© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
A fourth class of anti-dysrhythmic action? Effect of verapamil and ouabain toxicity, on atrial and ventricular intracellular potentials, and on other features of cardiac function
Cardiology Section (111E), UCLA School of Medicine, VAMC of West Los Angeles, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA
* Tel.: +1-310-268-3646; fax: +1-310-268-4288 bsingh{at}ucla.edu
KEYWORDS Antiarrhythmic agents; Atrial function; Ca-channel; Impulse formation; Membrane potential; Ventricular arrhythmias; Ventricular function
This paper was published on the basis of research performed in the laboratory of Dr Miles Vaughan Williams in the Department of Pharmacology, University of Oxford, during a tenure of a Nuffield Dominions Traveling Scholarship between the years 1969 and 1971. There are two aspects of the paper which may be of historical interest. The first relates to the fact that the data summarized therein formed an integral component of the thesis that was accepted by the University of Oxford to award me the degree of Doctor of Philosophy in 1971 [1] on the recommendation of the external examiners, Dr (Sir) James Black (then of University of London) and Dr Grant de J Lee (of the Radcliffe Infirmary, Oxford). Both examiners provided strong encouragement that I should continue the work after I left Oxford. The second issue about the paper is that it was the fourth in the series from the overall work for the doctoral thesis at Oxford that formed the basis for the classification of antiarrhythmic drugs [2–4] that provided the framework with minor additions and modifications [6,7] for the discussion of the mechanisms of antiarrhytmic agents. After three decades, the classification has remained essentially intact and had formed the basis for clinical use of antiarrhythmic drugs and for the synthesis and development of new compounds. The historical importance of the paper on the compound verapamil in Cardiovascular Research can only be placed in perspective relative to the overall mechanisms of antiarrhythmic compounds.
The anecdotal aspects of the ‘story’ behind the paper on verapamil and the others in the series have not been mentioned previously in print. I graduated from the University of Otage Medical School in New Zealand and completed training in internal medicine and subsequently in cardiology when I was nominated by my medical school for the award of Nuffield Scholarship to Oxford. My plans for going to Hammersmith Hospital in London for postgraduate training promptly changed when acceptance in the Department of Pharmacology became a reality. My first three months in Oxford overlapped with the last three months of Dr Julius Papp from Hungary. He kindly introduced me to the microelectrode technique for recording transmembrane potentials in cardiac muscle which became the basis for the major work that I did in Oxford for the doctoral degree. At the time I commenced work in Dr Vaughan Williams’ laboratory, there were a number of compounds on the shelves. Their electrophysiologic actions had not been elucidated. Of particular interest were verapamil, amiodarone, solatol, and propranolol (along with a number of other beta-blockers) All four of these compounds had been synthesized as anti-anginal or antiischemic agents in 1962 — verapamil and amiodarone as coronary vasodilators, sotalol and propranolol as beta-blockers. In the event, the work I undertook in isolated cardiac muscle and in the arrhythmia model in intact anaesthesized guinea pigs, showed, quite surprisingly, that both solalol and amiodarone had little effect on conduction but both prolonged the duration of the action potential in atrial as well as ventricular muscle of rabbits, sotalol acutely and amiodarone after chronic administration. Both drugs also exerted an antifibrillatory effect in the guinea pig arrhythmia model. Thus, this action of sotalol and amiodarone were designated a class III effect, since the action of quinidine produced depression of conduction velocity by blocking sodium currents it was designated as a class I agent and beta-blockers as class II agents by virtue of their anti-adrenergic effects.
Although, a number of investigators had previously believed that verapamil was a form of a beta-blocker, work that we performed in Oxford in 1971 and reported in 1972 did not support such a notion. As reported in our 1972 paper in Cardiovascular Research, in our hands the drug was found to shorten the action potential duration while virtually abolishing contractility in isolated cardiac muscle. The electrophysiological picture was consistent with a blocking effect on transmembrane influx of calcium. Similarly, increases in contractility induced by histamine, glucagon and ouabain were attenuated by verapamil. Since the drug was found to be very effective also in preventing the onset of ventricular fibrillation in animals given high doses of ouabain, its antiarrhythmic actions were attributed to the antagonistic effect on calcium currents. Thus, it appeared to be a unique hitherto unrecognized mechanism of action of an antiarrhythmic agent, a pharmacological property that was tentatively designated a class IV effect. It was no longer after that the effects of the drug were tested critically in various clinical laboratories including our own [8]. Subsequently, the advent of the voltage clamp technique clearly demonstrated that verapamil did selectively block calcium currents in the heart and such an effect in the atrio-ventricular node in patients led to the prompt termination of supraventricular tachycardia with re-entrant circuit encompassing the AV node. These advances have followed in the wake of the information in the paper in Cardiovascular Research. Class IV antiarrhythmic action, created because of the action of verapamil as demonstrated in isolated cardiac muscle and antifibrillatory effects in anesthesized animal models, remains an intact concept in arrhythmia control [9] almost three decades after the original speculation and suggestion by Singh and Vaughan Williams. [5]
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- Singh BN. Pharmacological Actions of Certain Cardiac Drugs and Hormones: Focus on Antiarrhythmic Mechanisms. D. Phil Thesis, 1971; Hertford College and University of Oxford, UK. Published also by Futura Publishing Co. Mt Kisco, NY, 1991, pp. 1–98.
- Singh B.N., Vaughan Williams E.M. A third class of anitarrhythmic action. Effects of atrial and ventricular intracellular potentials, and pharmacological actions on cardiac muscle, of MJ1999 and AH 3474. Br J Pharmacol (1970) 39:675–687.[Web of Science][Medline]
- Singh B.N., Vaughan Williams E.M. The effect of amiodarone, a new anti-anginal drug, on cardiac muscle. Br J Pharmacol (1970) 39:657–667.[Web of Science][Medline]
- Vaughan Williams E.M. Symposium on cardiac arrhythmias. Sandoe E., Flenstedt-Johnson E., Olesen K.H., eds. (1970) Sodertalje, Sweden: Ab Astra. 440–469.
- Singh B.N., Vaughan Williams E.M. A fourth class of antidysrythmic action? Effect of verapamil on ouabain toxicity, on atrial and ventricular intracellular potentials, and on other features of cardiac function. Cardiovasc Res (1972) 6(2):109–119.
[Abstract/Free Full Text] - Singh B.N., Hauswirth O. Comparative mechanisms of action of antiarrhythmic drugs. Am Heart J (1974) 87:367–377.[CrossRef][Web of Science][Medline]
- Campbell J.C. Kinetic of onset rate-dependent effects of class I antiarrhythmic drugs are important in determining their effects of refractoriness in guinea-pig ventricle, and provide a theoretical basis for their subclassification. Cardiovasc Res (1983) 17:344–352.
[Abstract/Free Full Text] - Heng M.K., Singh B.N., Roche A.H.G., Norris R.M., Mercer C.J. Effects of intravenous verapamil on cardiac arrhythmias and on the electrocardiogram. Am Heart J (1975) 90:487–578.[CrossRef][Web of Science][Medline]
- Singh B.N. Current antiarrhythmic drugs: An overview of mechanisms of action and potential clinical utility. J Cardiovasc Electrophysiol (1999) 10:283–301.[Web of Science][Medline]
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