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Effects of noradrenaline and isoprenaline, in combination with - and -receptor blocking substances, on the action potential of cardiac Purkinje fibres

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Abstract

1. The effects of noradrenaline and isoprenaline on the repolarization phase of the action potential have been studied in the Purkinje fibres of sheep heart, electrically driven at constant rates.2. Isoprenaline (2, 5 and 8 x 10(-8) g/ml.) increases the slope of phase 2 of repolarization and decreases the plateau length; the resulting decrease in action potential duration is concentration dependent, but not rate dependent.3. The effect of isoprenaline on the action potential duration is entirely blocked by propranolol (10(-7) g/ml.) and unaffected by phentolamine (5 x 10(-7) g/ml.).4. In phentolamine (5 x 10(-7) g/ml.) pretreated preparations the response induced by noradrenaline (5 x 10(-8), 1 and 5 x 10(-7) g/ml.) is very similar to that induced by isoprenaline.5. In propranolol (2.5 x 10(-7) g/ml.) pretreated preparations noradrenaline causes a lengthening of the plateau phase and an increase in action potential duration.6. The relationship of these results to the presence of both alpha- and beta-receptors in cardiac Purkinje fibres is discussed.

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... Alterations in the automaticity of myocardial tissues produced by antiarrhythmics probably represent the most fundamental mechanism whereby these substances produce their therapeutic actions. Although the ionic basis of automaticity is as yet incompletely understood and likely is not identical in all regions of the heart, the ability of antiarrhythmics such as lidocaine (136) and propranolol (87,137) to modify transmembrane fluxes of K + has been implicated in their actions on cardiac automaticity. Model studies in erythrocytes (87) have demonstrated that propranolol, at concentrations causing stabilization of erythrocytes (52) and an enhancement of K + efflux from canine Purkinje fibers (137), produces an increase in K" efflux from these cells, presumably as the result of drug-induced membrane structural perturbations leading to the displacement of membrane-bound Ca ++ (87). ...
... Although the ionic basis of automaticity is as yet incompletely understood and likely is not identical in all regions of the heart, the ability of antiarrhythmics such as lidocaine (136) and propranolol (87,137) to modify transmembrane fluxes of K + has been implicated in their actions on cardiac automaticity. Model studies in erythrocytes (87) have demonstrated that propranolol, at concentrations causing stabilization of erythrocytes (52) and an enhancement of K + efflux from canine Purkinje fibers (137), produces an increase in K" efflux from these cells, presumably as the result of drug-induced membrane structural perturbations leading to the displacement of membrane-bound Ca ++ (87). ...
... Because computerized measurement techniques did not exist, early studies focused largely on measurements of discrete timepoints after isoprenaline infusion. Nevertheless, hysteresis was noted (RR decrease before QT) [43], as was dosedependent reduction in action potential duration in fixed atrial pacing [44], and presence of biphasic change in action potential duration (i.e., an increase preceding the decrease) [45]. Sympathetic nerve stimulation was shown to shorten refractory period in epicardial and endocardial tissue by similar amounts [46] and produce biphasic change in monophasic action potential duration despite fixed atrial rate [47]. ...
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Background: An increased QT/RR slope is hypothesized to be predictive of sudden cardiac death after myocardial infarction. Previous studies have shown that beta-adrenergic stimulation increases QT/RR slope, but the effects of beta-adrenergic stimulation on QT/RR slope in heart failure are unknown. Methods: New Zealand White rabbits underwent coronary ligation (n=15) or sham surgery (n=11), and implantation of a pediatric pacemaker lead in the right ventricle for chronic ECG recording. Eight weeks after surgery, unsedated rabbits were given intravenous administrations of 0.25 to 2.0 ml of 1 micromol/l isoprenaline, while peak QRS to QRS (RR) and Q to T peak (QT) intervals were measured. Results: Ligated rabbits (n=6) had lower LVEF than sham rabbits (n=7, p<.0001), but similar baseline RR (269 +/- 15 vs 292 +/- 23 ms, p=.07), QT (104 +/- 17 vs 91 +/- 9 ms, p=.1) and minimum RR (204 +/- 11 vs 208 +/- 6 ms, p=.4) intervals induced by isoprenaline (0.79 +/- 0.18 vs 0.73 +/- 0.14 ml, p=.6). Hysteresis in QT vs TQ interval plots displayed biphasic restitution and regions of negative slope. The slope of the positive slope region was >1 in ligated rabbits (1.27 +/- 0.66) and <1 in sham rabbits (0.35 +/- 0.14, p=.004). Absolute value of the negative slope was greater in ligated rabbits (-0.81 +/- 0.52 vs -0.35 +/- 0.14, p=.04). Conclusion: Ischaemic heart failure produces steeper restitution slopes during beta-adrenergically induced QT/TQ hysteresis. This could underlie the propensity of failing hearts to arrhythmias. Comment: 27 pages
... Because computerized measurement techniques did not exist, early studies focused largely on measurements of discrete time points after isoprenaline infusion. Nevertheless, hysteresis was noted (RR decrease before QT) [44], as was dose-dependent reduction in action potential duration in fixed atrial pacing [45] and presence of biphasic change in action potential duration (i.e., an increase preceding the decrease) [46]. Sympathetic nerve stimulation was shown to shorten refractory period in epicardial and endocardial tissue by similar amounts [47] and produce biphasic change in monophasic action potential duration despite fixed atrial rate [48]. ...
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Roughly speaking, restitution is the dependence of recovery time of cardiac electrical activity on heart rate. Increased restitution slope is theorized to be predictive of sudden death after heart injury such as from coronary artery occlusion (ischemia). Adrenaline analogs are known to increase restitution slope in normal hearts, but their effects in failing hearts are unknown. Twenty-six rabbits underwent coronary ligation (n = 15) or sham surgery (n = 11) and implantation of a lead in the heart for recording electrocardiograms. Eight weeks later, unanesthetized rabbits were given 0.25-2.0 ml of 1 μmol/L isoprenaline intravenously, which increased heart rate. Heart rate was quantified by time between QRS peaks (RR) and heart activity duration by R to T peak time (QTp). Ligated rabbits (n = 6) had lower ejection fraction than sham rabbits (n = 7, p < 0.0001) indicative of heart failure, but similar baseline RR (269 ± 15 vs 292 ± 23 ms, p = 0.07), QTp (104 ± 17 vs 91 ± 9 ms, p = 0.1), and isoprenaline-induced minimum RR (204 ± 11 vs 208 ± 6 ms, p = 0.4). The trajectory of QTp vs TQ plots displayed hysteresis and regions of negative slope. The slope of the positive slope region was >1 in ligated rabbits (1.27 ± 0.66) and <1 in sham rabbits (0.35 ± 0.14, p = 0.004). The absolute value of the negative slope was greater in ligated rabbits (- 0.81 ± 0.52 vs - 0.35 ± 0.14, p = 0.04). Isoprenaline increased heart rate and slopes of restitution trajectory in failing hearts. The dynamics of restitution trajectory may hold clues for sudden death in heart failure patients.
... However, the role of I Ks at physiological HRs in humans has been debated: It has been observed not to contribute significantly to APD in the absence of sympathetic stimulation or compromised repolarization (diminished repolarization reserve) ( 1991). In isolated cells, activation of ß-receptors abbreviates whereas activation of α-receptors prolongs APD (GIOTTI ET AL. 1973). Priori and Corr reported that small concentrations of isoprenaline prolonged whereas larger concentrations markedly abbreviated APD (PRIORI AND CORR 1990). ...
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The autonomic nervous system is an important modulator of ventricular repolarization and arrhythmia vulnerability. This study explored the effects of cardiovascular autonomic function tests on repolarization and its heterogeneity, with a special reference to congenital arrhythmogenic disorders typically associated with stress-induced fatal ventricular arrhythmias. The first part explored the effects of standardized autonomic tests on QT intervals in a 12-lead electrocardiogram and in multichannel magnetocardiography in 10 healthy adults. The second part studied the effects of deep breathing, Valsalva manouvre, mental stress, sustained handgrip and mild exercise on QT intervals in asymptomatic patients with LQT1 subtype of the hereditary long QT syndrome (n=9) and in patients with arrhythmogenic right ventricular dysplasia (ARVD, n=9). Even strong sympathetic activation had no effects on spatial QT interval dispersion in healthy subjects, but deep respiratory efforts and Valsalva influenced it in ways that were opposite in electrocardiographic and magnetocardiographic recordings. LQT1 patients showed blunted QT interval and sinus nodal responses to sympathetic challenge, as well as an exaggerated QT prolongation during the recovery phases. LQT1 patients showed a QT interval recovery overshoot in 2.4 ± 1.7 tests compared with 0.8 ± 0.7 in healthy controls (P = 0.02). Valsalva strain prolonged the T wave peak to T wave end interval only in the LQT1 patients, considered to reflect the arrhythmogenic substrate in this syndrome. ARVD patients showed signs of abnormal repolarization in the right ventricle, modulated by abrupt sympathetic activation. An electrocardiographic marker reflecting interventricular dispersion of repolarization was introduced. It showed that LQT1 patients exhibit a repolarization gradient from the left ventricle towards the right ventricle, significantly larger than in controls. In contrast, ARVD patients showed a repolarization gradient from the right ventricle towards the left. Valsalva strain amplified the repolarization gradient in LQT1 patients whereas it transiently reversed it in patients with ARVD. In conclusion, intrathoracic volume and pressure changes influence regional electrocardiographic and magnetocardiographic QT interval measurements differently. Especially recovery phases of standard cardiovascular autonomic functions tests and Valsalva manoeuvre reveal the abnormal repolarization in asymptomatic LQT1 patients. Both LQT1 and ARVD patients have abnormal interventricular repolarization gradients, modulated by abrupt sympathetic activation. Autonomic testing and in particular the Valsalva manoeuvre are potentially useful in unmasking abnormal repolarization in these syndromes. Autonominen, eli tahdosta riippumaton hermosto osallistuu moniin elimistön säätelytoimintoihin, vaikuttaen suoraan myös sydämeen. Autonominen hermosto jaetaan sympaattiseen hermostoon, joka aktivoituu äkillisissä elimistön kriisitilanteissa kuten vihastumisen, stressin ja rasituksen yhteydessä, sekä parasympaattiseen hermostoon, joka puolestaan toimii vilkkaammin elimistön lepotilassa. Äkillisesti lisääntynyt sympaattisen hermoston aktiivisuus lisää vakavien rytmihäiriöiden vaaraa mm. kasvattamalla ohimenevästi sydämen sähköiseen toipumisvaiheen (repolarisaatioon) keston alueellisia eroja. Tämän ilmiön merkitys korostuu tietyissä vakaville rytmihäiriöille altistavissa perinnöllisissä taudeissa, joissa repolarisaatio on valmiiksi poikkeava. Näille taudeille on tunnusomaista henkeä uhkaavan rytmihäiriön ilmaantumisen riski tilanteissa joissa autonomisen hermoston toiminta muuttuu äkillisesti. Väitöskirjatutkimuksessa selvitettiin vakioitujen autonomisen hermoston toimintakokeiden vaikutuksia sydämen repolarisaatioon, mittaamalla monikanavaisesta sydänsähkökäyrästä (EKG) repolarisaatiota kuvaavaa QT-aikaa lyönti lyönniltä. Erityisesti tutkittiin testisarjan (syväänhengityskoe, Valsalvan koe, henkinen stressitesti, isometrinen puristuskoe, kevyt rasitus) vaikutuksia QT-aikaan kahdessa perinnöllisessä rytmihäiriösairaudessa; 1-tyypin pitkä-QT oireyhtymässä (LQT1) ja oikean kammion arytmogeenisessä dysplasiassa (ARVD). LQT1-potilailla syketaajuuden nousu ja QT-ajan lyheneminen olivat normaalia vaimeampia sympaattiseen aktivaation aikana, ja tunnusomaista oli QT-ajan poikkeava piteneminen testien palautumisvaiheissa. Lisäksi Valsalvan kokeen ponnistusvaihe pidensi ohimenevästi T-aallon huipusta T-aallon loppuun mitattua aikaintervallia, mikä katsotaan olevan rytmihäiriöriskiä parhaiten kuvaava EKG-ilmiö tässä oireyhtymässä. ARVD-potilailla havaittiin merkkejä poikkeavasta oikean kammion repolarisaatiosta, ja sen muuttumisesta sympaattisen aktivaation vaikutuksesta. Tutkimuksessa esitettiin lisäksi uusi tapa kuvata repolarisaation epäyhtenäisyyttä, arvioimalla EKG:n avulla sydämen oikean ja vasemman kammion välistä repolarisaatiogradienttia. Gradientti oli normaalia suurempi ja suunnaltaan vasemmalta oikealle LQT1-potilailla, mutta päinvastainen eli oikealta vasemmalle ARVD-potilailla. Valsalvan kokeen ponnistusvaihe korosti entisestään gradienttia LQT1-potilailla ja käänsi ohimenevästi sen suuntaa ARVD-potilailla. Autonomisen hermoston testit ja niistä erityisesti Valsalvan koe osoittautuivat käyttökelpoiseksi poikkeavan repolarisaation paljastamisessa LQT1- ja ARVD-potilailla. Kuvatuista menetelmistä saattaa jatkossa olla apua näiden sairauksien hoitolinjauksissa ja rytmihäiriöriskin arvioimisessa.
... Thus, during sleep, when there is a predominance of parasympathetic over sympathetic activity, we found the atrial effective refractory period reaches its highest values. Previous studies have shown that vagal stimulation shortens the atrial effective refractory period [11][12][13][14][15] , while sympathetic stimulation can either increase or decrease the atrial effective refractory period by stimulating the -or -receptors, respectively [16][17][18] . In this study, despite the increased vagal activity occurring during the night, the decrease in sympathetic stimulation seemed to have led to an increase in the atrial effective refractory period via reduced activation of the -receptors. ...
Article
Aims To examine whether atrial and ventricular effective refractory periods exhibit circadian variation and whether the latter is correlated with fluctuations in autonomic nervous system tone. Methods and Results We studied 24 patients aged 67·1±9·6 years, 11 of whom were paced for complete heart block and 13 for sick sinus syndrome. Atrial and ventricular effective refractory periods were measured bihourly over a 24-h period, using the pacemaker programming capabilities, at basic cycle lengths of 600ms and 500ms. During the same time period we evaluated autonomic nervous system activity in patients paced for complete heart block, expressed by spectral power indexes in low frequency and high frequency areas of heart rate variability. Atrial and ventricular effective refractory periods showed significant circadian variation at both basic cycle lengths, with the highest values occurring between 22:00 and 06:00. At times, the atrial and ventricular effective refractory periods of the patients with sick sinus syndrome differed significantly from those with complete heart block. Furthermore, atrial and ventricular effective refractory periods in patients with complete heart block exhibited a strong negative correlation with the low frequency/high frequency ratio. Conclusion Our data show that atrial and ventricular effective refractory periods in DDD paced patients exhibit significant circadian variation that is strongly correlated with variations in autonomic nervous system activity in patients with complete heart block.
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The authors have previously shown that 40% of patients whose ventricular arrhythmias respond to propranolol require plasma concentrations in excess of those producing substantial beta-receptor blockade (> 150 ng/ml). However, the electrophysiologic actions of propranolol have only been examined in human beings after small intravenous doses achieving concentrations of less than 100 ng/ml. In this study, the electrophysiologic effects of a wider concentration range of propranolol was examined in nine patients. Using a series of loading and maintenance infusions, measurements were made at baseline, at low mean plasma propranolol concentrations (104 ± 17 ng/ml) and at high concentrations (472 ± 68 ng/ml). Significant (p < 0.05) increases in AH interval and sinus cycle length were seen at low concentrations of propranolol, with no further prolongation at the high concentrations; these effects are typical of those produced by beta-blockade. However, progressive shortening of the endocardial monophasic action potential duration and QTc interval were seen over the entire concentration range tested (p < 0.05). At high concentrations, there was significant (p < 0.05) further shortening of both the QTc and monophasic action potential duration beyond that seen at low propranolol concentrations, along with a progressive increase in the ratio of the ventricular effective refractory period to monophasic action potential duration. No significant changes were seen in HV interval, QRS duration or ventricular effective refractory period.In summary, the concentration-response relations for atrioventricular conductivity and sinus node automat-icity were flat above concentrations of 150 ng/ml. On the other hand, the durations of the monophasic action potential and the QTc interval shortened at high concentrations. It is concluded that propranolol, in addition to blocking beta-receptors, produces other beta-receptor independent electrophysiologic effects in human beings.
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The electrophysiologic changes produced by the intravenous administration of 0.6 mg/kg of sotalol were studied in 12 patients aged 45 to 85 years (mean 68 years). Effects upon atrioventricular (AV) nodal conduction time (AH interval) and His-Purkinje conduction time (HV interval) were assessed at identical rates. The Wenckebach cycle length was determined by rapid atrial stimulation. Refractory periods before and after the drug were compared at the same cycle length. Retrograde conduction was studied, with special reference to reentry phenomena within the His-Purkinje system. Sinoatrial function was evaluated using sinus node recovery time and sinoatrial conduction time. The following changes were noted: (1) decrease in sinus rate, (2) prolongation of QT interval, (3) depression of AV nodal conduction (prolonged AH interval) and increase in effective and functional refractory periods of the AV node, (4) increase in relative refractory period of the His-Purkinje system with no associated change in HV interval, (5) prolongation of effective refractory period in the atrium and ventricle, and (6) increase in retrograde refractory period of specialized ventricular tissue and depressed conduction of premature ventricular responses. Reentry phenomena in the His-Purkinje system were not significantly affected by the drug. Thus certain of the electrophysiologic effects of sotalol in humans were found to be in favor of a class III antiarrhythmic mechanism of action. These results justify further studies to evaluate the usefulness of this drug as an antiarrhythmic agent.
Article
We determined age-related differences in automaticity and responsiveness of cardiac Purkinje fibers from adult and neonatal dogs to graded concentrations of epinephrine, isoproterenol, and phenylephrine. Purkinje fibers were studied with standard microelectrode techniques during superfusion with Tyrode's solution at 37 degrees C. Control spontaneous rates for adults and neonates did not differ significantly. There was a biphasic response to all agonists such that rate decreased at low and increased at high concentrations. The decrease was greater with phenylephrine and epinephrine than with isoproterenol. The increase in rate was greater with isoproterenol and epinephrine than with phenylephrine. Propranolol shifted the dose-response curves downward and to the right for all agonists; phentolamine, shifter the curves upward and to the left. Epinephrine and isoproterenol dose-response curves for the neonates were upward and to the left of those for adults. Phenylephrine curves were identical for adults and neonates. Thus there are alpha- and beta-adrenergic effects on Purkinje fiber automaticity; the former decrease and the latter increase rate. Furthermore, the effects on automiticity of beta-adrenergic amines are greater in the neonates than in the adult.
Article
The effects of histamine (10–7–10–5 M) on the cardiac action potential have been studied in ventricular strips of guinea pig heart, electrically driven at a constant rate.A decrease of action potential was constantly observed at histamine concentrations above 10–6 M.No significant variations of the other electrophysiological parameters were induced by the amine.The decrease in the duration of the action potential was blocked by burimamide at a concentration (10–4 M) which induced only slight changes in action potential outline.It is suggested that the shortening of the repolarization phase induced by histamine is due to the H2 receptor-mediated activation of the calcium inward current, which can increase the intracellular calcium concentration influencing the potassium permeability.
Thesis
Malignant ventricular arrhythmias continue to be the major cause of death in relation to myocardial ischaemia. The basic electrophysiological alterations that accompany the onset of myocardial ischaemia have been extensively studied in in vitro preparations and animal studies. However, studies of myocardial ischaemia in man are limited by the difficulty in recording basic electrophysiological changes in the beating heart. Furthermore, such studies require production of controlled ischaemia and the ability to detect and verify such ischaemia during the electrophysiological study. This thesis has developed this technically complex approach. The advent of the monophasic action potential (MAP) recording technique using pressure contact electrodes has allowed the study of myocardial cellular repolarization characteristics in human hearts during cardiac catheterisation. Also, advances in myocardial perfusion imaging techniques with the development of newer 99m technetium isonitrile analogues have made possible, the use of myocardial perfusion scintigraphy to document myocardial perfusion characteristics during interventions in the cardiac catheterisation laboratory. This thesis is based on a series of studies that have examined the use of MAPs to document typical early electrophysiological changes of myocardial ischaemia during experimental myocardial ischaemia and its use in combination with technetium 99m hexakis-2-methoxy-2-methylpropyl-isonitrile (99mTc- MIBI) myocardial perfusion scintigraphy to study myocardial ischaemia in patients during cardiac catheterisation. An initial study in intact porcine hearts during transient coronary occlusion examined the ability of action potentials recorded by the MAP technique to register early changes of myocardial ischaemia from the ventricular endocardium. A second study in 26 patients undergoing cardiac catheterisation used endocardial recordings of the MAP during atrial pacing to angina threshold. Ischaemic areas of myocardium were identified by injection of 99m Tc-MIBI at peak pacing stress. Recordings from the ischaemic endocardial regions showed a significantly greater shortening of action potential duration corrected for heart rate changes compared with the non-ischaemic areas. Sensitivity and specificity of various changes in MAP duration per unit change in heart rate for the detection of myocardial ischaemic were derived. The third study used endocardial recordings of the MAP as a measure of myocardial ischaemia during dypiridamole myocardial perfusion imaging in patients with coronary artery disease.Finally, the combination of MAP recordings and 99m Tc-MIBI perfusion scintigraphy was employed to study regional and potential arrhythmogenic effects of beta adrenoceptor stimulation in potentially ischaemic versus normal areas of human myocardium. MAPs were recorded simultaneously from the right and left ventricular endocardium in 14 patients (28 recording sites) during infusion of dobutamine. Perfusion at the recording site was assessed by the injection of 99m Tc-MIBI at peak doses of dobutamine. Action potential duration during dobutamine was compared to that during atrial pacing to identical pacing rates in the absence of dobutamine. In 21 recordings from normally perfused recordings, dobutamine produced a variable effect on the action potential duration over and above that produced by atrial pacing alone to identical pacing rates either lengthening or shortening the action potential duration. In the ischaemic zones, dobutamine invariably shortened the action potential duration. The data provide a possible mechanistic basis for the beneficial effects of beta adrenergic blockade in ischaemic heart disease. A unique series of studies combining basic electrophysiological studies with a radionuclide imaging technique is presented. Validation and application of the two techniques to evaluate regional myocardial ischaemia and arrhythmogenic potential in the human heart are addressed.
Article
Full-text available
The present study was designed to examine the properties of cyclic AMP-dependent protein kinase from normal and hypothyroid rat tissues. The activity of the liver enzyme decreased in hypothyroid rats and this reduced activity may be due to the decrease in synthesis of enzyme protein. The enzyme activity from the kidney of hypothyroid rats increased by 35% in the absence of cyclic AMP. Further, the enzyme from the kidney of hypothyroid animals responded to phenylephrine and isoproterenol. In the heart, the basal enzyme activity was the same in both groups, but the enzyme from the heart of hypothyroid animals did not respond to isoproterenol. When hypothyroid rats were treated with 3,3’,5-triiodothyronine, the enzyme activities from those rat tissues showed essentially the same level as those of the corresponding normal ones. These results suggest that thyroid hormone regulates adrenergic agonists-mediated responses both at the sites of adrenoceptors and that of protein phosphorylation. Furthermore, the dependence on thyroid hormone varies according to the tissue.
Chapter
Die Zellmembran ist eine anatomisch, biochemisch und physiologisch definierbare Struktureinheit zwischen Zelle und Umgebung. Stofftransport und selektive Ionenpermeabilität sind wesentliche Funktionen der Zellmembran. Enzymsysteme, Antigene und Rezeptoren determinieren ihre weiteren funktionellen Eigenschaften.
Chapter
Classification of antiarrhythmic drugs has always been a controversial subject. In recent years it has become increasingly so with so many new compounds appear­ing on the pharmacological horizon. Furthermore there is no complete under­standing of either the electropharmacology of the antiarrhythmic agent or the mechanisms engendering various cardiac arrhythmias, despite the recent contri­butions by investigators using ultramicroelectrode and His bundle recording.
Chapter
The importance of the adrenergic system in the electrical activity of the heart can be briefly summarized by stating that the endogeneous catecholamines liberated by sympathetic excitation may substantially affect those electrophysiologic parameters of the heart which have been shown to play a significant role in the regulation of cardiac rate and rhythm and in the genesis of cardiac arrhythmias. Increased tone of the sympathetic nervous system as well as administration of catecholamines or other sympathomimetic agents closely resembling in structure the naturally occurring adrenergic activators may produce a variety of arrhythmias, from simple extrasystoles to lethal ventricular fibrillation. If the concentration of the adrenergic activators is high enough as in the case of pheochromocytoma, neuroblastoma, or overdosage of these agents, this may alone account for their arrhythmogenic action. On the other hand sensitivity to catecholamines can also be increased as in hyperthyroidism or when some hydrocarbon anesthetics are applied. Sometimes other potentially arrhythmogenic situations such as hypoxia of the heart, local myocardial ischemia due to coronary occlusion, ionic changes, (e.g., hypo- or hyperpotassemia) and high level of free fatty acids may produce manifest arrhythmias, if the cardiac sympathetic tone is increased or adrenergic activators are given. Since the term “cardiac arrhythmia” denotes the irregular activity of the whole cardiac syncitium, none of the electrophysiologic effects alone, even the most impressing changes determined by intracellular recordings or membrane current measurements, can account directly for the arrhythmic action of the adrenergic activators.
Chapter
Data derived from both multicenter clinical trials and experimental animals indicate that β-adrenergic stimulation of the myocardium can increase the propensity to malignant arrhythmias and that β-adrenergic blockade significantly reduces the incidence of sudden cardiac death [4, 19, 32, 34]. Despite these important findings, a very large number of patients taking β-adrenergic blocking agents post-myocardial infarction die, presumably of sudden death secondary to abnormalities in cardiac rhythm [4, 19, 32, 34]. In this brief review, we will consider recent experimental evidence from our laboratory and others indicating that in the ischemic heart, the effects of catecholamines may be mediated through stimulation of a-, as well as β-adrenergic receptors. These findings may be relevant not only to arrhythmogenesis but, to the development of irreversible injury in the ischemic and reperfused heart, due to the recently recognized effect of α-adrenergic stimulation on myocardial calcium.
Chapter
A neonatal rat model was prepared for studying the development of α-adrenergic actions on cardiac rhythm. Newborn rats were administered either nerve growth factor (NGF), its antibody (Ab), or placebo for the first 10 days of life. As compared to the placebo group, those treated with NGF had accelerated sympathetic nerve growth, an increase in the presence of a 41 kDa GTP regulatory protein that is a pertussis toxin substrate and that transduces α-1 adrenergic actions on cardiac automaticity, and a response to α-1 agonist effects on automaticity consistent with that in the mature rat. In contrast, the Ab treated animals had minimal innervation, a lower level of the GTP regulatory protein and an immature response to α-1 agonists. Moreover, the Abtreated animals had an abnormally prolonged Q-T interval on ECG. α-1 and β-adrenergic receptor number and affinity were not significantly different among the 3 groups. These data indicate that the failure of normal sympathetic innervation to develop is associated with abnormalities in repolarization and in the response to α-1 adrenergic stimulation. Whether these abnormalities are associated with arrhythmias, as in the congenital long Q-T syndrome, remains to be tested.
Chapter
Adrenergic stimulation of the heart usually induces an increase in cardiac rate. However, recent studies of pacemaker fibers in the ventricles and atria have shown there not only are positive chronotropic effects that are mediated by the beta-receptors, but also, alpha-receptor-mediated negative chronotropic effects. We have studied both these actions in the adult and neonatal canine heart in an effort to determine how they are altered by cardiac and sympathetic growth and maturation.
Chapter
The term “catecholamine” refers to any compound composed of a catechol nucleus and an amine-containing side chain; these substances are of low molecular weight. The catecholamines, known to occur in man, are dopamine, norepinephrine, and epinephrine. They are involved in neural and endocrine functions. Dopamine serves as a neurotransmitter in the central nervous system and to a minor extent in some sympathetic ganglia. The adrenergic nervous system and circulating catecholamines can play an important role in normal physiology and pathophysiology of the heart. A vast array of experimental physiological and pharmacological manipulations can change the concentrations and turnover rate of catecholamines in the heart. The sympathetic nervous system to the heart and vascular system may be differentially controlled, that is, activation or inhibition of the sympathetic nerves to one organ or area can occur without a similar response to others. Somatic and visceral afferent nerves can excite and inhibit postganglionic nerves to the heart and blood vessels. This chapter discusses the adrenergic receptors and their influence on coronary blood flow.
Chapter
The autonomic nervous regulation of the heart takes a prominent part in the mechanism of certain cardiac rhythm disturbances. The arrhythmogenic role of the autonomic nervous regulation of the heart is especially conspicuous under certain pathological conditions. In earlier experiments, it was demonstrated that in the heart in situ of anesthetized cats, the electrical flutter thresholds of the auricles and the ventricles were reduced at lower body temperature. This change was reversed after the acute denervation of the heart or in the isolated heart-lung preparation. In the absence of autonomic control, only a rise of both thresholds appeared. In some of the experiments, it was discussed that increased extrasystolic activity induced by coronary occlusion in the heart in situ of anesthetized dogs was absent in the isolated heart perfused with the blood of a donor animal. The importance of the sympathetic innervation in the genesis of arrhythmias is firmly established. In the non-automatic normal cardiac cells, the resting membrane potential and the rate of fast depolarization are not affected significantly by adrenergic stimulation, whereas a shortening in the total action potential duration together with a slight elevation of the plateau has been observed in most cases but occasionally a prolongation in repolarization is also recorded. These changes appear independently of the heart rate.
Chapter
Myocardial ischemia frequently results in activation of the sympathetic nervous system [146], with clinical manifestations including sinus tachycardia and hypertension [158]. Of more concern than these hemodynamic alterations produced by sympathetic neural activation is the electrical instability which ensues after an ischemic event and during evolving myocardial infarction. Several lines of evidence suggest that increases in sympathetic neural activity induced by ischemia may be of primary importance in arrhythmogenesis and that stimulation of both α- and β-adrenergic receptors in the myocardium contributes to the electrophysiological derangements leading to malignant ventricular tachycardia or ventricular fibrillation resulting in sudden cardiac death. Prior to considering the electrophysiological effects of catecholamines and their relation to arrhythmogenesis in the ischemic heart, the anatomic and neurophysiological substrates underlying this relationship and the mechanisms responsible for sympathetic activation will briefly be discussed. The present review will concentrate solely on the sympathetic branch of the autonomic nervous system. The reader is referred to other reviews [31, 35] for a more detailed account of the interactions between the sympathetic and parasympathetic nervous systems.
Chapter
The importance of the autonomic nervous system in the genesis of cardiac arrhythmias has become progressively more evident [4, 32]. Clinical and experimental observations have brought new insights into the relationship between cardiac arrhythmias and the autonomic nervous system and have suggested new strategies for the prevention of sudden cardiac death. Holter recordings of the minutes preceding the onset of lethal arrhythmias, together with the results of clinical trials with antiadrenergic interventions in postmyocardial infarction patients, have further established the relation between sympathetic activity and life-threatening ventricular arrhythmias.
Chapter
In the normal ventricle conduction velocity is hardly influenced by sympathetic stimulation, whereas refractory periods shorten. The projection of sympathetic nerves to the ventricles is inhomogeneous and variable between individuals of the same species. Therefore, the effects of sympathetic stimulation on electrophysiological parameters are inhomogeneous as well. This inhomogeneity of effects may add up to or mitigate basic dispersion. It is not known whether electrical instability caused by sympathetic stimulation in the normal heart can be large enough to initiate life-threatening arrhythmias. During acute ischemia there are almost immediate changes in extracellular K+ concentration. Conduction velocity starts to decrease after 2 to 3 min of ischemia; refractory periods increase even earlier. Both factors increase the chances for reentrant arrhythmias. Dispersion in refractory periods develops over the ischemic border between the normal and ischemic myocardium, but also within the central ischemic area. This was assessed with measurement of local fibrillation intervals, because refractory periods cannot be measured at more than one site at a time. Dynamic conditions such as acute ischemia or sympathetic stimulation require multiple simultaneous measurements, because parameters — for instance, diastolic threshold for excitation — change continuously. Sympathetic stimulation increases conduction velocity during acute ischemia. In itself, this would be an anti-arrhythmogenic factor. Local fibrillation intervals are prolonged by sympathetic stimulation, whereas they are shortened in the normal heart. This indicates that sympathetic stimulation provokes opposite effects on refractoriness in normal and ischemic myocardium. Such an effect would increase the propensity to reentrant arrhythmias, especially during mild ischemia.
Chapter
Thus far, the chapters in this book have been concerned with the characteristics of the slow inward current and its role in the electrical and mechanical characteristics of the individual cardiac cells and of the intact heart. An appreciation of these characteristics is essential to an understanding of the effects of antiarrhythmic drugs on the slow inward current on the intact heart and on clinically encountered arrhythmias.
Chapter
Although the arrhythmogenic role of sympathetic activation acting over an ischemic substrate has been established [1, 2], the mechanisms involved remain largely speculative. In fact, due to their electrophysiologic properties, catecholamines influence several determinants of cardiac excitability thus creating a rather complex picture which is difficult to unravel. This complexity is largely due to the fact that adrenergic activation, besides acting on the electrophysiologic characteristics of the heart, affects most cardiac functions such as contractility, metabolism, and coronary circulation. Furthermore, depending on the substrate on which catecholamines are released, i.e., whether the heart is normally perfused or acutely ischemic or has suffered a myocardial infarction, the consequences of adrenergic activation can vary.
Chapter
A direct study of the electrophysiological properties of accessory pathways (AP) is virtually impossible. While cardiac tissues of different species are readily available for characterization of their properties, Kent bundles are not in the market. A dog discovered to have ventricular preexcitation (VP) was flown from Philadelphia to Duke University — so the story goes — for electrophysiological studies. On this precious specimen, propagation velocity in the AP was estimated to be 0.33 M/s [1, 2], which is slightly less than average for ventricular muscle (normal, 0.4 M/s). This estimation could be approximated from the activation times between adjacent atrium and ventricle (25 ms) and measurement of length of the connection (8 mm). In clinical cases, in which those parameters are unknown, conduction velocity cannot be estimated. Since both length and width of the AP vary sometimes substantially [3, 4], any conduction velocity similar to that occurring in atrial, ventricular or Purkinje fibers may explain the short P-R interval of VP.
Chapter
The purpose of this chapter is to review the mechanisms responsible for normal impulse initiation and propagation, as well as the mechanisms for cardiac arrhythmias. We hope not only to provide an understanding of the pathophysiology of cardiac arrhythmias but - in addition - to provide a basis for the discussion of antiarrhythmic drug actions and antiarrhythmic therapy that will follow. The approach to be taken will rely heavily on cellular electrophysiology. By referring to data obtained from the single cardiac cell that is the final common denominator of cardiac electrical activity, as well as the interactions among groups of cells, we can describe the cellular electrophysiologic mechanisms responsible for normal electrical activity as well as arrhythmogenesis.
Chapter
Our purpose in this chapter is to review the cellular electrophysiologic effects of autonomic stimulation, and to demonstrate its complexity in two ways: by describing the changes in cardiac autonomic interactions that occur with growth and development, and by describing how autonomic mediators modulate cardiac arrhythmias.
Chapter
Developed specifically as a coronary vasodilator and an antianginal compound in 1962, in the past 10 years or so amiodarone hydrochloride (Fig. 1) has recently attracted much experimental and clinical interest as an antiarrhythmic agent. Few, if any, other antidysrhythmic compounds have stimulated as much interest as has amiodarone in relation to the control of refractory arhythmias. Its extreme potency in the prophylactic control of most supraventricular and ventricular arrhythmias is now well established (Rosen- Baum et al. 1976, 1983; Heger et al. 1981, 1984; Nademanee et al. 1981, 1982a, 1983; Graboys et al. 1983; Zipes et al. 1984; Singh et al. 1980). However, the fundamenal mechanism whereby it induces its salutary effects is far from being certain. For this reason, the effects of the compound on cardiac electrophysiology relative to its associated pharmacologic properties are of much theoretical as well as practical importance.
Chapter
The modulation of cardiac K+ channels by the cholinergic and adrenergic divisions of the autonomic nervous system is central to regulating chronotropy and inotropy in the heart. Interaction of drugs with autonomic receptors in cardiac tissues represents an important intervention in the control of arrhythmias, heart failure, hypertension, hypotension, and shock. The effects of adrenergic and cholinergic stimulation on cardiac K+ currents have been well described. More recent advances in molecular biology have also allowed us to better understand the signal transduction and effector mechanisms underlying these effects at a subcellular level and can provide a unifying approach to understanding the seemingly diverse effects of autonomic stimulation on cardiac K+ currents and function. Furthermore, there is substantial overlap between the effects of cholinergic and adrenergic responses. Finally, activation of one population of autonomic receptors may accentuate or antagonize the effects of another. This complex cross talk allows a finer control over cardiac K+ channel function and may arise at any level of the signal transduction pathways, including receptors, G-proteins, second messengers, downstream effectors, or even the channel proteins themselves.
Article
Although myocardial ischaemia is by far the most frequent cause of ventricular fibrillation, the precise mechanisms which immediately induce this arrhythmia are unclear. Complete coronary occlusion is frequently absent in victims of sudden death (Basche et al., 1975) and experimental studies indicate that both coronary occlusion and reperfusion are associated with ventricular fibrillation (Penkoske et al., 1978). The picture is further complicated by the fact that clinical and experimental arrhythmias are both most intense soon after the onset of myocardial ischaemia, at a time when several pathophysiological processes are occurring simultaneously. Many studies have been carried out in an attempt to distinguish which of these are arrhythmogenic. The present chapter is concerned with the possibility that α-adrenoceptor activity may contribute to the development of ventricular fibrillation during myocardial ischaemia. Interest in this possibility arose out of studies with the α-blocking drug phentolamine, which was found to prevent ventricular arrhythmias induced by a variety of techniques. Thus Leimdorfer (1953) reported that intravenous administration of phentolamine prevented arrhythmias due to nicotine or adrenaline and converted methacholine-induced atrial fibrillation in dogs. Others (Vargaftig and Coignet, 1969) reported that phentolamine prevented arrhythmias induced by aconitine or by inhalation of chloroform.
Chapter
In cardiac cells there are four main sources of EMF, as noted in the preceding chapter, engendered by concentration differences across the cell membrane of Na, Ca, K and Cl ions, which would be in equilibrium at intracellular potentials of approximately +56, +120, -94 and -40mV respectively. In order that current from these sources may be used for physiological functions, ion- selective pathways through the membrane can be opened and closed. The function of sodium current is to depolarize atrial and ventricular muscle cells and Purkinje cells, and of calcium current to depolarize nodal cells. Slow depolarization in the central SA node cells permits faster depolarization in the surrounding transitional cells, when they reach threshold, to overtake them and synchronize firing of the node as a whole, from which a ring of excitation spreads outwards in all directions. Slow depolarization of the AV node provides the delay of conduction required while blood is transferred from atrium to ventricle. Calcium current is also involved in excitation-contraction coupling, and can be increased by the opening of an additional set of pathways under the control of adrenergic stimulation. The main function of potassium current is repolarization, but the function of chloride current is uncertain. High Cl permeability in P cells (pale sinoatrial node (SAN) cells) may provide a sink for depolarizing neighbours in the pacemaking process. Chloride-bicarbonate exchange may be concerned in the control of intracellular pH (Vaughan-Jones 1979).
Chapter
It has been known for decades that stimulation of the sympathetic nerves to the heart (von Bezold, 1863; Gaskell, 1884), injection of suprarenal extracts (Oliver and Schäfer, 1895) or addition of adrenaline (Elliott, 1905) increase the force of contraction of the heart and the heart rate. These changes are now generally accepted to be primarily due to stimulation of β-adrenergic receptors (β-adrenoceptors). However, recent evidence suggests that α-adrenoceptors are also present in the myocardium and that positive inotropic effects may be produced by stimulation of these receptors.
Article
The mechanism of cardiovascular changes produced by activation of the central nervous system with picrotoxin (2 mg/kg, iv) was studied in chloralose-anesthetized cats. Effects occurred in two phases. During the early phase, there were decreases in arterial blood pressure and heart rate, and in a few cats, bradyarrhythmias. These changes were transient and superceded by an increase in arterial blood pressure and, in most cases, ventricular tachyarrhythmias. The early phase changes were mediated primarily by the cardiac vagus nerve whereas the later phase changes were mediated primarily by sympathetic nerves and the adrenal medulla. The ventricular tachyarrhythmias were unaffected by pretreatment with atropine, bilateral vagotomy, or beta adrenergic blocking agents. On the other hand, bilateral extirpation of the stellate ganglia and adrenal glands prevented the ventricular arrhythmias from occurring. In addition, administration of drugs that blocked alpha adrenergic receptors effectively counteracted picrotoxin-induced ventricular arrhythmias. These results indicate that the centrally induced ventricular arrhythmias were mediated by cardiac sympathetic nerves and/or release of catecholamines from the adrenal medulla. More importantly, these results indicate that one cannot equate beta adrenergic blockade with elimination of sympathetic influence on the heart. Finally, sympathetically induced arrhythmias resistant to beta adrenergic blockade appear to respond to drugs that block cardiac adrenergic alpha receptors.
Article
The action of epinephrine (5×10−6 g/ml) on cellular Ca-exchange of isolated, electrically driven guinea pig atria was investigated by means of the isotope 45Ca. Experiments were performed in Tyrode solution with reduced Ca-concentration (0,45 mM). In this Ca-poor solution the difference between contraction amplitude of the atria under control conditions and that under the influence of epinephrine was much more marked as in Ca-rich solution. Epinephrine increased the 45Ca-uptake (=Ipm/100 mg wet weight) in isolated atria during the first 20 minutes of its action. Specific 45Ca-activity in the atria (=Ipm/0,1 μEq Ca in tissue) was increased by the action of the substance over 1 hour of loading. There was a small net loss of tissue Ca. In epinephrine treated atria relative specific activity (=specific activity of cellular Ca/specific activity of Tyrode solution×100), which is a measure of rate of Ca exchange in tissue, has been 3,5 times that of control preparations after 3 minutes of loading. 45Ca-release from guinea pig atria was significantly increased by the action of epinephrine. Half time of the initial phase of Ca-efflux was fastened by epinephrine. It is concluded that epinephrine increases membrane permeability for Ca ions in the heart. The results are discussed in relation to the positive inotropic action of the substance.
Article
Phentolamine, 5 μg/ml, when applied to sheep Purkinje fibres electrically driven at a constant rate, strongly decreased the maximum rate of depolarization of the action potential upstroke. The duration of the action potential and, at a lesser extent, the effective refractory period were shortened. The maximum diastolic potential was slightly reduced. Moreover the drug shifted to the right and down the curve relating the upstroke velocity to the level of the transmembrane potential. It is suggested that phentolamine may cause a direct stabilizing effect on the cardiac cell membrane, partially blocking the sodium-carrying system.
Article
Studies have been carried out on the effect of phenylephrine hydrochloride, at various concentrations (2×10−6, 5×10−6, 1×10−5 g/ml), on transmembrane action potentials and effective refractory period in the Purkinje fibres of sheep heart. The amine, at all three concentrations, increased the duration of the action potential and effective refractory period in electrically driven preparations.When applied at the higher concentration, phenylephrine induced a positive chronotropic effect in spontaneously beating preparations; this effect was associated with an increased steepness of the pacemaker potential.The results may be interpreted according to the point of view that myocardial alpha receptors contribute to the modulation of the repolarization phases of the action potential.
Article
Conduction block in heart cells by K+ rich, or Na+ depleted solutions can be overcome by adrenaline. In order to explain this phenomenon, the effect of adrenaline on the membrane resting and action potentials of cow Purkinje fibers was measured at various extracellular concentrations of Na+, K+ and Ca++, in the presence of tetrodotoxin, Mn++ and beta-receptor antagonists. It was found that adrenaline specifically increases the amplitude and duration of the plateau phase of the cardiac action potential. Plateu-like action potentials, without preceding Na+-spike, can be generated and conducted in an all-or-nothing way. In K+ rich solutions and under the influence of adrenaline, the depolarization proceeds in two steps. The first step corresponds to the Na+-spike. The second step or secondary depolarization corresponds to the plateau; it was not modified by changes of the membrane potential between −85 and −55 mV, or by reduction of extracellular Na+ ions, but was specifically blocked by Mn++ ions and beta-receptor antagonists. Its amplitude increased by 17 mV for a tenfold change in extracellular Ca++. Tetrodotoxin preferentially blocked the Na+-spike, but also slowed the rate of potential change during the secondary depolarization. The simplest explanation for the observed phenomena can be found in an increase of Ca++ inward current under the influence of adrenaline. The existence of an inward Na++ current, different in characteristics from the Na+ conductance during the fast upstroke, cannot be ruled out. Some data are in accord with a decrease in K+ conductance.
Article
The influence of phentolamine on the uptake of exogenous noradrenaline infused into the aortic cannula and on the overflow of endogenous noradrenaline caused by sympathetic nerve stimulation was investigated in the isolated perfused rabbit heart. 10−6 M phentolamine doubled the overflow of endogenous noradrenaline, but did not change noradrenaline uptake. 10−5 M phentolamine increased the stimulation-induced overflow of noradrenaline 4-fold and inhibited amine uptake by about 50%. 10−4 M phentolamine elevated the overflow of noradrenaline less than 10−5 and 3×10−5 M did. The augmentation of transmitter overflow was only partly reversed by 13 min perfusion with drug-free medium. Pretreatment of hearts with 1.5×10−5 M cocaine or with 10−7 or 10−6 M desipramine did not change the effect of phentolamine on the overflow of noradrenaline evoked by nerve impulses. Pretreatment of hearts with 10−5 M, but not with 10−6 M, phentolamine prevented the increase of transmitter overflow by cocaine. It is concluded that low concentrations of phentolamine potentiate the overflow of noradrenaline during nerve stimulation by a mechanism different from that of cocaine, i.e. different from inhibition of neuronal re-uptake. The nature of this mechanism is discussed.
Article
Chronotropic and inotropic dose-response curves for epinephrine and phenylephrine were determined in rabbit atria spontaneously beating and electrically-driven. The curves were obtained in the absence and in the presence of propranolol, 10−7 M, or phentolamine, 2 × 10−6 M. Propranolol antagonized the chronotropic effects of epinephrine and phenylephrine, and the inotropic effects of epinephrine. This antagonist reduced the inotropic responses to high doses of phenylephrine, but left unaltered the effects of low doses. Phentolamine antagonized the inotropic effects of low doses of phenylephrine which were unaffected by propranolol. The inotropic curve for epinephrine was shifted 2.5-fold to the right by phentolamine. In contrast, phentolamine did not modify the chronotropic responses to these amines.The ability of α- and β-blocking agents of antagonizing the inotropic effects of adrenergic amines suggest that the receptors mediating these effects possess pharmacological characteristics which are common to both types of receptors. Thus, a two-receptor system appears to operate in the production of inotropic responses to adrenergic stimuli. In addition, the results confirm the role played by β-receptors in the cardiac actions of adrenergic amines.
Article
Papillary muscle-false tendon tissue preparations isolated from dog hearts were perfused with Tyrode's solution containing propranolol in concentrations ranging from 0.1 to 20.0 mg/liter. Transmembrane action potentials of both ventricular muscle fibers and Purkinje fibers were recorded. With sufficient concentration of drug, the velocity of the upstroke and the overshoot of both fiber types decreased. The curve relating upstroke velocity to level of membrane potential for Purkinje fibers was displaced to the right and down. The ability of both ventricular muscle fibers and Purkinje fibers to respond to rapid frequencies of stimulation was decreased. Repolarization of Purkinje fibers was accelerated by propranolol, but repolarization of ventricular muscle fibers was unaffected. Duration of the effective refractory period of Purkinje fibers decreased; that of ventricular muscle fibers was unchanged. Graded responses and decremental impulse conduction in Purkinje fibers were abolished in the presence of propranolol. Low doses of propranolol which caused no change in the transmembrane potential completely blocked the increase in Purkinje diastolic depolarization normally induced by epinephrine. The possible mechanisms by which propranolol might exert its antiarrhythmic actions on ventricular arrhythmias were discussed.
Article
1. The effects of adrenaline on the inward currents flowing through the cardiac membranes were investigated in trabeculae of frog atria, by voltage clamp experiments. TTX was used as an inhibitor of the fast sodium channel and Mn as an inhibitor of a slow calcium-sodium channel. 2. The fact that adrenaline increases the amplitude of the plateau of the cardiac action potentials has been confirmed. This substance does not appreciably modify the current flowing through the fast channel but considerably increases the inward current which, according to previous investigations, is carried by Ca++ and Na+. For this reason, adrenaline can be considered as an activator of the slow channel. The increase of an inward calcium current by adrenaline can partly explain the positive inotropic effect of the substance. 3. Besides increasing the amplitude of the slow response, adrenaline decreases its threshold. This effect can explain that adrenaline is able to restore impaired conduction due to the action of TTX on fast sodium channel, as other workers observed.
Blockade of alpha adrenergic receptors
  • M Nicxzrson
  • Erg Hollm
NIcxzRsoN, M. & HoLLM ERG, N. K. (1967). Blockade of alpha adrenergic receptors. In Physiological Pharmacology, vol. 4. New York and London: Academic Press.