Action Potential Duration Heterogeneity Research Articles

Electrophysiological characterization of BRL-32872 in canine Purkinje fiber and ventricular muscle: Effect on early after-depolarizations and repolarization dispersion

Amongst the different pharmacological approaches to the treatment of cardiac arrhythmias, compounds with multiple electrophysiological activities appear to exhibit a reduced adverse effect profile. BRL-32872 ( N-(3,4-dimethoxyphenyl)- N-[3[[2-(3,4-dimethoxyphenyl) ethyl] propyl]-4-nitrobenzamide hydrochloride) is a typical example of an antiarrhythmic agent with combined K + and Ca 2+ blocking actions. In this study, we investigated the effects of BRL-32872 on early after-depolarizations and on dispersion of repolarization. Action potentials were recorded either in canine cardiac Purkinje fibers alone or in preparations containing both ventricular muscle and the attached Purkinje fibers. In Purkinje fibers, BRL-32872 (0.3–10 μM) induced a bell-shaped concentration-dependent increase in action potential duration. At 90% of repolarization, the action potential was prolonged at concentrations up to 1 μM and was shortened when the concentration of BRL-32872 was further increased. In all 17 experiments, BRL-32872 did not cause early after-depolarizations in Purkinje fibers. On the contrary, BRL-32872 (3 μM) systematically suppressed early after-depolarizations induced by clofilium (4-chloro- N, N-diethyl- N-heptylbenzenebutanaminium tosylate, 1 μM), a selective inhibitor of the delayed rectifier K + current. A similar effect was observed once with 1 μM BRL-32872, a concentration able to prolong Purkinje fiber action potentials. Simultaneous recording of action potentials in ventricular and Purkinje preparations showed that increasing concentrations of BRL-32872 (0.3–10 μM) induced a limited increase in the difference of repolarization time between the two tissues. The selective K + channel inhibitor E-4031 ( N-(4-(1-[2-(6-methyl-2-pyridyl) ethyl]-4-piperidyl)-carbonyl] phenyl) methanesulfonamide dihydrochloride dihydrate) exhibited a significant concentration-dependent increase in dispersion of repolarization. We conclude from the present results that the Ca 2+ blocking activity of BRL-32872 (i) prevents the occurrence of early after-depolarizations associated with action potential prolongation and (ii) limits an excessive increase in action potential duration heterogeneity. These electrophysiological features might represent the basis for antiarrhythmic compounds with reduced proarrhythmic profile.

Effects of IKr and IKs heterogeneity on action potential duration and its rate dependence: a simulation study.

A growing body of evidence suggests that heterogeneity of ion channel expression and electrophysiological characteristics is an important property of the ventricular myocardium. The 2 components of the delayed rectifier potassium current, IKr (rapid) and IKs (slow), play a dominant role in the repolarization of the action potential and are important determinants of its duration. In this report, the effects of heterogeneities of IKr and IKs on action potential duration (APD) and its rate dependence (adaptation) are studied with the use of the LRd model of a mammalian ventricular cell. Results demonstrate the importance of IKs density variations in heterogeneity of repolarization. Cells with reduced IKs (eg, mid-myocardial M cells) display long APD and steep dependence of APD on rate. Mechanistically, accumulation of IKs activation and increased sodium calcium exchange current, INaCa, secondary to Na+ accumulation at a fast rate underlie the steep APD-rate relation of these cells. When cells are electrotonically coupled in a multicellular fiber through resistive gap junction, APD differences are reduced. The results demonstrate strong dependence of APD heterogeneity on the degree of intercellular coupling even in the normal physiological range. Highly reduced coupling maximizes APD heterogeneity. Heterogeneity of IKs:IKr density strongly influences APD and its rate dependence. However, in the intact myocardium, the degree of gap-junction coupling may be an important factor that determines the manifestation of APD heterogeneity and dispersion of repolarization. The clinical significance of this study is in the context of repolarization abnormalities and associated arrhythmias (eg, long QT syndrome and torsade de pointes).

Modulation of electrical heterogeneity by compensated hypertrophy in rat left ventricle.

Modulation of the regional distribution of the action potential by left ventricular hypertrophy and the role of the L-type Ca2+ current (I(Ca)) and transient outward current (I(to)) in the action potential duration (APD) were investigated in normal and hypertrophied rat ventricular myocytes from the apex (A), septum (S) and left ventricular free wall (FW) by using whole cell current- and voltage-clamp techniques. Hypertrophy was induced by abdominal aortic constriction. In control cells, the APD measured at 20% repolarization (APD20) assumed the shortest values in the A and the longest in the S, whereas FW cells showed intermediate values. Hypertrophy significantly prolonged the APD20 and increased APD variability within the A and FW regions but did not modify the APD in S cells. Analysis of the APD, I(Ca), and I(to) at the instant of 20% repolarization in the same cell showed that in control cells the shortest APD20 was associated with a prominent I(to) in the A and FW, whereas the long APD20 was identified with a lower I(to) in S myocytes. Hypertrophy-induced prolongation ofAPD20 was associated with a reduction in the I(to) in the A and FW. Significant correlations could be established between the APD20 and the "net current," defined as the algebraic addition of I(to) and I(Ca) in the A and FW control groups but not in the control S or hypertrophied cells whatever their origin. Our results indicate that interregional APD heterogeneity is lost while intraregional APD variability is increased in the A and FW during the hypertrophic process. These effects are largely due to a change in the balance between the I(Ca) and I(to), which is a major contributing factor to the heterogeneity of the initial phase of repolarization in the normal rat ventricle.

Modelling propagation and re-entry in anisotropic and smoothly heterogeneous cardiac tissue

Cardiac muscle is modelled by a simple, three-dimensional, coupled map lattice with component maps that show appropriate rate-dependent changes in action-potential duration. Anisotropy of conduction velocity and heterogeneity of action-potential duration is produced by a uniform spatial gradient along one axis of one parameter of the model, for parameters that control the coupling between maps and the action-potential duration. Non-uniformity of the coupling parameter in a direction orthogonal to the organising filament and of the parameter controlling the action-potential duration in a direction parallel to the organising filament gives rise to distortion and then breakdown of the scroll wave, producing new, interacting vortices.

Electrophysiological Studies of Penticainide (CM 7857), a New Antiarrhythmic Agent, in Mammalian Myocardium

The intracellular electrophysiologic properties of a new antiarrhythmic substance, penticainide, were studied in isolated rabbit, dog, and guinea pig myocardial preparations superfused or perfused with oxygenated Tyrode's solution. "Therapeutic" concentrations of penticainide (1.5 to 3 X 10(-5) M) had little effect on sinus node automaticity; sinoatrial conduction was slightly delayed. In atrial, Purkinje and ventricular fibers, amplitude, and maximal rate of rise of phase O (dV/dtmax) were decreased by penticainide; Purkinje-ventricle conduction velocity was depressed. Penticainide did not significantly modify action potential duration (APD) of rabbit atria and dog ventricle and reduced APD and effective refractory period (ERP) of dog Purkinje and guinea pig ventricular fibers. Penticainide reduced APD heterogeneity of Purkinje-ventricle junction with a preferential effect at the gate and decreased tension amplitude of perfused papillary muscle in dog heart. The effect of penticainide on dV/dtmax was voltage and rate dependent; the resting block was weak. Thus, penticainide is a class 1 antiarrhythmic agent with properties of class 1B agents such as APD reduction and properties of class 1C agents such as slow recovery kinetic of rate-dependent block.