Mechanisms of make and break excitation revisited: paradoxical break excitation during diastolic stimulation

Abstract

Nikolski, Vladimir P., Aleksandre T. Sambelashvili, and Igor R. Efimov. Mechanisms of make and break excitation revisited: paradoxical break excitation during diastolic stimulation. Am J Physiol Heart Circ Physiol 282: H565-H575, 2002; 10.1152/ajpheart.00544.2001. Onset and termination of electric stimulation may result in "make" and "break" excitation of the heart tissue. Wikswo et al. (30) explained both types of stimulations by virtual electrode polarization. Make excitation propagates from depolarized regions (virtual cathodes). Break excitation propagates from hyperpolarized regions (virtual anodes). However, these studies were limited to strong stimulus intensities. We examined excitation during weak near-threshold diastolic stimulation. We optically mapped electrical activity from a 4 ϫ 4-mm area of epicardium of Langendorff-perfused rabbit hearts (n ϭ 12) around the pacing electrode in the presence (n ϭ 12) and absence (n ϭ 2) of 15 mM 2,3-butanedione monoxime. Anodal and cathodal 2-ms stimuli of various intensities were applied. We imaged an excitation wavefront with 528-s resolution. We found that strong stimuli (ϫ5 threshold) result in make excitation, starting from the virtual cathodes. In contrast, near-threshold stimulation resulted in break excitation, originating from the virtual anodes. Characteristic biphasic upstrokes in the virtual cathode area were observed. Break and make excitation represent two extreme cases of near-threshold and far-above-threshold stimulations, respectively. Both mechanisms are likely to contribute during intermediate clinically relevant strengths. optical mapping; virtual electrode; pacing THE ABILITY OF ELECTRIC POINT STIMULATION to produce a response in excitable tissues (11, 28) and induce (12) or terminate (17) arrhythmia in the heart is well known. However, the exact mechanisms of electric stimulation have been obscure until the recent discovery of virtual electrode polarization (VEP) produced by point stimulation (13,15,24,30,31). It results in a characteristic "dogbone" pattern of positive and negative polarizations. These polarizations of opposite sign are thought to be induced by a so-called virtual cathode and virtual anode. These virtual electrodes represent the driving force, which can be mathematically expressed as an activating function (19,27), which is also referred to as secondary sources (10). The activating function is governed by two major parameters: the gradient of extracellular electric field and structural heterogeneity of the heart, contributing to the polarization of the cellular membrane during stimulus. Active ionic properties of the heart, particularly calcium channels, modulate these polarizations (2,18,20,22).Dekker (4) demonstrated that both the onset (make) and termination (break) of stimulation of appropriate intensity and duration could produce a propagated response. Roth (20) and Wikswo et al. (30) provided the first mechanistic explanation of the "make" and "break" stimulation based on the VEP phenomenon.According to their theory...

Nonlinear effects in subthreshold virtual electrode polarization

“…In two additional experiments, guinea pig hearts (n ϭ 2) were used to check for possible interspecies differences. The hearts were placed onto a Langendorff apparatus where they were retrogradely perfused with oxygenated modified Tyrode solution as previously described (21). Motion artifacts in optical recordings were suppressed by 15 mM 2,3-butanedione monoxime (BDM).…”

“…The optical mapping setup used for acquisition of the optical signals was described previously (20,21). Briefly, the light produced by a 250-W quartz-tungsten-halogen DC-powered light source passed through a 520 Ϯ 45-nm excitation filter, was reflected by a 585-nm dichroic mirror, and passed through a 50-mm lens before it illuminated a rabbit heart.…”

Virtual electrode theory explains pacing threshold increase caused by cardiac tissue damage

“…The experiments were performed on New Zealand White rabbit hearts (n ϭ 5) in vitro. The hearts were placed on a Langendorff apparatus and retrogradely perfused with oxygenated modified Tyrode solution as previously described (36). Motion artifacts in optical recordings were suppressed by 15 mM 2,3-butanedione monoxime (BDM).…”

Effects of Hyperpolarization-Activated Channel Blocker ZD7288 on Polar Excitations of Frog Sciatic Nerve

“…The underlying mechanism of polar excitations has been mainly described from the properties of Na channels [1][2][3]. Although recent studies revisiting the mechanisms of polar excitations have proposed alternative models to the one initially described by Hodgkin and Huxley [4][5][6][7], none have suggested a contribution of ionic channels other than Na + or K + channels to the generation of polar excitation.…”

“…The terminal of the stimulation triggers another action potential (equal to AE) as an off-response, because the membrane potential shifts in the depolarizing direction by breaking the stimulation. A scant few reports have revisited the mechanisms of polar excitations [4][5][6][7], but none has suggested a contribution of different ionic channels other than Na + and K + channels.…”