We have previously shown that inhibitory G protein Galphai2 (Gαi2) is important in mediating vagal tone to the murine heart with global Gαi2 knockout (KO) mice developing tachycardia with loss of high frequency (HF) power and resistant to the effects of the muscarinic agonist Carbachol. However, it is unclear whether the effect is mediated entirely via Gαi2 signaling at the end-organ level or whether there is a central component. We sought to investigate this by studying mice with conditional KO of Gαi2 in the cardiac pacemaker tissue.Methods
Using the Cre/loxP approach, Gαi2 was deleted by Tamoxifen inducible Cre-recombinase driven by the promoter HCN-4, which is selectively expressed in cardiac pacemaker cells. Littermates without either the Cre and/or loxP alleles acted as controls. 48 hour ECG tracings in freely moving mice were obtained using implantable telemetry probes. The mice were injected with Tamoxifen i/p (1mg/25g body weight for 5 days) and the ECG telemetry recordings were repeated 10 days after the last dose. Heart rate (HR) and heart rate variability (HRV) was then derived from the ECG tracings.Results
6 KO and 7 control mice aged between 3-4 months were studied. There was no significant difference in mean HR between the groups pre-Tamoxifen (508 ± 104 v 536 ± 96 bpm, p=0.12). Post Tamoxifen, KO mice were more tachycardic (538 ± 91 v 496 ± 79 bpm, p=0.06), with a significant increase in daytime HR (530 ± 85 v 457 ± 63 bpm, p < 0.001) (Figure). On HRV analysis, there was a reduction in daytime HF power in the KO mice (41 ± 21 v 24 ± 12 ms2, p=0.03).Conclusion
Our findings suggest that Gαi2 signaling at the level of the pacemaker system is important in mediating parasympathetic effect on murine hearts in vivo.