Prolongation of refractoriness and activation time in normal canine ventricular myocardium following bolus administration of lidocaine

Mdrtins, James B.; Kelly, Kevin J.

doi:10.1016/0002-8703(85)90559-9

Cited by 3 publications

(2 citation statements)

References 18 publications

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“…Thus, although reduction in K + permeability compensates for the change in VERP, it overcompensates for the change in APD 90 , rendering the APD 90 longer than the VERP, in fitting with experimental results and with the proarrhythmic effect of hypokalemia. Previous studies have reported that although exposure to lidocaine increases VERP through an effect on the gating of fast Na + -channels [32, 34], it has a proportionately smaller effect on action potential duration [5]. Exposure to lidocaine is thus established to result in postrepolarization refractoriness [39], in fitting with experimental results and with the antiarrhythmic effect of lidocaine.…”

Section: Discussionmentioning

confidence: 61%

The contribution of refractoriness to arrhythmic substrate in hypokalemic Langendorff-perfused murine hearts

Sabir

Fraser

Killeen

et al. 2007

Pflugers Arch - Eur J Physiol

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The clinical effects of hypokalemia including action potential prolongation and arrhythmogenicity suppressible by lidocaine were reproduced in hypokalemic (3.0 mM K + ) Langendorff-perfused murine hearts before and after exposure to lidocaine (10 μM). Novel limiting criteria for local and transmural, epicardial, and endocardial re-excitation involving action potential duration (at 90% repolarization, APD 90 ), ventricular effective refractory period (VERP), and transmural conduction time (Δlatency), where appropriate, were applied to normokalemic (5.2 mM K + ) and hypokalemic hearts. Hypokalemia increased epicardial APD 90 from 46.6± 1.2 to 53.1 ± 0.7 ms yet decreased epicardial VERP from 41±4 to 29± 1 ms, left endocardial APD 90 unchanged (58.2±3.7 to 56.9±4.0 ms) yet decreased endocardial VERP from 48±4 to 29±2 ms, and left Δlatency unchanged (1.6±1.4 to 1.1±1.1 ms; eight normokalemic and five hypokalemic hearts). These findings precisely matched computational predictions based on previous reports of altered ion channel gating and membrane hyperpolarization. Hypokalemia thus shifted all re-excitation criteria in the positive direction. In contrast, hypokalemia spared epicardial APD 90 (54.8±2.7 to 60.6±2.7 ms), epicardial VERP (84±5 to 81±7 ms), endocardial APD 90 (56.6± 4.2 to 63.7±6.4 ms), endocardial VERP (80±2 to 84± 4 ms), and Δlatency (12.5±6.2 to 7.6±3.4 ms; five hearts in each case) in lidocaine-treated hearts. Exposure to lidocaine thus consistently shifted all re-excitation criteria in the negative direction, again precisely agreeing with the arrhythmogenic findings. In contrast, established analyses invoking transmural dispersion of repolarization failed to account for any of these findings. We thus establish novel, more general, criteria predictive of arrhythmogenicity that may be particularly useful where APD 90 might diverge sharply from VERP.

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Section: Discussionmentioning

confidence: 61%

The contribution of refractoriness to arrhythmic substrate in hypokalemic Langendorff-perfused murine hearts

Sabir

Fraser

Killeen

et al. 2007

Pflugers Arch - Eur J Physiol

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“…Of these, only a few (Anderson et al 1980;Keefe & Kates 1982) have also measured myocardial drug concentration. For example, Martins and Kelly (1985) demonstrated that in open-chested dogs, maximum prolongation of the ventricular effective refractory period (ERP) occurred approximately 2 minutes after cessation of bolus injection of lignocaine, and that some prolongation of ERP persisted for a further 10 to 25 minutes. While maximum lignocaine effects on ERP were correlated with plasma drug concentrations, no attempts were made to assess drug concentrations in the myocardium.…”

Section: Studies Of Plasma Concentration-effect Relationshipsmentioning

confidence: 99%

Myocardial Uptake of Drugs and Clinical Effects

Horowitz

Powell

1986

Clinical Pharmacokinetics

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The process of uptake of cardioactive drugs into the myocardium is a major determinant of the efficacy and potential toxicity of such agents. Evaluation of responses to anti-arrhythmic and positive inotropic agents is best performed with reference to their concentration in the myocardium, and the potential toxicity of drugs such as tricyclic antidepressants and anthracycline antineoplastics is likely to be related to peak myocardial drug concentrations. Although it has been appreciated for many years that even during long term drug administration the myocardial drug content may not be readily predictable on the basis of estimation of plasma drug concentrations, methodology for direct assessment of myocardial drug content has remained limited. The results of in vitro experiments, utilising tissue culture preparations of myocardial cells or isolated atria, have shed some light on the role of local factors as determinants of myocardial drug uptake. For many agents, attainment of maximal cardiac drug content in vitro is a very slow process (taking up to 3 hours), although maximal inotropic and electrophysiological effects may occur more rapidly. The prolonged time course of drug washout from these preparations also reflects their extensive and slow intracellular accumulation. Mechanical activity of the myocardium appears to accelerate drug uptake, particularly for otherwise slowly equilibrating agents, but the major determinant of the extent of drug uptake into isolated myocardial preparations is lipophilicity, perhaps reflecting the passage of drugs through the sarcolemma. In intact animals, assessment of myocardial drug content after acute drug administration has been performed utilising serial myocardial biopsy or sacrifice of animals. Studies in open-chested dogs suggest that acute accumulation of agents may be most closely predicted from the second compartment of a 3-compartment pharmacokinetic model, and that there is a variable correlation between changes in plasma and myocardial drug concentrations. For example, bretylium concentrations within the myocardium continue to increase for up to 6 hours after drug administration. Factors which may influence drug uptake into the myocardium in intact animals include ischaemia, which usually results in a delay in both drug uptake and subsequent clearance. This change can also be inferred from the time course of onset of antiarrhythmic drug effects in some models of myocardial ischaemia. Anoxia may also inhibit myocardial drug uptake.(ABSTRACT TRUNCATED AT 400 WORDS)

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Short-term myocardial uptake of lidocaine and mexiletine in patients with ischemic heart disease.

Horowitz¹,

Dynon²,

Woodward³

et al. 1986

Circulation

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Determination of short-term myocardial drug uptake and subsequent redistribution was performed in 27 patients with ischemic heart disease for the antiarrhythmic agents lidocaine and mexiletine, using frequent simultaneous measurements of drug concentration in aortic and coronary sinus blood, combined with measurement of coronary sinus blood flow after intravenous bolus injection of the drug. Maximal myocardial drug content per unit resting coronary sinus blood flow (MDC:F) was significantly greater in patients in whom coronary sinus pacing at 100 beat/min was performed during the initial period of drug uptake. Maximal myocardial drug content occurred after 2.4 + 0.2 (SEM) for lidocaine and after 5.5 ± 0.6 min for mexiletine (p < .001), and pacing did not affect time to maximum myocardial drug content. In nonpaced, but not paced, patients maximal MDC:F was greater in the lidocaine group than that in the mexiletine group. The subsequent efflux of lidocaine from the myocardium was more rapid that that of mexiletine in both paced and nonpaced groups. Circulation 73, No. 5, 987-996, 1986 able has been derived from conventional pharmacokinetic studies, which use peripheral venous blood sampling to examine the clearance of drugs from blood or plasma1-3 and rely on the assumption that drug uptake into the myocardium is a component of "central compartment" kinetics.' However, short-term studies correlating electrophysiologic effects of drugs such as procainamide5 and verapamil6 with plasma drug concentrations have served to emphasize the lack of equilibrium between plasma and myocardium under non--steady-state conditions and have raised the possiblity that at least part of the myocardium acts as a "peripheral" compartment of drug uptake despite relatively high global perfusion.7We now report the development of a method for the determination of short-term drug uptake in man and of the subsequent pattern of drug efflux from the myocardium. This method has been applied initially to the type IB antiarrhythmic agent lidocaine and to its derivative mexiletine, and offers a potential means of correlating myocardial drug content, drug effects, and the results of conventional pharmacokinetic studies. MethodsPatients

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Prolongation of refractoriness and activation time in normal canine ventricular myocardium following bolus administration of lidocaine

Cited by 3 publications

References 18 publications

The contribution of refractoriness to arrhythmic substrate in hypokalemic Langendorff-perfused murine hearts

The contribution of refractoriness to arrhythmic substrate in hypokalemic Langendorff-perfused murine hearts

Myocardial Uptake of Drugs and Clinical Effects

Short-term myocardial uptake of lidocaine and mexiletine in patients with ischemic heart disease.

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