Effects of unipolar stimulation on voltage and calcium distributions in the isolated rabbit heart

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Abstract
Background The effect of electric stimulation on the polarization of cardiac tissue (virtual electrode effect) is well known; the corresponding response of intracellular calcium concentration ([Ca2+] i ) and its dependence on coupling interval between conditioning stimulus (S1) and test stimulus (S2) has yet to be elucidated. Objective Because uncovering the transmembrane potential (V m)–[Ca2+] i relationship during an electric shock is imperative for understanding arrhythmia induction and defibrillation, we aimed to study simultaneous V m and [Ca2+] i responses to strong unipolar stimulation. Methods We used a dual-camera optical system to image concurrently V m and [Ca2+] i responses to unipolar stimulation (20 ms ± 20 mA) in Langendorff-perfused rabbit hearts. RH-237 and Rhod-2 fluorescent dyes were used to measure V m and [Ca2+] i , respectively. The S1–S2 interval ranged from 10 to 170 ms to examine stimulation during the action potential. Results The [Ca2+] i deflections were less pronounced than changes in V m for all S1–S2 intervals. For cathodal stimulation, [Ca2+] i at the central virtual cathode region increased with prolongation of S1–S2 interval. For anodal stimulation, [Ca2+] i at the central virtual anode area decreased with shortening of the S1–S2 interval. At very short S1–S2 intervals (10–20 ms), when S2 polarization was superimposed on the S1 action potential upstroke, the [Ca2+] i distribution did not follow V m and produced a more complex pattern. After S2 termination [Ca2+] i exhibited three outcomes in a manner similar to V m: non-propagating response, break stimulation, and make stimulation. Conclusions Changes in the [Ca2+] i distribution correlate with the behavior of the V m distribution for S1–S2 coupling intervals longer than 20 ms; at shorter intervals S2 creates more heterogeneous [Ca2+] i distribution in comparison with V m. Stimulation in diastole and at very short coupling intervals caused V m–[Ca2+] i uncoupling at the regions of positive polarization (virtual cathode).