Prolongation of the human cardiac monophasic action potential by sotalol

Echt, Debra S.; Berte, Larry E.; Clusin, William T.; Samuelsson, Rolf G.; Harrison, Donald C.; Mason, Jay W.

doi:10.1016/0002-9149(82)90421-0

Cited by 113 publications

(28 citation statements)

References 13 publications

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“…It is now well established that sotalol, unlike other 3-adrenergic-blocking drugs,2' lengthens the duration of the cardiac action potential,2' and hence the QTc interval, of the surface electrocardiogram.5I 22 The electrophysiologic effects noted in our study in man are consistent with these observations. Our data confirm and extend the earlier clinical reports that the drug significantly lengthens the effective refractory period of all cardiac tissues' 4 and, as in patients on long-term amiodarone treatment,'I it prolongs the monophasic cardiac action potentials as recorded by suction electrodes placed in intracardiac chambers.7 9 In our studies, the intravenously administered drug increased the ERP more in the atria than in the ventricle. There was also a significant increase in this parameter corresponding to an increase in the QTc interval and the slowing of the ventricular tachycardia cycle length in patients in whom the drug did not prevent the induction of the arrhythmia.…”

Section: Discussionsupporting

confidence: 92%

Electrophysiologic and antiarrhythmic effects of sotalol in patients with life-threatening ventricular tachyarrhythmias.

Nademanee¹,

Feld²,

Hendrickson³

et al. 1985

Circulation

151

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Sotalol is a unique fl-blocker that lengthens cardiac repolarization and effective refractory period (ERP). Its efficacy after intravenous (1.5 mg/kg) and oral (160 to 480 mg bid) administration was therefore evaluated in 37 patients with refractory recurrent ventricular tachycardia/fibrillation (VT/VF). Thirty-five patients, 33 with inducible VT/VF, underwent electrophysiologic testing. Intravenous sotalol lengthened the ERP in the atrium ( + 24.6%, p .01), atrioventricular node ( + 24.9%, p < .01), and ventricle (+ 14.9%, p < .01). It also significantly lengthened sinus node recovery time, corrected QT interval (QTc), and the AH interval, but not the HV interval. Sotalol prevented reinduction of VT/VF in 15 patients (45.5%). Twenty-five of the 33 patients (15 with positive results of electrophysiologic tests; 10 with negative results) were given oral sotalol. The drug was ineffective in seven (26.9%) and aggravated arrhythmia in one (3.8%). In four patients sotalol was withdrawn because of side effects; arrhythmias recurred late in two (7.7%). Eleven patients (42.3%) have continued on oral sotalol over a mean follow-up period of 9.2 + 8.6 months. Sotalol reduced (n = 21) total premature ventricular complex (PVC) count on the Holter electrocardiogram by 73% (p < .01), paired PVCs by 89% (p < .01), and beats of ventricular tachycardia by 95% (p < .01). In 52% (n = 11), total reduction in PVCs was at least 85%, and incidence of paired and tachycardiac beats was reduced at least 90% (group A). In the remainder (n = 10), PVC suppression was not significant (group B). Group A included nine patients with nonreinducible VT/VF and two in whom it was reinducible; in group B, eight of 10 patients had reinducible VT/VF. The difference between the two groups (Fisher exact test) was significant (p < .01). The prevention of reinduction of VT/VF by intravenous sotalol and suppression of spontaneously occurring arrhythmias by the oral drug were both predictive of longterm drug efficacy. Sotalol is a significant advance in the short-and long-term management of lifethreatening ventricular tachyarrhythmias. Circulation 72, No. 3, 555-564, 1985. ALTHOUGH SOTALOL was introduced as a specific ,8-blocking drug 24 Protocol. All patients were admitted to the coronary care unit for continuous electrocardiographic monitoring. Previously prescribed antiarrhythmic drugs were discontinued for at least five elimination half-lives of these agents. Whenever possible a 24 hr ambulatory electrocardiographic recording was obtained at a time the patients were not taking any other antiarrhythmic drugs. This recording served as a baseline with respect to the spontaneously occurring tachyarrhythmias and was subsequently used for gauging the efficacy of drug therapy. Thirty-five patients underwent electrophysiologic studies for the evaluation of the effects of 1.5 mg/kg iv sotalol hydrochloride (BristolMyers, Evansville, IN), administered over a period of 5 to 10 min, on the inducibility of ventricular tachycardia relative to the electrop...

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Section: Discussionsupporting

confidence: 92%

Electrophysiologic and antiarrhythmic effects of sotalol in patients with life-threatening ventricular tachyarrhythmias.

Nademanee¹,

Feld²,

Hendrickson³

et al. 1985

Circulation

151

View full text Add to dashboard Cite

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“…Levels up to approximately 40 JAM have been found in patients immediately following acute intravenous injection of DL-sotalol (Nademanee et al, 1985) but it is unlikely that the concentrations would remain so high for long (Campbell et al, 1985). Indeed, severe toxicity has been described at blood levels of 25 gM and 53 JM following deliberate overdosage (Elonen et al, 1979 Effects on human atrial cells DL-Sotalol has been shown to be beneficial in the treatment of atrial tachyarrhythmias in man at concentrations below 10 JAM (Campbell et al, 1985) and to prolong human atrial repolarization in similar concentrations (measured as monophasic action potential duration; Echt et al, 1982;Hayward & Taggart, 1986). These facts strongly suggest the possibility that human atrial cells may be more sensitive than those of rabbits or guinea-pigs to the class III actions of solatol.…”

Section: Discussionmentioning

confidence: 99%

“…Blood levels were presented only for the first of these studies where peak plasma sotalol levels were approximately 5-991M. Acute therapy with other Padrenoceptor blocking agents does not prolong atrial action potential duration (Echt et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

Cellular electrophysiological effects of d‐and dl‐sotalol in guinea‐pig sinoatrial node, atrium and ventricle and human atrium: differential tissue sensitivity

Campbell¹

1987

British J Pharmacology

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1 The effects of racemic DL-sotalol and D-sotalol on guinea-pig sino-atrial node, atrium and ventricle and on human atrium were studied using standard microelectrode techniques. Both compounds increased spontaneous sinus node cycle length largely by prolonging the repolarization phase of the action potentials. This effect was attributed to blockade of outward potassium current. 2 Ventricular action potential duration was similarly prolonged by DL-sotalol at concentrations of 5 -50 JLM.3 DL-Sotalol 1-5011M had no effect on guinea-pig atrial action potential duration and D-sotalol produced minor prolongation only at the highest concentration (50 pM).4 Human atrial action potentials were, however, significantly prolonged by both DL-and D-sotalol 10 JM. This indicates differential sensitivities to sotalol for human and guinea-pig atrium and explains the ability of sotalol to prolong atrial monophasic action potential duration in clinical studies.

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“…Concentrations were increased after the naloxone infusion in all 12 patients and the differences compared with pre-naloxone levels were significant in both groups; 20 pug kg-1 min-': median (IQR) 3. naloxone concentrations and the degree of QT prolongation in our patients highlights these problems. However, in the clinical arena, the acute intravenous administration of other Class III antiarrhythmic agents such as sotalol does prolong QT interval, monophasic action potential duration and refractory periods within a matter of minutes [13].…”

Section: Resultsmentioning

confidence: 99%

Failure to reproduce the in vitro cardiac electrophysiological effects of naloxone in humans.

Oldroyd¹,

Rankin²,

Gray³

et al. 1994

Brit J Clinical Pharma

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1 Opioid receptor antagonists such as naloxone have shown antiarrhythmic activity in animal models of coronary artery occlusion. Studies have indicated that these effects are stereospecific but both isomers of naloxone prolong action potential duration and refractoriness in guinea-pig and rabbit isolated ventricular myocardium (Class III effect). 2 This study was performed to identify whether this Class III effect of naloxone could be reproduced in human myocardium in vivo. Twenty patients with coronary artery disease received intravenous racemic naloxone (1-40 ,ug kg-' min-'). Surface electrocardiographic parameters were measured and refractory periods were determined during fixed rate pacing by programmed stimulation. 3 The corrected QT interval during sinus rhythm (SR-QTc) was prolonged by 5(3)% (P = 0.06) at a dose of 20 ,ug kg-' min-' and by 9(10)% at 40 ,ug kg-' min-' (P = 0.03).These small changes were lost at higher paced heart rates. No significant effects on atrial, atrioventricular nodal or ventricular refractoriness were seen. 4 Plasma naloxone concentrations well into the micromolar range were achieved with both of the higher doses of naloxone administered. Plasma ,3-endorphin concentrations invariably increased following naloxone infusion. There was no statistical relationship between peak plasma naloxone concentrations and the absolute or percent prolongation of SR-QTc. 5 It seems unlikely that racemic naloxone would have any clinical utility as an antiarrhythmic agent. Racemic naloxone may enhance cardiac adrenergic nerve activity and this receptor mediated effect may have prevented the demonstration of any nonreceptor mediated prolongation of cardiac refractoriness. Studies with the individual stereoisomers of naloxone would be of interest.

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Prolongation of the human cardiac monophasic action potential by sotalol

Cited by 113 publications

References 13 publications

Electrophysiologic and antiarrhythmic effects of sotalol in patients with life-threatening ventricular tachyarrhythmias.

Electrophysiologic and antiarrhythmic effects of sotalol in patients with life-threatening ventricular tachyarrhythmias.

Cellular electrophysiological effects of d‐and dl‐sotalol in guinea‐pig sinoatrial node, atrium and ventricle and human atrium: differential tissue sensitivity

Failure to reproduce the in vitro cardiac electrophysiological effects of naloxone in humans.

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