tetrodotoxin and Atrial-Fibrillation

Topics: Action Potentials; Animals; Atrial Fibrillation; Atrial Flutter; Atrioventricular Node; Calcium Channel Blockers; Cardiac Pacing, Artificial; Coronary Disease; Death, Sudden; Diltiazem; Dogs; Haplorhini; Humans; Ion Channels; Nifedipine; Rabbits; Rats; Tachycardia; Tetrodotoxin; Ventricular Fibrillation; Verapamil; Wolff-Parkinson-White Syndrome

The role of the Na

Topics: Action Potentials; Animals; Atrial Fibrillation; Cells, Cultured; Diastole; Guinea Pigs; Lidocaine; Male; Membrane Potentials; Myocytes, Cardiac; Pulmonary Veins; Pyridines; Sodium; Tetrodotoxin; Triazoles

Slowly inactivating Na+ channels conducting "late" Na+ current (INa,late) contribute to ventricular arrhythmogenesis under pathological conditions. INa,late was also reported to play a role in chronic atrial fibrillation (AF). The objective of this study was to investigate INa,late in human right atrial cardiomyocytes as a putative drug target for treatment of AF. To activate Na+ channels, cardiomyocytes from transgenic mice which exhibit INa,late (ΔKPQ), and right atrial cardiomyocytes from patients in sinus rhythm (SR) and AF were voltage clamped at room temperature by 250-ms long test pulses to -30 mV from a holding potential of -80 mV with a 100-ms pre-pulse to -110 mV (protocol I). INa,late at -30 mV was not discernible as deviation from the extrapolated straight line IV-curve between -110 mV and -80 mV in human atrial cells. Therefore, tetrodotoxin (TTX, 10 μM) was used to define persistent inward current after 250 ms at -30 mV as INa,late. TTX-sensitive current was 0.27±0.06 pA/pF in ventricular cardiomyocytes from ΔKPQ mice, and amounted to 0.04±0.01 pA/pF and 0.09±0.02 pA/pF in SR and AF human atrial cardiomyocytes, respectively. With protocol II (holding potential -120 mV, pre-pulse to -80 mV) TTX-sensitive INa,late was always larger than with protocol I. Ranolazine (30 μM) reduced INa,late by 0.02±0.02 pA/pF in SR and 0.09±0.02 pA/pF in AF cells. At physiological temperature (37°C), however, INa,late became insignificant. Plateau phase and upstroke velocity of action potentials (APs) recorded with sharp microelectrodes in intact human trabeculae were more sensitive to ranolazine in AF than in SR preparations. Sodium channel subunits expression measured with qPCR was high for SCN5A with no difference between SR and AF. Expression of SCN8A and SCN10A was low in general, and lower in AF than in SR. In conclusion, We confirm for the first time a TTX-sensitive current (INa,late) in right atrial cardiomyocytes from SR and AF patients at room temperature, but not at physiological temperature. While our study provides evidence for the presence of INa,late in human atria, the potential of such current as a target for the treatment of AF remains to be demonstrated.

Topics: Action Potentials; Aged; Animals; Arrhythmia, Sinus; Atrial Fibrillation; Female; Heart Atria; Humans; Ion Channel Gating; Male; Mice; Middle Aged; Myocytes, Cardiac; Protein Subunits; Ranolazine; Sodium Channels; Temperature; Tetrodotoxin

The mechanisms by which Na+-channel blocking antiarrhythmic drugs terminate atrial fibrillation (AF) remain unclear. Classical "leading-circle" theory suggests that Na+-channel blockade should, if anything, promote re-entry. We used an ionically-based mathematical model of vagotonic AF to evaluate the effects of applying pure Na+-current (I(Na)) inhibition during sustained arrhythmia. Under control conditions, AF was maintained by 1 or 2 dominant spiral waves, with fibrillatory propagation at critical levels of action potential duration (APD) dispersion. I(Na) inhibition terminated AF increasingly with increasing block, terminating all AF at 65% block. During 1:1 conduction, I(Na) inhibition reduced APD (by 13% at 4 Hz and 60% block), conduction velocity (by 37%), and re-entry wavelength (by 24%). During AF, I(Na) inhibition increased the size of primary rotors and reduced re-entry rate (eg, dominant frequency decreased by 33% at 60% I(Na) inhibition) while decreasing generation of secondary wavelets by wavebreak. Three mechanisms contributed to I(Na) block-induced AF termination in the model: (1) enlargement of the center of rotation beyond the capacity of the computational substrate; (2) decreased anchoring to functional obstacles, increasing meander and extinction at boundaries; and (3) reduction in the number of secondary wavelets that could provide new primary rotors. Optical mapping in isolated sheep hearts confirmed that tetrodotoxin dose-dependently terminates AF while producing effects qualitatively like those of I(Na) inhibition in the mathematical model. We conclude that pure INa inhibition terminates AF, producing activation changes consistent with previous clinical and experimental observations. These results provide insights into previously enigmatic mechanisms of class I antiarrhythmic drug-induced AF termination. The full text of this article is available online at http://circres.ahajournals.org

Topics: Algorithms; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Computer Simulation; Electroencephalography; Fourier Analysis; Models, Cardiovascular; Sheep; Sodium; Sodium Channel Blockers; Sodium Channels; Tetrodotoxin; Video Recording

Rapid firing within pulmonary vein sleeves frequently initiates atrial fibrillation. The role of the autonomic nervous system in facilitating spontaneous firing is unknown.. The purpose of this study was to determine if autonomic nerve stimulation within canine atrium and pulmonary vein sleeves initiates arrhythmia formation.. Extracellular bipolar and intracellular microelectrode recordings were obtained from isolated superfused canine pulmonary veins (N = 28) and right atrium (N = 5) during local autonomic nerve stimulation.. Autonomic nerve stimulation decreased pulmonary vein sleeve action potential duration (APD90 = 160 +/- 17 to 92 +/- 24 ms; P < .01) and initiated rapid (782 +/- 158 bpm) firing from early afterdepolarizations in 22 of 28 pulmonary vein preparations. The initial spontaneous beat had a coupling interval of 97 +/- 26 ms. Failure to induce arrhythmia was associated with a failure to shorten APD90 (151 +/- 18 to 142 +/- 8 ms; P = .39). Muscarinic receptor blockade (atropine: 3.2 x 10(-8) M) prevented APD90 shortening in 8 of 8 preparations and suppressed firing in 6 of 8 preparations, whereas beta1-adrenergic receptor blockade (atenolol: 3.2 x 10(-8) M) suppressed firing in 8 of 8 preparations. Suppression of the Ca transient with ryanodine (10(-5) M) completely suppressed firing in 6 of 6 preparations. Inhibition of forward Na/Ca exchange by a transient increase in [Ca+2]o completely suppressed firing in 4 of 6 preparations. The same stimulus trains produce atropine-suppressed APD90 shortening in superfused right atrial free wall but fail to produce triggered arrhythmia.. The data demonstrate triggered firing within canine pulmonary veins with combined parasympathetic and sympathetic nerve stimulation. Both an enhanced Ca transient and increased Na/Ca exchange may be required for arrhythmia formation.

Topics: Animals; Atenolol; Atrial Fibrillation; Atropine; Autonomic Nervous System; Dogs; Electric Stimulation; Electrophysiologic Techniques, Cardiac; Heart Atria; Male; Pulmonary Veins; Ryanodine; Tetrodotoxin

Topics: Animals; Atenolol; Atrial Fibrillation; Atropine; Autonomic Nervous System; Dogs; Electric Stimulation; Electrophysiologic Techniques, Cardiac; Heart Atria; Male; Pulmonary Veins; Ryanodine; Tetrodotoxin

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

Pituitary adenylate cyclase-activating polypeptide (PACAP) receptors exist, but the physiologic role of PACAP is unclear in the heart in situ. We investigated effects of PACAP-38 on sinus rate and on the negative chronotropic response to acetylcholine (ACh) or stimulation of the intracardiac parasympathetic nerve fibers to the sinoatrial nodal region in the automatically decentralized heart of the open chest, anesthetized dog. PACAP-38 (0.1-1 nmol) injected directly into the sinus node artery caused transient positive followed by negative chronotropic responses. Both pretreatment with atropine and tetrodotoxin inhibited the negative chronotropic responses to PACAP-38. However, hexamethonium did not block the negative responses to PACAP-38. After treatment with PACAP-38 (0.1-1 nmol), ACh induced atrial fibrillation significantly (p < 0.01). On the other hand, the negative chronotropic responses to intracardiac parasympathetic stimulation were not changed. These results suggest that (a) PACAP-38 induces negative chronotropic responses and liberates ACh from intracardiac postganglionic parasympathetic nerves, and that (b) PACAP-38 reduces ACh-induced atrial fibrillation threshold in the dog heart in situ.

Topics: Acetylcholine; Anesthesia; Animals; Atrial Fibrillation; Atropine; Dogs; Female; Heart Rate; Hexamethonium; Male; Neuropeptides; Parasympathetic Nervous System; Pituitary Adenylate Cyclase-Activating Polypeptide; Propranolol; Sinoatrial Node; Tetrodotoxin

We investigated the effects of a neuropeptide, pituitary adenylate cyclase-activating polypeptide- (PACAP) 27, on the sinoatrial nodal pacemaker activity and the mechanisms for the cardiac effects of PACAP-27 in the autonomically decentralized heart of the anesthetized dog. PACAP-27 (0.01-0.3 nmol) injected into the sinus node artery increased followed by decreased sinus rate. PACAP-27 (0.1 and 0.3 nmol) caused atrial fibrillation spontaneously. After atropine, PACAP-27 never decreased but only increased sinus rate as did vasoactive intestinal peptide. However, propranolol did not affect the negative and positive chronotropic effects. Tetrodotoxin but not hexamethonium abolished the negative chronotropic response to PACAP-27 in atropine nontreated dogs, and tetrodotoxin also inhibited the positive chronotropic response by 34% in atropine-treated dogs. In atropine- and propranolol-treated dogs, positive chronotropic responses to PACAP-27 were inhibited by PACAP-(6-27), a PACAP receptor antagonist but not by vasoactive intestinal peptide (10-28), a vasoactive intestinal peptide receptor antagonist. These results indicate that PACAP-27 causes the negative chronotropic effect through the postganglionic parasympathetic nerve activation and it produces the positive chronotropic effect mediated by PACAP receptors with an activation of non-adrenergic, nonvasoactive intestinal peptide-ergic nerves at least in part in the dog heart. Atropine and tetrodotoxin abolished atrial fibrillation induced by PACAP-27 but other blockers did not. These results suggest that neurally released acetylcholine induced by PACAP-27 participates in the induction of atrial fibrillation.

Topics: Anesthesia; Animals; Atrial Fibrillation; Atropine; Dogs; Female; Heart Rate; Hexamethonium; Male; Neuropeptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Propranolol; Sinoatrial Node; Tetrodotoxin; Vasoactive Intestinal Peptide

Topics: Acetylcholine; Animals; Atrial Fibrillation; Atrial Function; Atropine; Autonomic Nervous System; Cholinesterases; Depression, Chemical; Dogs; Electrocardiography; Heart Block; Heart Conduction System; Heart Rate; Hemicholinium 3; Neostigmine; Norepinephrine; Perfusion; Physostigmine; Propranolol; Stellate Ganglion; Stimulation, Chemical; Tetrodotoxin; Time Factors; Vagus Nerve

Topics: Action Potentials; Adult; Alkaloids; Animals; Atrial Fibrillation; Dogs; Electric Stimulation; Electrocardiography; Humans; Male; Membrane Potentials; Sinoatrial Node; Tachycardia; Tetrodotoxin

Topics: Acetylcholine; Adrenergic beta-Antagonists; Animals; Atrial Fibrillation; Atropine; Bethanechol Compounds; Blood Pressure; Carbachol; Dogs; Drug Synergism; Electrocardiography; Epinephrine; Heart Rate; Injections, Intra-Arterial; Methacholine Compounds; Propranolol; Tetrodotoxin

Topics: Acetylcholine; Aconitum; Action Potentials; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Calcium; Heart; In Vitro Techniques; Phenytoin; Propranolol; Rabbits; Stimulation, Chemical; Tetrodotoxin

Topics: Aconitum; Animals; Atrial Fibrillation; Calcium; Electrodes; Electrophysiology; Heart Atria; Heart Conduction System; Rabbits; Tetrodotoxin

Topics: Aconitum; Action Potentials; Animals; Atrial Fibrillation; Cardiac Complexes, Premature; Heart Conduction System; In Vitro Techniques; Membrane Potentials; Sheep; Sodium; Tetrodotoxin; Ventricular Fibrillation