Modulation of Spontaneous Action Potential Rate by Inositol Trisphosphate in Myocytes from the Rabbit Atrioventricular Node.

The atrioventricular node (AVN) is a key component of the cardiac conduction system and takes over pacemaking of the ventricles if the sinoatrial node fails. IP (inositol 1,4,5 phosphate) can modulate excitability of myocytes from other regions of the heart, but it is not known whether IP receptor (IP-R) activation modulates AVN cell pacemaking. Consequently, this study investigated effects of IP on spontaneous action potentials (APs) from AVN cells isolated from rabbit hearts. Immunohistochemistry and confocal imaging demonstrated the presence of IP-R2 in isolated AVN cells, with partial overlap with RyR2 ryanodine receptors seen in co-labelling experiments. In whole-cell recordings at physiological temperature, application of 10 µM membrane-permeant Bt-(1,4,5)IP-AM accelerated spontaneous AP rate and increased diastolic depolarization rate, without direct effects on I, I, I or I. By contrast, application via the patch pipette of 5 µM of the IP-R inhibitor xestospongin C led to a slowing in spontaneous AP rate and prevented 10 µM Bt-(1,4,5)IP-AM application from increasing the AP rate. UV excitation of AVN cells loaded with caged-IP led to an acceleration in AP rate, the magnitude of which increased with the extent of UV excitation. 2-APB slowed spontaneous AP rate, consistent with a role for constitutive IP-R activity; however, it was also found to inhibit I and I, confounding its use for studying IP-R. Under AP voltage clamp, UV excitation of AVN cells loaded with caged IP activated an inward current during diastolic depolarization. Collectively, these results demonstrate that IP can modulate AVN cell pacemaking rate.