Electrophysiologic correlates of the inotropic effects of Isoproterenol in canine myocardium

doi:10.1016/0022-2828(75)90002-4

Journal of Molecular and Cellular Cardiology

Volume 7, Issue 1, January 1975, Pages 1-15

https://doi.org/10.1016/0022-2828(75)90002-4 Get rights and content

Abstract

The action of l-isoproterenol was studied in isolated canine papillary muscles. The simultaneous action potential and contraction traces were first recorded in digital form on magnetic tape and later measured and analyzed by a computer program. The data were controlled and grouped to permit a three-way analysis of variance in order to test significant effects and correlations. Complete dose-response curves were performed both before and after beta-adrenergic blockade with (±)propranolol. It was demonstrated that isoproterenol produced and increase in the peak potential, the height and duration of the plateau (phase 3), and the rate of repolarization of the action potential (phase 4). Corresponding increases in peak tension, time to peak tension, rate of tension development, and rate of relaxation of the contraction were noted. At the highest isoproterenol concentrations, occasional after-potentials and after-contractions occurred. The changes in the action potential were explained by changes in the inward calcium current, while the inotropic effect on the contraction was attributed to the resulting increase in intracellular calcium concentration. These effects were all blocked by the addition of propranolol, but the blockade could be overcome by increasing the isoproterenol concentration of the perfusate.

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Most forms of sustained ventricular tachycardia (VT) are caused by re-entry, resulting from altered myocardial conduction and refractoriness secondary to underlying structural heart disease. In contrast, VT caused by triggered activity (TA) is unrelated to an abnormal structural substrate and is often caused by molecular defects affecting ion channel function or regulation of intracellular calcium cycling. This review summarizes the cellular and molecular bases underlying TA and exemplifies their clinical relevance with selective representative scenarios. The underlying basis of TA caused by delayed afterdepolarizations is related to sarcoplasmic reticulum calcium overload, calcium waves, and diastolic sarcoplasmic reticulum calcium leak. Clinical examples of TA caused by delayed afterdepolarizations include sustained right and left ventricular outflow tract tachycardia and catecholaminergic polymorphic VT. The other form of afterpotentials, early afterdepolarizations, are systolic events and inscribe early afterdepolarizations during phase 2 or phase 3 of the action potential. The fundamental defect is a decrease in repolarization reserve with associated increases in late plateau inward currents. Malignant ventricular arrhythmias in the long QT syndromes are initiated by early afterdepolarization–mediated TA. An understanding of the molecular and cellular bases of these arrhythmias has resulted in generally effective pharmacologic-based therapies, but these are nonspecific agents that have off-target effects. Therapeutic efficacy may need to be augmented with an implantable defibrillator. Next-generation therapies will include novel agents that rescue arrhythmogenic abnormalities in cellular signaling pathways and gene therapy approaches that transfer or edit pathogenic gene variants or silence mutant messenger ribonucleic acid.
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Cardiac arrhythmias result from abnormalities in the initiation of impulses or in conduction of these impulses through the heart. 58, 60 Arrhythmias caused by abnormalities in impulse initiation may result from either automaticity or triggered activity. Arrhythmias caused by abnormalities in conduction are often the result of reentrant excitation. Such alterations in impulse initiation or conduction are readily apparent in recordings of extracellular signals from the heart in the form of either the electrocardiogram (ECG) or more direct electrographic recordings from the atria and ventricles. The recording of transmembrane electrical events of individual myocardial cells with microelectrodes, however, has provided the information necessary for understanding the mechanisms that are responsible for arrhythmias. Although arrhythmias may have many different pathologic causes, in the final analysis, all arrhythmias are the result of critical alterations in cellular electrophysiology. This article discusses the cellular mechanisms responsible for abnormalities in impulse initiation and how they are manifested on the ECG.
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The isoproterenol-induced chloride current and cardiac resting potential
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Isoproterenol can induce potentially arrhymthogenic depolarizations of the resting membrane of single guinea-pig ventricular myocytes [1]. This effect on resting potential of single guinea-pig ventricular myocytes differs qualitatively from results obtained by others from intact cardiac muscle preparations [2–5] and also differs from our experience with single dog ventricular myocytes. We performed experiments on dog and guinea-pig ventricular myocytes in an attempt to clarify the effects of isoproterenol on the resting potential of mammalian ventricular myocytes. Voltage recordings with 40–60 mΩ 3 m potassium chloride filled microelectrodes revealed an isoproterenol-induced depolarization of 4.3 ± 1.0 mV in guinea-pig but no depolarization in dog myocytes. Activation of an outwardly rectifying chloride current is responsible for the isoproterenol-induced depolarization of guinea-pig ventricular myocytes [6–9]. Our whole cell patch clamp recordings consistently revealed such a current in guinea-pig cells but always failed to demonstrate an insoproterenol-induced chloride current in dog myocytes under identical conditions.
In contrast to single cells, isoproterenol did not depolarize intact guinea-pig papillary muscle when potential was recorded with 40–60 mΩ 3 m KCl filled electrodes. Furthermore, we saw no depolarization in single guinea-pig myocytes when recording electrodes did not contain chloride. We conclude that: (1) despite activation of a chloride current, isoproterenol does not significantly depolarize guinea-pig ventricular muscle unless the driving force for the current at the resting potential is increased by elevating [Cl]_i above physiological levels, and (2) an isoproterenol-induced chloride current, although demonstrable in guinea-pig ventricular cells, is not present in healthy dog ventricular cells.
Pharmacology of bipyridine phosphodiesterase III inhibitors
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The bipyridine phosphodiesterase III inhibitors amrinone and milrinone form a new class of positive inotropic vasodilator agents that are beneficial in the treatment of acute or decompensated heart failure. These agents inhibit the intracellular hydrolysis of cyclic adenosine monophosphate, thereby promoting cyclic adenosine monophosphate-catalyzed phosphorylation of sarcolemmal calcium channels and activating the calcium pump. They have a wider therapeutic index than do the cardiac glycosides. They also have vasodilator and lusitropic actions and are devoid of the central stimulant actions that narrow the therapeutic index of theophylline and other methylxanthines. Receptor down-regulation, which curtails the inotropic efficacy of β-adrenoreceptor agonists, does not compromise the efficacy of phosphodiesterase inhibitors. The effectiveness of these new agents is, however, dependent on some degree of basal adenylate cyclase activity.
Cellular electrophysiologic mechanisms of cardiac arrhythmias
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Cardiac arrhythmias result from abnormalities in the initiation of impulses or in the conduction of these impulses through the heart. Arrhythmias caused by impulse initiation may be caused by either automaticity or triggered activity. Arrhythmias caused by abnormalities in conduction are often the result of reentrant excitation. These arrhythmogenic mechanisms arise because of alterations in the transmembrane potentials of cardiac cells that are often caused by disease. These cellular mechanisms causing arrhythmias are the subject of this article.

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^☆: This investigation was supported in part by Research Grants HL-12824 and RR-7 from the National Institutes of Health, Public Health Service.

^†: Present address: Department of Medicine, University of sherbrooke, Sherbrooke, Quebec.

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Journal of Molecular and Cellular Cardiology

Abstract

References (18)

Voltage clamp experiments on ventricular myocardial fibres

Journal of Physiology (London)

Membrane calcium current in ventricular myocardial fibres

Journal of Physiology (London)

The relation between membrane potential membrane currents and activation of contraction in ventricular myocardial fibres

Journal of Physiology (London)

Evaluation of the cardiac effects of several beta adrenergic blocking agents

Annals of the New York Academy of Sciences

Mechanism of action of epinephrine and glucagon on the canine heart: evidence for increase in sarcotubular calcium stores mediated by cyclic 3′, 5′-AMP

Circulation Research

Membrane currents in mammalian ventricular heart muscle fibers using a voltage-clamp technique

Journal of General Physiology

The effect of the internal sodium concentration on calcium fluxes in isolated guinea-pig auricles

Journal of Physiology (London)

The effects of various drugs on calcium exchange in the isolated guinea-pig left auricle

Journal of Pharmacology and Experimental Therapeutics

Cited by (32)

Ventricular Tachycardia Due to Triggered Activity: Role of Early and Delayed Afterdepolarizations

Cellular electrophysiology mechanisms of cardiac arrhythmias

Review: Milrinone: Basic and Clinical Pharmacology and Acute and Chronic Management

The isoproterenol-induced chloride current and cardiac resting potential

Pharmacology of bipyridine phosphodiesterase III inhibitors

Cellular electrophysiologic mechanisms of cardiac arrhythmias

Electrophysiologic correlates of the inotropic effects of Isoproterenol in canine myocardium☆

Abstract

Voltage clamp experiments on ventricular myocardial fibres

Journal of Physiology (London)

Membrane calcium current in ventricular myocardial fibres

Journal of Physiology (London)

The relation between membrane potential membrane currents and activation of contraction in ventricular myocardial fibres

Journal of Physiology (London)

Evaluation of the cardiac effects of several beta adrenergic blocking agents

Annals of the New York Academy of Sciences

Mechanism of action of epinephrine and glucagon on the canine heart: evidence for increase in sarcotubular calcium stores mediated by cyclic 3′, 5′-AMP

Circulation Research

Membrane currents in mammalian ventricular heart muscle fibers using a voltage-clamp technique

Journal of General Physiology

The effect of the internal sodium concentration on calcium fluxes in isolated guinea-pig auricles

Journal of Physiology (London)

The effects of various drugs on calcium exchange in the isolated guinea-pig left auricle

Journal of Pharmacology and Experimental Therapeutics