tetrodotoxin and Coronary-Disease

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

Combination therapy with mexiletine and quinidine has been shown to be more effective than either monotherapy in treating patients with ventricular tachycardia. This enhanced efficacy was associated with prolongation of ventricular refractoriness and conduction time in the infarct zone. As sodium channel activity is a determinant of both conduction time and refractoriness we formed the hypothesis that the mexiletine-quinidine interaction was due at least in part to interactions involving the sodium channel. To assess the role of sodium channel blockade in the enhanced anti-arrhythmic activity of mexiletine-quinidine combination we determined whether the electrophysiological and anti-arrhythmic effects of tetrodotoxin combined with mexiletine or quinidine mimicked the effect seen with mexiletine combined with quinidine. Eighty isolated perfused rabbit hearts were treated with mexiletine, quinidine and tetrodotoxin either alone or in combination before and after circumflex occlusion-reperfusion. Ventricular fibrillation occurred in response to single extrastimuli in all 24 hearts treated with a saline control infusion. Combinations of mexiletine and quinidine at concentrations which alone had little electrophysiological activity produced anti-arrhythmic activity greater than that seen with high concentrations of mexiletine or quinidine alone. The combination of similarly low concentrations of tetrodotoxin and quinidine also produced enhanced anti-arrhythmic efficacy and enhanced prolongation of ventricular refractoriness and conduction which mimicked the effect of mexiletine and quinidine in combination. In contrast, the combination of mexiletine and tetrodotoxin did not produce enhanced anti-arrhythmic and electrophysiological activity. Since tetrodotoxin is a highly specific sodium channel blocker, these data suggest that the enhanced antiarrhythmic activity of mexiletine-quinidine combination therapy involves, at least in part, blockade of the cardiac sodium channel.

Topics: Action Potentials; Animals; Coronary Disease; Drug Synergism; Drug Therapy, Combination; Heart; Heart Ventricles; Mexiletine; Myocardial Infarction; Myocardial Reperfusion; Quinidine; Rabbits; Sodium Channels; Tetrodotoxin; Ventricular Fibrillation

Blockade of ventricular sodium conductance (gNa) is believed to play an important role in the beneficial antiarrhythmic effects of class I antiarrhythmic agents. The present study was undertaken to examine the importance of ventricular gNa blockade by assessing the antiarrhythmic profile of tetrodotoxin (TTX), a selective sodium channel blocker. Experiments were performed in pentobarbital-anesthetized and artificially ventilated rats. Two doses of TTX were tested for antiarrhythmic action: a low dose (low TTX, 10 micrograms/kg of bolus + infusion of 10 micrograms/kg/hr) which blocked only neuronal activity, and a high dose (TTXh, 50 micrograms/kg of bolus + infusion of 50 micrograms/kg/hr) which also produced signs of ventricular gNa blockade in normal hearts. To control for the decreases in blood pressure and heart rate caused by TTX, hexamethonium, nitroprusside and propranolol were also used. Only TTXh possessed antiarrhythmic activity in rats subjected to myocardial ischemia (produced by ligation of the left anterior descending coronary artery). Arrhythmia scores (mean, n = 9) were: saline, 3.8; hexamethonium, 3.8; nitroprusside, 3.2; nitroprusside + propranolol, 4.3; low TTX, 3.9; and TTXh, 0.9. Only TTXh reduced dV/dt max. of the action potential (recorded in vivo by means of 3 M KCl filled microelectrodes) as well as action potential height, and concomitantly prolonged the P-R and QRS intervals of normal hearts. In conclusion, our study demonstrated that drugs which produced hypotension, bradycardia and loss of autonomic function were not antiarrhythmic. On the other hand, the marked antiarrhythmic activity of TTXh appeared to depend upon ventricular gNa blockade. Thus, TTX provides a useful tool for examining the antiarrhythmic properties of ventricular gNa blockade.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Blood Pressure; Coronary Disease; Electric Stimulation; Electrocardiography; Heart Rate; Male; Myocardial Contraction; Rats; Rats, Inbred Strains; Sodium Channels; Tetrodotoxin

We have developed a new model for electrophysiological studies on ischemic myocardium in situ. Pieces of ventricular tissue (1 X 1 mm) excised from the neonatal rat heart were transplanted into the renal capsular space of the adult rat of the pure strain F 344-NSlc. Electrophysiological properties of the transplanted cells during normal circulation and during ischemia induced by ligation of the renal artery were examined in situ 7-10 days later, when the tissues were fully vascularized, by means of conventional microelectrode techniques. Transmembrane potentials varied in individual cells, ranging from -60 to -90 mV. The amplitude, duration, and configuration of spontaneously occurring action potentials recorded from the transplanted cells were similar to those obtained in neonatal and adult rat myocardium. At 2-5 min after ligation of the renal artery, the frequency of the action potentials decreased markedly and their duration was transiently prolonged and then shortened. During the initial stage of ischemia (5-15 min), most of the cells were markedly depolarized and spontaneous activity ceased. Within 20-30 min, after the ligation, the cells did not respond to electrical stimulation. Reperfusion of the tissue by releasing the ligation restored the electrical activity of the cells within 15 min when a certain limited time of ischemia (30-40 min) was not exceeded.

Topics: Animals; Coronary Circulation; Coronary Disease; Electrocardiography; Female; Heart Ventricles; Male; Models, Cardiovascular; Myocardium; Oxygen Consumption; Rats; Tetrodotoxin; Verapamil

In this study we examined the possibility that local anaesthetic agents such as tetrodotoxin may exacerbate electrical changes during acute myocardial ischaemia by inhibiting fast sodium channels, both in cardiac cells and in sympathetic nerve terminals. Bipolar electrograms were recorded during serial 2 to 5 min occlusions of the left anterior descending coronary artery in open-chest, anaesthetised dogs. Tetrodotoxin (1 or 2 micrograms X kg-1 iv) given prior to occlusion did not affect activation times or electrograms in normal myocardium but exacerbated activation delay and loss of electrogram amplitude during ischaemia. Bilateral stellectomy reversed the effects of tetrodotoxin during ischaemia. Tetrodotoxin (1 microgram X kg-1 iv) reduced changes in heart rate and mean arterial blood pressure produced by stellate ganglia stimulation. Intracoronary infusion of tetrodotoxin (10(-5) mol X litre-1) during normal perfusion lengthened mean effective ventricular refractory periods and propranolol (0.5 mg X kg-1 iv) or bilateral stellectomy prevented this effect. Thus, tetrodotoxin appeared to increase ventricular refractoriness and exacerbate ischaemia-induced activation delay by inhibiting sympathetic nerve activity. Other agents with local anaesthetic properties may have similar effects.

Topics: Action Potentials; Animals; Blood Pressure; Coronary Disease; Dogs; Electrocardiography; Female; Heart; Heart Rate; Ion Channels; Male; Sodium; Stellate Ganglion; Tetrodotoxin; Time Factors

Using standard microelectrode techniques, the cellular electrophysiologic features of ventricular myocardium resected from 8 patients with refractory arrhythmias were studied in vitro. Action potentials from damaged myocardium compared with normal myocardium had reduced resting membrane potential, amplitude, and maximal upstroke velocity. Tetrodotoxin, but not verapamil, suppressed 3 action potentials with resting potentials of -60 to -64 mV and Vmax less than 70 V/s. Verapamil, but not tetrodotoxin, suppressed 4 action potentials with resting potentials of -44 to -57 mV and Vmax less than 20 V/s. Unidirectional block, Wenckebach block, and summation occurred in damaged zones. Exit block from and frequency-dependent entrance block into an ectopic focus were noted. Subthreshold responses in the focal area induced by action potentials in the surrounding myocardium and by subthreshold current pulses injected through the recording microelectrode altered the spontaneous discharge rate of the focus, as previously described for modulated parasystole. Pulses early in the spontaneous cycle delayed the next expected discharge, and later pulses accelerated the subsequent discharge. Pulses injected at the singular point completely suppressed automaticity (annihilation). Tetrodotoxin and verapamil suppressed automaticity in some fibers. Single action potentials induced in quiescent fibers triggered and terminated sustained rhythmic activity. These data suggest that depressed fast responses, slow responses, and subthreshold potentials can generate and modulate ectopic activity in damaged human ventricle and that fast- and slow-channel blocking agents and single premature stimuli can terminate such activity.

Topics: Action Potentials; Aged; Cardiac Pacing, Artificial; Coronary Disease; Electrophysiology; Heart Block; Heart Conduction System; Heart Ventricles; Humans; Middle Aged; Tachycardia; Tetrodotoxin; Verapamil

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

Topics: Adenine Nucleotides; Aerobiosis; Animals; Coronary Disease; Guanosine Triphosphate; Heart; Hypoxia; Insulin; Male; Muscle Proteins; Myocardium; Perfusion; Phenylalanine; Rats; 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

Topics: Action Potentials; Animals; Coronary Disease; Dogs; Electric Stimulation; Endocardium; Heart Conduction System; Hypoxia; In Vitro Techniques; Lidocaine; Membrane Potentials; Purkinje Fibers; Tetrodotoxin

Intracoronary injection of 14 mcg. of tetrodotoxin into the ischemic isolated rat heart resulted in immediate cessation of mechanical activity. Upon reperfusion with oxygenated, modified Krebs-Henseleit bicarbonate buffer in a modified Langendorff apparatus, all hearts recovered normal rate, rtythm, and contractile vigor after up to 60 minutes of ischemia. In contrast, all hearts not administered tetrodotoxin showed bradycardia, irregular rhythm, and weak contraction upon reperfusion after 30 and 45 minutes of ischemia; after 60 minutes, no mechanical activity was evident. The improved cardiac function following ischemia in the tetrodotoxin-treated hearts was associated with persistence of normal adenosine triphosphate (ATP) levels after up to 30 minutes of ischemia and normal or elevated creatine phosphate (CP) levels after up to 60 minutes of ischemia. On the other hand, ATP and CP levels progressively declined to reach 50 per cent of normal values after 30 minutes in the ischemic hearts without tetrodotoxin. These findings indicate that postarrest ATP and CP levels play an important role in myocardial recovery after ischemic arrest.

Topics: Adenosine Triphosphate; Animals; Bicarbonates; Buffers; Coronary Disease; Disease Models, Animal; Heart; Heart Arrest; Heart Conduction System; Heart Rate; Myocardium; Perfusion; Phosphocreatine; Rats; Tetrodotoxin; Time Factors

Interruption of coronary flow during cardiac surgical procedures provides a bloodless flaccid heart and allows precise and rapid correction of complex cardiac defects. However, myocardial damage occurs in direct proportion to the duration of the ischemia. As the induction of cardioplegia simulataneous with the initiation of cardiac ischemia helps to preserve cardiac energy reserves and thus myocardial integrity, the identification of a consistently reliable cardioplegic technique is desirable. Isolated perfused working rat hearts were made ischemic for one hour by aortic cross-clamping and were compared with hearts rendered cardioplegic at the onset of ischemia by the intracoronary administration of 5 ml of a hypothermic solution: 1) Krebs-Henseleit buffer, 2) Ringer's lactate, 3) tetrodotoxin, 4) potassium chloride, or 5) potassium citrate. Cardiac output, heart rate, aortic pressure and coronary flow were determined pre and post-ischemia. When compared to time-matched controls and hearts arrested with potassium or tetrodotoxin, the ischemia and ischemia-Ringer's lactate groups showed significant post cross-clamp depression of all measured parameters. Intracoronary Ringer's lactate, although often used as an adjunct to ischemic arrest, was not of significant value. In contrast, hearts arrested with tetrodotoxin, potassium chloride or potassium citrate showed no significant post-ischemic functional or histologic deficit. Perfusion with hypothermic Krebs-Henseleit buffer protected the myocardium better than did Ringer's lactate but less well than the tetrodotoxin or isotonic high potassium solutions. The induction of hypothermic metabolic arrest of the heart by briefly perfusing the coronary arteries via the aortic root with isotonic buffered solutions results in markedly improved myocardial tolerance to one hour of ischemia and avoids the problems of low cardiac output and ventricular irritability previously reported with hypertonic potassium citrate arrest.

Topics: Animals; Cardiac Output; Cardiopulmonary Bypass; Citrates; Coronary Circulation; Coronary Disease; Coronary Vessels; Heart Arrest; Heart Rate; Hypertonic Solutions; Isotonic Solutions; Myocardial Contraction; Perfusion; Potassium; Potassium Chloride; Rats; Tetrodotoxin

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