The effect of amiodarone, a new anti‐anginal drug, on cardiac muscle
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.
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TL;DR: Experimental and clinical data suggest that verapamil will become an important and safe addition to existing drug regimens, especially as an agent of choice for the short-term treatment of most cases of paroxysmal supraventricular tachycardias and in the maintenance of sinus rhythm following cardioversion of atrial fibrillation.
Abstract: Synopsis: Verapamil is a novel antiarrhythmic and antianginal agent which, although introduced in 1962, has only recently gained prominence not only as a significant agent in cardiovascular therapeutics but also as a powerful tool to examine the nature of some of the biophysical phenomena at the membrane of cardiac and other excitable tissues. Verapamil is the prototype of those agents which selectively inhibit membrane transport of calcium, an action which accounts for the drug’s peripheral and coronary vasodilator properties, its effect on excitation-contraction coupling and hence its negative inotropic propensity, as well as its depressant effects on the sinus node and atrioventricular conduction. Its pharmacological effects are largely independent of the autonomic nervous system. The main therapeutic uses of the drug are in the management of atrial tachyarrhythmias, angina, and possibly hypertension. The overall experimental and clinical data suggest that verapamil will become an important and safe addition to existing drug regimens, especially as an agent of choice for the short-term treatment of most cases of paroxysmal supraventricular tachycardias. The initial experience in other arrhythmias, angina and hypertension, is also sufficiently encouraging to justify further detailed clinical trials to define its potential role in cardiovascular therapeutics.
798 citations
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
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
TL;DR: With regard to currently available class III agents, although their class III effect may reduce the likelihood of tachycardia initiation, their reverse use-dependent prolongation of action potential duration reduces their effectiveness during tachycardsias and may even render them proarrhythmic, especially after long diastolic intervals.
Abstract: With regard to currently available class III agents, although their class III effect may reduce the likelihood of tachycardia initiation, their reverse use-dependent prolongation of action potential duration reduces their effectiveness during tachycardias and may even render them proarrhythmic, especially after long diastolic intervals. In contrast, agents that exhibit normal use-dependent prolongation of refractoriness hold great promise: While having relatively less effects on the normal heart beat, they could induce self-termination of a tachycardia. Prolongation of refractoriness can be achieved by lengthening of action potential duration and delaying recovery of excitability. Combination of these drug actions may yield important clinical applications.
610 citations
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 "The effect of amiodarone, a new ant..."
...It was triggered by the finding that amiodarone, an antianginal drug, caused considerable prolongation of the action potential duration in isolated rabbit atrial or ventricular muscle fibers (579)....
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...In 1970, Vaughan-Williams (579) introduced a classification system for antiarrhythmic drugs, which, as the name implies, are used to restore normal heart rhythm and contraction....
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References
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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 Article•
TL;DR: It was observed that when adrenaline was added to procaine and the mixture was compared with cocaine by the guinea-pig method, the log dose-effect lines became parallel and it was suggested to use procaine as a standard of comparison.
Abstract: 1. Two methods are described for testing the potency of local anaesthetics. 2. With a certain range of concentrations a linear relationship exists between the logarithm of the concentration of the local anaesthetics which were examined and the time at which plexus anaesthesia in frogs develops. 3. When the intracutaneous wheal in guinea-pigs is used, a similar linear relation exists between the logarithm of the concentration of the local anaesthetic and an index expressing both intensity and duration of anaesthesia. 4. The lines for β-eucaine, procaine and nupercaine, though parallel to each other, are not parallel to that for cocaine. It is suggested, therefore, to use procaine as a standard of comparison. It was observed that when adrenaline was added to procaine and the mixture was compared with cocaine by the guinea-pig method, the log dose-effect lines became parallel.
185 citations
Journal Article•
108 citations
TL;DR: In isolated rabbit atria (–)‐, (+)‐ and (±)‐propranolol, and I.C.I. 50172, which has hardly any local anaesthetic activity, greatly reduce the rate of rise of the intracellularly recorded action potential at concentrations which have no significant effect on electrical threshold, contractions, spontaneous frequency, maximum driving frequency, repolarization time or conduction velocity.
Abstract: 1. (+)-propranolol and (+/-)-propranolol are comparable in their potency as a local anaesthetic on the intact and desheathed frog sciatic nerve.2. (+/-)-propranolol is much more potent than (+)-propranolol as a beta-receptor blocking agent and also more effective than the latter in protecting guinea-pigs against ouabain-induced ventricular fibrillation.3. In isolated rabbit atria (-)-, (+)- and (+/-)-propranolol, and I.C.I. 50172, which has hardly any local anaesthetic activity, greatly reduce the rate of rise of the intracellularly recorded action potential at concentrations which have no significant effect on electrical threshold, contractions, spontaneous frequency, maximum driving frequency, repolarization time or conduction velocity.
91 citations