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Journal ArticleDOI

A third class of anti-arrhythmic action: Effects on atrial and ventricular intracellular potentials, and other pharmacological actions on cardiac muscle, of MJ 1999 and AH 3474

01 Aug 1970-British Journal of Pharmacology (John Wiley & Sons, Ltd)-Vol. 39, Iss: 4, pp 675-687
TL;DR: It was concluded that direct depression of depolarization could have contributed little to the protection against ouabain‐induced fibrillation, and it is suggested that this effect contributes to anti‐arrhythmic activity.
Abstract: Summary 1 Both MJ 1999 and AH 3474 protected guinea-pigs anaesthetized with urethane against ouabain-induced ventricular fibrillation. 2 MJ 1999 had 1/90, and AH 3474 1/30, of the activity of procaine in reducing the height of the action potential of frog sciatic nerve. 3 MJ 1999 and AH 3474 reduced the rate of rise of intracellularly recorded action potentials at concentrations in excess of 160 × 10−6m (50 mg/l.). It was concluded that direct depression of depolarization could have contributed little to the protection against ouabain-induced fibrillation. 4 MJ 1999, but not AH 3474, greatly prolonged the duration of the action potential in acute experiments on isolated atrial and ventricular muscle, and prolonged the Q-Tc interval of the electrocardiogram in anaesthetized guinea-pigs. It is suggested that this effect contributes to anti-arrhythmic activity. 5 At concentrations up to 80 × 10−6m AH 3474 had positive chronotropic and inotropic effects on isolated rabbit atrial muscle, but at higher concentrations these were superseded by negative effects. MJ 1999 was depressant at all concentrations studied, the threshold concentrations being 19 × 10−6m for chronotropic, and 162 × 10−6m for inotropic effects.
Citations
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Journal ArticleDOI
TL;DR: All but one of the new antiarrhythmic drugs introduced since 1972 have turned out to possess one or more of the four classes of action originally described, and recent research suggests that inhibition of slow inward current may lead, as a secondary consequence of lowered [Ca]i, to improved cell-to-cell conduction.
Abstract: The past decade has seen the introduction of many new class 1 drugs, restricting fast inward current. Confirmative evidence has been obtained that the antiarrthymic action of lidocaine and diphenylhydantoin is indeed due to their effect as class 1 agents depressing conduction. The original class 3 drug, amiodarone, is increasingly in use as an antiarrhythmic of first choice for WPW and for arrhythmias associated with hypertrophic myopathy, and as a reserve drug in resistant arrhythmias of other types. Other compounds delaying repolarization have proved to be clinically effective as antiarrhythmics. In addition to their class 2 antiarrhythymic action exhibited acutely, on long-term treatment beta blockers have a class 3 action, which might be, at least in part, responsible for the protection of postinfarction patients against sudden death. Recent research suggests that inhibition of slow inward current may lead, as a secondary consequence of lowered [Ca]i, to improved cell-to-cell conduction. Finally, all but one of the new antiarrhythmic drugs, none of which existed in 1972, have turned out to possess one or more of the four classes of action originally described. This can hardly be a coincidence. The single exception, alinidine, a selective bradycardic agent, may restrict anionic currents, which would constitute a fifth class of action, but this is far from proved.

701 citations

Journal ArticleDOI
TL;DR: Amiodarone is superior for maintaining sinus rhythm, but both drugs have similar efficacy in patients with ischemic heart disease, and sustained Sinus rhythm is associated with an improved quality of life and improved exercise performance.
Abstract: background The optimal pharmacologic means to restore and maintain sinus rhythm in patients with atrial fibrillation remains controversial. methods In this double-blind, placebo-controlled trial, we randomly assigned 665 patients who were receiving anticoagulants and had persistent atrial fibrillation to receive amiodarone (267 patients), sotalol (261 patients), or placebo (137 patients) and monitored them for 1 to 4.5 years. The primary end point was the time to recurrence of atrial fibrillation beginning on day 28, determined by means of weekly transtelephonic monitoring. results Spontaneous conversion occurred in 27.1 percent of the amiodarone group, 24.2 percent of the sotalol group, and 0.8 percent of the placebo group, and direct-current cardioversion failed in 27.7 percent, 26.5 percent, and 32.1 percent, respectively. The median times to a recurrence of atrial f ibrillation were 487 days in the amiodarone group, 74 days in the sotalol group, and 6 days in the placebo group according to intention to treat and 809, 209, and 13 days, respectively, according to treatment received. Amiodarone was superior to sotalol (P<0.001) and to placebo (P<0.001), and sotalol was superior to placebo (P<0.001). In patients with ischemic heart disease, the median time to a recurrence of atrial fibrillation was 569 days with amiodarone therapy and 428 days with sotalol therapy (P=0.53). Restoration and maintenance of sinus rhythm significantly improved the quality of life and exercise capacity. There were no significant differences in major adverse events among the three groups. conclusions Amiodarone and sotalol are equally efficacious in converting atrial fibrillation to sinus rhythm. Amiodarone is superior for maintaining sinus rhythm, but both drugs have similar efficacy in patients with ischemic heart disease. Sustained sinus rhythm is associated with an improved quality of life and improved exercise performance.

637 citations

Journal ArticleDOI
TL;DR: The human ether-a-go-go related gene (hERG) encodes the pore-forming subunit of the rapid component of the delayed rectifier K(+) channel, Kv11.1, which is the gene product involved in chromosome 7-associated long QT syndrome (LQTS), an inherited disorder associated with a markedly increased risk of ventricular arrhythmias and sudden cardiac death.
Abstract: The human ether-a-go-go related gene (hERG) encodes the pore-forming subunit of the rapid component of the delayed rectifier K+ channel, Kv11.1, which are expressed in the heart, various brain regions, smooth muscle cells, endocrine cells, and a wide range of tumor cell lines. However, it is the role that Kv11.1 channels play in the heart that has been best characterized, for two main reasons. First, it is the gene product involved in chromosome 7-associated long QT syndrome (LQTS), an inherited disorder associated with a markedly increased risk of ventricular arrhythmias and sudden cardiac death. Second, blockade of Kv11.1, by a wide range of prescription medications, causes drug-induced QT prolongation with an increase in risk of sudden cardiac arrest. In the first part of this review, the properties of Kv11.1 channels, including biogenesis, trafficking, gating, and pharmacology are discussed, while the second part focuses on the pathophysiology of Kv11.1 channels.

565 citations


Cites background from "A third class of anti-arrhythmic ac..."

  • ...Newly identified drugs like amiodarone, which delayed repolarization and thereby prolonged both action potential duration and the effective refractory period, were categorized as class III antiarrhymic drugs (580)....

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Journal ArticleDOI
Jay W. Mason1
TL;DR: If antiarrhythmic-drug therapy is to be used to prevent recurrences of ventricular tachyarrhythmias, treatment with sotalol and assessment of its potential efficacy by Holter monitoring are a reasonable initial strategy.
Abstract: Background The relative efficacies of various antiarrhythmic drugs in the treatment of ventricular tachyarrhythmias are not well known. This study examined the effectiveness of imipramine, mexiletine, pirmenol, procainamide, propafenone, quinidine, and sotalol in patients with ventricular tachyarrhythmias who were enrolled in the Electrophysiologic Study versus Electrocardiographic Monitoring trial. Methods Patients were randomly assigned to undergo serial testing of the efficacy of the seven antiarrhythmic drugs by one of two strategies: electrophysiologic study or Holter monitoring together with exercise testing. The seven drugs were then tested for efficacy in random order in patients who were eligible to receive them. The frequencies of predictions of drug efficacy and of adverse drug effects during the initial drug titration were tabulated for all 486 randomized subjects. Patients received long-term treatment with the first antiarrhythmic drug that was predicted to be effective on the basis of drug t...

410 citations

References
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Journal ArticleDOI
TL;DR: Both isomers of propranolol were capable of preventing adrenaline‐induced cardiac arrhythmias in cats anaesthetized with halothane, but the mean dose of (–)‐pro Pranolol was 0.09 ± 0.02 mg/kg whereas that of (+), which attenuated the responses to isoprenaline was 4.2 ± 1.2mg/kg.
Abstract: 1. The optical isomers of propranolol have been compared for their β-blocking and antiarrhythmic activities. 2. In blocking the positive inotropic and chronotropic responses to isoprenaline, (+)-propranolol had less than one hundredth the potency of (-)-propranolol. At dose levels of (+)-propranolol which attenuated the responses to isoprenaline, there was a significant prolongation of the PR interval of the electrocardiogram. 3. The metabolic responses to isoprenaline in dogs (an increase in circulating glucose, lactate and free fatty acids) were all blocked by (-)-propranolol. (+)-Propranolol had no effect on fatty acid mobilization but significantly reduced the increments in both lactate and glucose. 4. Both isomers of propranolol possessed similar depressant potency on isolated atrial muscle taken from guinea-pigs. 5. The isomers of propranolol exhibited similar local anaesthetic potencies on an isolated frog nerve preparation at a level approximately three times that of procaine. The racemic compound was significantly less potent than either isomer. 6. Both isomers of propranolol were capable of preventing adrenaline-induced cardiac arrhythmias in cats anaesthetized with halothane, but the mean dose of (-)-propranolol was 0.09±0.02 mg/kg whereas that of (+)-propranolol was 4.2±1.2 mg/kg. At the effective dose level of (+)-propranolol there was a significant prolongation of the PR interval of the electrocardiogram. Blockade of arrhythmias with both isomers was surmountable by increasing the dose of adrenaline. 7. Both isomers of propranolol were also capable of reversing ventricular tachycardia caused by ouabain in anaesthetized cats and dogs. The dose of (-)-propranolol was significantly smaller than that of (+)-propranolol in both species but much higher than that required to produce evidence of β-blockade. 8. The implications of these results are discussed.

578 citations

Journal ArticleDOI
TL;DR: It was concluded that amiodarone had effects on cardiac action potentials similar to those which occur after thyroidectomy.
Abstract: 1. Amiodarone (2-butyl, 3-(4-diethylaminoethoxy, 3,5-diiodo, benzoyl) benzofuran hydrochloride), an anti-anginal drug which causes coronary dilatation and depresses myocardial oxygen consumption, was found to protect anaesthetized guinea-pigs against ouabain-induced ventricular fibrillation. 2. A 5% (73·4 mM) solution of amiodarone had no local anaesthetic action on guinea-pig skin. 3. Amiodarone, 20 mg/kg (29·4 μmol/kg) given daily for 6 weeks intraperitoneally, had no effect on the resting potential or action potential height, and only a small effect on the maximum rate of depolarization, of isolated rabbit atrial or ventricular muscle fibres as shown by intracellular recording. It caused a considerable prolongation of the action potential in both tissues. 4. Simultaneous administration of thyroxine (5 μg; 6·26 nmol), given daily for 3 weeks intraperitoneally, prevented the prolongation by amiodarone of the duration of the action potential. 5. Treatment of rabbits with 20 mg/kg of amiodarone daily intraperitoneally for 6 weeks had no effect on the weight of the thyroid gland, but was associated with a reduction in body growth rate. 6. Treatment of rabbits with 10 mg/kg (60·3 μmol/kg) of potassium iodide (equal in its iodine content to that of 20 mg/kg of amiodarone), given daily for 6 weeks intraperitoneally, had no effect on body growth rate or the duration of cardiac action potentials. 7. It was concluded that amiodarone had effects on cardiac action potentials similar to those which occur after thyroidectomy.

550 citations

Journal Article
TL;DR: Studies involving the responses of respiratory and uterine smooth muscle and cardiac muscle to isoproterenol have revealed potent and selective β-adrenergic blocking action as a property of two phenethanolamines bearing a methylsulfonamido radical at the para position on the benzene ring.
Abstract: Studies involving the responses of respiratory and uterine smooth muscle and cardiac muscle to isoproterenol have revealed potent and selective β-adrenergic blocking action as a property of two phenethanolamine compounds bearing a methylsulfonamido radical at the para position on the benzene ring. These compounds had no other significant peripheral actions, including no local anesthetic action, and only limited effects on the central nervous system. Acute toxicity studies in mice, rats, dogs, and rabbits, and subacute toxicity studies in rats and dogs, indicated extremely low toxic liability. Neither compound had harmful effects on the fetuses of mice or rabbits dosed during critical days of pregnancy.

223 citations

Journal ArticleDOI
TL;DR: A group of rabbits was made hypothyroid by thyroidectomy, and another group was injected daily with L‐thyroxine until alterations in thyroid state were confirmed by measurement of heart weight and of plasma iodine.
Abstract: 1. A group of rabbits was made hypothyroid by thyroidectomy, and another group was injected daily with L-thyroxine. After an appropriate interval respective alterations in thyroid state were confirmed by measurement of heart weight and of plasma iodine, and the animals' atria were isolated for recording. 2. Measurements were made of atrial contractions, conduction velocity, spontaneous heart rate and maximum driven frequency, and action potentials were recorded with intracellular micro-electrodes. 3. The resting potential and action potential heights were not affected by differences of thyroid state. 4. Atrial arrhythmias are common in hyperthyroidism, rare in myxoedema. The possibility that hypothyroidism might reduce the rate of rise of the action potential, as do anti-arrhythmic drugs, and hyperthyroidism increase it, was investigated. Although the rate of rise was slower in hypothyroid atria at some driving frequencies, this could not alone account for an anti-arrhythmic effect, because at frequencies near the spontaneous heart rate the rate of rise of the action potential was not reduced. 5. The duration of the repolarization phase of the action potential was greatly prolonged in atria from thyroidectomized rabbits, and was shortened in hyperthyroid atria. These changes could account for a reduced probability of arrhythmias in hypothyroidism, and the converse in hyperthyroidism.

210 citations

Journal ArticleDOI
TL;DR: As an experimental tool, a cardiac adrenergic blocking agent is clearly more useful the greater the range of concentrations over which it exerts its blocking action without producing other effects.
Abstract: Our experiments with beta adrenergic blocking agents have been prompted by three related interests. The first of these is the question of the separability of the positive chronotropic and inotropic effects of the sympathomimetic amines. Tha t is, are the effects of these substances on the strength and frequency of contraction of the heart mediated through interaction with a single receptor type, or are there separate, differentiable populations of receptors for the two effects? The study of the actions of adrenergic blocking agents provides one obvious approach to this question. The second interest has been in the nature of the antagonism between the various beta adrenergic blocking agents and the catecholamines a t the cardiac adrenergic receptors. We wanted information about such factors as the specificity and surmountability of the antagonism, the nature of the shifts produced in the dose-effect curves, and the time course of onset of blocking action. The third interest has been in the relation between the adrenergic blocking actions and other cardiac effects of some of the more promising new beta adrenergic blocking drugs. In high concentrations, all of these substances have negative inotropic and chronotropic effects; in lower concentrations, some of them-perhaps all-have sympathomimetic effects in some degree. As an experimental tool, a cardiac adrenergic blocking agent is clearly more useful the greater the range of concentrations over which it exerts its blocking action without producing other effects.

191 citations