The role of resistance to inhibitors of cholinesterase 8b in the control of heart rate.

We have assessed the role of ric-b8 in the control of heart rate after the gene was implicated in a recent genome-wide association study of resting heart rate. We developed a novel murine model in which it was possible to conditionally delete ric-8b in the sinoatrial (SA) node after the addition of tamoxifen. Despite this, we were unable to obtain homozygotes and thus studied heterozygotes. Haploinsufficiency of ric-8b in the sinoatrial node induced by the addition of tamoxifen in adult animals leads to mice with a reduced heart rate. However, other electrocardiographic intervals (e.g., PR and QRS) were normal, and there was no apparent arrhythmia such as heart block. The positive chronotropic response to isoprenaline was abrogated, whereas the response to carbachol was unchanged. The pacemaker current I