Atrio-Sinus Interaction Demonstrated by Blockade of the Rapid Delayed Rectifier Current

Abstract

Background-Proper pacemaking of the heart requires a specific organization of the sinoatrial (SA) node. The SA node drives the surrounding atrium but needs to be protected from its hyperpolarizing influence, which tends to suppress pacemaker activity. It has been suggested that the hyperpolarizing atrial influence is minimal at the site of the central nodal area. Methods and Results-Atrio-sinus interaction was assessed by specific depolarization of the SA node by blocking the HERG-encoded rapid delayed rectifier current (I K,r ) with the drug E-4031. In the SA node, E-4031 (1 mol/L) changed action potential configuration drastically but never resulted in pacemaker arrest. In the atrium, E-4031 did not affect the membrane resting potential, thereby leaving the normal hyperpolarizing load on the SA node intact. When the SA node was sectioned into strips and subsequently separated from the atrium, spontaneous electrical activity of the strip containing the primary pacemaker ceased on I K,r blockade. When not separated from the atrium, I K,r blockade never resulted in pacemaker arrest. A similar effective atrio-sinus interaction was demonstrated in computer simulations. Conclusions-Our results demonstrate that the atrium provides an effective hyperpolarizing load on the central SA nodal area and is at least one of the controlling mechanisms for normal pacemaking function. The present study can be of help in understanding why patients with long-QT2 syndrome secondary to a mutation in HERG do not show sinus arrest.

Effects of pacemaker currents on creation and modulation of human ventricular pacemaker: theoretical study with application to biological pacemaker engineering

“…In the systems with one to five BP cells, hyperpolarizing loads of the NP cell caused 1) prolongation of CL with an increase in oscillation amplitude, 2) irregular dynamics, and then 3) a bifurcation to quiescence (Hopf bifurcation), with increasing G C . These behaviors are essentially the same as those reported for interactions of the SA node cell and the atrial or ventricular myocyte (13,44,47,48). The critical G C value at the Hopf bifurcation to cause stabilization of EPs and cessation of BP activity increased with increasing number of BP cells.…”

“…Nevertheless, a real pacemaker system such as the intact SA node has much more complex architectures to facilitate optimization of the electrical loading by surrounding atrial or ventricular tissues (1,2,14,44). Thus more elaborate multicellular models are required for investigation of the structural stability to electrotonic loads and ability to drive the heart of a BP system in vivo and of how to create BP systems with robust pacemaking and driving.…”

Cardiac performance in the zebrafishbreakdancemutant

“…This can be the consequence of a drifting of genes, a change in the structure of the channel depending on the age of the larvae, or the presence or absence of associated proteins. Growth of cells might also modify the electrical properties and thus contribute to this phenomenon (Verheijck et al, 2002).…”

Roles of hyperpolarization-activated current If in sinoatrial node pacemaking: insights from bifurcation analysis of mathematical models

“…I f appears to play a pivotal role in preventing a bifurcation to quiescence or arrhythmic dynamics of the peripheral cell, especially that via electrotonic modulations. The greater effect of I f on the peripheral robustness to electrotonic loads, as well as higher I f density in the periphery (59), are reasonable because in vivo peripheral cells directly suffer the electrotonic load of adjacent atrial myocytes (18,19,51,54) and thus must be more robust to electrotonic modulations than central cells, which are distant from the crista terminalis. These regional differences in the I f effects may reflect different roles of I f in the center and periphery of the rabbit SAN: I f may contribute mainly to the robust pacemaking against electrotonic loads of the atrium in the periphery, but mainly to the sympathetic regulation of pacemaker frequency in the center.…”