hearts, but produced a marked and sustained inotropic effect on guinea pig left atria. The toxin also produced arrhythmias in rat and guinea pig hearts, characterized by ventricular tachycardia and A-V blockade. Sympatholytic procedures (beta blockade or reserpine pretreatment) partially blocked the positive inotropic effects, and eliminated the ventricular tachycardia, but not the A-V blockade. Tetrodotoxin markedly inhibited the positive inotropic effect of GbTX-B. Brevetoxin-B did not inhibit guinea pig cardiac Na,K-ATPase activities. The results show that GbTX-B is a potent cardiotoxin and suggest that GbTX-B exerts positive inotropic and arrhythmogenic effects by increasing sarcolemmal sodium permeability, and by releasing catecholamines from sympathetic nerve endings.

Topics: Animals; Arrhythmias, Cardiac; Dose-Response Relationship, Drug; Guinea Pigs; Heart; In Vitro Techniques; Male; Marine Toxins; Myocardial Contraction; Myocardium; Oxocins; Oxygen Consumption; Rats; Sodium; Sodium-Potassium-Exchanging ATPase; Stimulation, Chemical; Tetrodotoxin

Functional determinants of postrepolarization refractoriness were studied with microelectrodes in isolated cat and dog ventricular muscle preparations mounted in a three-chambered bath. Frequency-dependent conduction delay and block were readily manifested when the central segment (1 mm) was superfused with high potassium (20-30 mM) Tyrode's solution. Conduction disorders were attributed to postrepolarization refractoriness involving slow recovery in the amplitude of elicited subthreshold depolarizations in depressed fibers distal to the central blocked zone. Investigations of subthreshold phenomena in homogeneously depressed tissues indicated that a relatively large local response participated in the voltage displacement induced by subthreshold depolarizing currents. The local response was blocked by tetrodotoxin (10 micrograms/ml) or verapamil (2 micrograms/ml) when resting membrane potential was near -70 or -50 mV, respectively. At either level of reduced membrane potential, gradual recovery in diastolic excitability correlated closely with time-dependent recovery of the local response, the rate of which was also proportional to the current intensity applied. Thus, postrepolarization refractoriness in depressed ventricular muscle fibers is a function of the time for recovery of active subthreshold properties (the local response), as well as intensity of excitatory current input. These factors may play a role in the development of delayed conduction and reentry that occur at faster heart rates under ischemic conditions.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Cats; Dogs; Electric Stimulation; Electrophysiology; Heart Block; Heart Ventricles; Membrane Potentials; Potassium; Tetrodotoxin; Time Factors; Verapamil

Effects of desipramine (DPr), a tricyclic antidepressant, on isolated trabeculae of the right rabbit atrial myocardium were studied using a standard microelectrode technique. Between 10(-7) and 10(-4) g/ml DPr reduced the maximum upstroke velocity Vmax of the action potentials. The membrane responsiveness was found to be depressed for DPr increased the time constant of the recovery of Vmax in a concentration-dependent manner distinctly. The voltage-Vmax relationships were shifted to more positive potentials and were flattend by increasing the concentration of DPr. DPr prolonged the duration of the action potentials on all levels of repolarization. Between 10(-7) and 10(-5) g/ml both resting and overshoot potential were found to be unchanged. At concentrations higher than 10(-5) g/ml slow response action potential insensitive to 10(-5) mol/l TTX were evoked, the resting transmembrane potential depolarized, spatial inhomogeneities in transmembrane potential and triggered activity could be observed. DPr may act antiarrhythmogenically in a quinidine-like manner at concentrations between 10(-7) and 10(-5) g/ml by (1) decreasing the fast channel conductance, (2) delaying the recovery of the fast channel. At concentrations higher than 10(-5) g/ml DPr could effect arrhythmogenic actions by a complete depression of fast response action potentials, unmasking of slow response action potentials and generation of severe spatial inhomogeneities.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Atrial Function; Cell Membrane; Desipramine; Female; Heart; Heart Rate; Male; Membrane Potentials; Microelectrodes; Rabbits; Tetrodotoxin

To study transmembrane electrophysiological properties of blood-perfused mammalian heart cells during normal perfusion and during acute ischemia, 1- to 2-mm cubes of neonatal hamster atrial and ventricular myocardium were transplanted to the adult hamster cheek pouch and studied with microelectrodes 4--7 days later, when vascularization and spontaneous contractions occurred. Action potentials recorded from the transplants were similar to those recorded from neonatal and adult hamster myocardium studied in vitro. Interrupting blood flow to spontaneously beating transplants reduced diastolic depolarization and suppressed automaticity. After automaticity ceased, the transplants were paced with a bipolar electrode or intracellular microelectrode. Action potential amplitude, resting potential, and dV/dtmax decreased during ischemia. Action potential duration and the intracellular current threshold for excitation increased initially, subsequently decreased to values less than control, and increased again prior to the onset of inexcitability. Conduction delay and block occurred during the late stages of ischemia. Depressed action potentials recorded during ischemia were suppressed by tetrodotoxin (10(-5) M) but not by verapamil (2 x 10(-6) M). These data indicate that: (1) the electrophysiological properties of cheek pouch cardiac transplants are normal, (2) ischemia suppresses transplant automaticity, (3) cellular excitability increases during the early stages of ischemia and decreases at a time when conduction delay and block occur, and (4) action potentials generated during the later stages of ischemia appear to be depressed fast responses, rather than slow responses.

Topics: Animals; Arrhythmias, Cardiac; Coronary Circulation; Cricetinae; Electrocardiography; Heart Conduction System; Heart Transplantation; Models, Cardiovascular; Myocardial Contraction; Tetrodotoxin; Verapamil

Lidocaine (4--12 mg/kg) and the specific fast sodium current blocker tetrodotoxin (TTX) (1--6 mg/kg, i. v.) reduced ventricular arrhythmias that occurred 24 h after coronary artery ligation in dogs. Infusion of a mixture of subthreshold doses of lidocaine and TTX decreased ventricular arrhythmias to the same degree as infusion of threshold doses of either agent alone. This finding suggests that the antiarrhythmic action of lidocaine in the late stage of myocardial infarction is due to inhibition of the fast inward, sodium current. The possible mechanisms of rhythm disturbances in the late stage of myocardial infarction are discussed.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Dogs; Drug Therapy, Combination; Female; Ion Channels; Lidocaine; Male; Myocardial Infarction; Myocardium; Sodium; Tetrodotoxin

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Calcium; Coronary Disease; Guinea Pigs; Heart; Hydrogen-Ion Concentration; Hypoxia; Isoproterenol; Potassium; Sodium; Tetrodotoxin

Reentrant ventricular arrhythmias (RVA) were analyzed in dogs 3--7 days after ligation of the anterior descending coronary artery using averaged "composite" recordings of electrical activity of reentrant pathways (RP) from the epicardial surface of the infarction zone (IZ). Verapamil (V) and D-600 (D) (0.2--0.5 mg/kg i.v.) resulted in slight-to-moderate improvement of conduction in RP with abolition of spontaneous RVA and RVA initiated by premature depolarizations. The effect of V was not blocked by pretreatment with propranolol (0.5 mg/kg i.v.). Using a standard microelectrode technique and strips of epicardial muscle from the IZ, D (0.5--1 X 10(-6) g/ml) slightly improved the upstroke velocity and membrane responses of depressed ischemic cells. In contrast, tetrodotoxin (5 X 10(-7) g/ml) further depressed or abolished action potentials of ischemic cells. We conclude: 1) the moderate antiarrhythmic effect of V and D on RVA is the result of improved conduction in RP; 2) this action is partly explained by improvement of a depressed sodium channel and is not related to catecholamine release; 3) slow-response action potentials play no significant role in the genesis of ischemia-related RVA, which probably results from depression of the fast response.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Coronary Disease; Dogs; Electrocardiography; Gallopamil; Heart Conduction System; Heart Ventricles; Myocardial Infarction; Tetrodotoxin; Time Factors; Verapamil

We have demonstrated recently that grayanotoxin I (GTX I) produces a positive inotropic effect in isolated guinea-pig atria. In order to determine whether this effect of GTX I is related to the reported action of this compound to increase the sodium permeability of cytoplasmic membranes, the effect of GTX I and alpha-dihydrograyanotoxin II (alpha-2H-GTX II) on electrical and mechanical properties and transmembrane cation movements were studied in guinea-pig myocardium. In electrically driven guinea-pig left atrial preparations, both grayanotoxins produced a slight depolarization and appear to decrease the upstroke velocity of the action potential, with a concomitant increase in isometric contractile force in the presence or absence of propranolol. Pretreatment with propranolol shifted the dose-response curves for the inotropic effect of both grayanotoxins slightly to the right. The magnitudes of changes in the electrical and mechanical properties induced by GTX I and alpha-2H-GTX II were similar. The rate of development and subsequent washout of the positive inotropic effects, however, was faster with alpha-2H-GTX II than with GTX I, consistent with a previous report that the action of alpha-2H-GTX II to increase membrane sodium permeability develops more rapidly than that of GTX I. At higher concentrations, both grayanotoxins produced arrhythmias. Arrhythmias induced by GTX I were characterized by extrasystoles whereas those induced by alpha-2H-GTX II were characterized by initial extrasystoles followed by a failure of the atria to follow electrical stimulation. Positive inotropic and arrhythmic effects of both grayanotoxins were reversible after the washout of the drug. Both types of arrhythmias produced by either GTX I or alpha-2H-GTX II were reversed by tetrodotoxin, an agent which has been demonstrated to antagonize the action of the grayanotoxins to increase membrane sodium permeability. Although both grayanotoxins had no marked effect on partially purified Na+, K+-adenosine triphosphatase, they produced dose-dependent increases in ouabain-sensitive 86Rb uptake of ventricular slices under conditions in which the intracellular sodium concentration determines the rate of active monovalent cation transport by the Na+, K+-adenosine triphosphatase system. These data suggest that the positive inotropic effects of grayanotoxins are due to an increased membrane sodium permeability and are consistent with a hypothesis that alterations in transmembrane sodium

Topics: Action Potentials; Adenosine Triphosphatases; Animals; Arrhythmias, Cardiac; Biological Transport, Active; Diterpenes; Drug Interactions; Electric Stimulation; Female; Heart; In Vitro Techniques; Male; Membrane Potentials; Mice; Myocardial Contraction; Myocardium; Polycyclic Compounds; Potassium; Propranolol; Radioisotopes; Rubidium; Sodium; Tetrodotoxin; Time Factors; Toxins, Biological

Arrhythmogenic effects of anaphylaxis and histamine were studied in guinea pigs by measuring changes of transmembrane potentials from isolated papillary muscles. Antigenic challenge of preparations obtained from passively sensitized animals induced ventricular automaticity in 1/3 of the experiments. The arrhythmogenic effects of cardiac anaphylaxis could be reproduced by exogenous histamine. Abnormal automaticity was associated with a stable diastolic membrane potential in most of the ventricular fibres and only occasionally ectopic pacemaker potentials were observed in fibres near the ventricular septum. The effective refractory period, maximum rate of depolarization of the action potential and electrical threshold were not significantly changed in ventricular anaphylaxis but in the presence of histamine the refractory time was shortened. Ventricular arrhythmias induced by histamine were increased at high extracellular Ca2+ concentrations and inhibited by Mn2+ and D 600 but were only moderately antagonized by tetrodotoxin. Pretreatment with reserpine had no effect on the abnormal automaticity. Spontaneous ventricular activity caused by histamine was markedly inhibited by the histamine H2-receptor antagonist burimamide and also by the antiarrhythmic drug, prajmalium bitartrate. The H1-receptor antagonist brompheniramine, hydrocortisone and propranolol had little or no antiarrhythmic effect.

Topics: Action Potentials; Anaphylaxis; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium; Female; Guinea Pigs; Heart; Histamine; In Vitro Techniques; Male; Manganese; Myocardial Contraction; Reserpine; Tetrodotoxin

Electrical stimulation of the fastigial nucleus produced a pressor response with cardiac arrhythmia in cats. The arrhythmic response was abolished by tetrodotoxin (3 microgram/kg, i.v.), atropine (0.5 mg/kg, i.v.) or vagotomy, and suppressed slightly by propranolol or verapamil (0.5-1.0 mg/kg, i.v.). It was not abolished by the carotid sinus nerve section. The effects of the drug suggest that arrhythmia seems to be due to an interplay of sympathetic and parasympathetic influences with the latter effect predominating. The pressor and arrhythmic response to stimulation of the fastigial nucleus was increased by stimulation, and decreased by lesion of the posterior hypothalamus, indicating that some connection between the two structures exists.

Topics: Animals; Arrhythmias, Cardiac; Atropine; Cats; Cerebellar Nuclei; Electric Stimulation; Female; Hypothalamus, Posterior; Male; Pressoreceptors; Propranolol; Tetrodotoxin; Verapamil

The effects of neurotransmitters injected into the posterior and the anterior septal artery on the automaticity of the atrioventricular (AV) junctional area were examined in the excised, blood-perfused canine AV node preparation. An AV rhythm of 57.4 +/- 2.8 beats/min (N = 28) developed after the destruction of the sinoatrial node. l-Norepinephrine injected into the anterior septal artery increased the frequency of AV rhythm, but l-norepinephrine injected into the posterior septal artery caused a pacemaker shift from the anterior septal artery area to the posterior septal artery area. Acetylcholine injected into the posterior septal artery blocked retrograde conduction but did not decrease the frequency of AV rhythm; however, acetylcholine injected into the anterior septal artery decreased AV rhythm but did not affect retrograde conduction. Destruction of the posterior septal artery area failed to change AV rhythm. The surgically separated anterior septal artery preparation had the same rate as did the AV node preparation. The posterior septal artery preparation had a definitely lower rate and responded to smaller doses of l-norepinephrine than did the AV node preparation. The results of the present study indicate that AV rhythm in the AV node originates in the area supplied by the anterior septal artery and that the area supplied by the posterior septal artery, which has extremely low automaticity, is highly responsive to l-norepinephrine, resulting in nodal tachycardia.

Topics: Acetylcholine; Animals; Arrhythmias, Cardiac; Atrioventricular Node; Coronary Vessels; Dogs; Electrocardiography; Ethanol; Female; Heart Conduction System; Injections, Intra-Arterial; Male; Neurotransmitter Agents; Norepinephrine; Synaptic Transmission; Tetrodotoxin; Time Factors

In vivo, atropine or tetrodotoxin prevent arrhytmias which are due to acetylcholine released by the scorpion's venom. On the contrary, atropine is ineffective against cardiotoxicity of the purified gamma toxin and tetrodotoxin aggravates its effects. These findings allow us to postulate the mechanism of action which differs in these two toxin groups.

Topics: Animals; Arrhythmias, Cardiac; Atropine; Electrocardiography; Heart; Hindlimb; Muscle Contraction; Rats; Scorpions; Snake Venoms; Tetrodotoxin; Toxins, Biological; Venoms

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Caffeine; Calcium; Coronary Disease; Cyclic AMP; Epinephrine; Heart Arrest; Heart Conduction System; Humans; Isoproterenol; Lanthanum; Manganese; Myocardial Infarction; Potassium; Propranolol; Tetrodotoxin

Topics: Aconitum; Animals; Arrhythmias, Cardiac; Carotid Arteries; Dogs; Electric Stimulation; Electrodes, Implanted; Hypothalamus; Lanatosides; Tetrodotoxin; Time Factors; Vagotomy; Vagus Nerve; Ventricular Fibrillation

Topics: Adolescent; Animals; Arrhythmias, Cardiac; Consciousness; Edrophonium; Fishes, Poisonous; Foodborne Diseases; Glucose; Humans; Infusions, Parenteral; Intubation, Intratracheal; Male; Paralysis; Plasma Substitutes; Potassium Chloride; Respiration, Artificial; Sodium Chloride; Tetrodotoxin

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Body Temperature; Cardiac Output; Central Venous Pressure; Dogs; Electrocardiography; Female; Heart; Heart Rate; Heart Ventricles; Tetrodotoxin

Topics: Aconitum; Animals; Arrhythmias, Cardiac; Asphyxia; Drug Antagonism; Male; Rats; Tetrodotoxin

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Contracture; Electrocardiography; Heart; Male; Paralysis; Rats; Respiratory Insufficiency; Respiratory Paralysis; Scorpions; Tetrodotoxin; Venoms

Topics: Aconitum; Animals; Arrhythmias, Cardiac; Biological Transport; Drug Antagonism; Electrocardiography; Rats; Sodium; Sodium Chloride; Tetrodotoxin

Topics: Aconitum; Action Potentials; Animals; Arrhythmias, Cardiac; Heart Atria; Heart Rate; Heart Ventricles; In Vitro Techniques; Manganese; Membrane Potentials; Rabbits; Tetrodotoxin

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Cardiovascular System; Cats; Dogs; Electrocardiography; Female; Heart; Heart Rate; Male; Ouabain; Phenoxybenzamine; Propranolol; Reserpine; Tetrodotoxin

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Carotid Arteries; Crustacea; Electroencephalography; Heart Rate; Mice; Rats; Tetrodotoxin; Toxins, Biological

Topics: Animals; Arrhythmias, Cardiac; Electric Stimulation; Guinea Pigs; Heart; Heart Atria; In Vitro Techniques; Phenytoin; Procaine; Quinidine; Tetrodotoxin; Toxins, Biological