J020 A functional role for Cav1.3 channels in muscarinic regulation of heart rate (HR) and automaticity in pacemaker cells: experimental results

Aim To investigate the effects of different agonist for the muscarinic receptor on cardiac automaticity in Cav1.3-/-, Kir 3.4-/- and Cav1.3-/-Kir3.4-/- mice. Method In vivo: mice received methoxamine or CCPA once intraperitoneally and telemetric recordings were run continuously over 8 h. Quantitative ECG analyses were performed. In vitro: action potentials were recorded in isolated SAN cells before and after application of different doses of Ach, the variation in the spontaneous firing rate was evaluated. Result In vivo: in WT, in Cav1.3-/- and in Cav1.3-/-Kir3.4-/- mice, methoxamine (6 mg/kg) reduces the HR (p In vitro: the pacemaker activity in WT SAN cells is strongly reduced with 10 nM Ach (42 %, p 0.05) at each of the three doses tested. Concerning Kir3.4-/- cells, we have seen a reduction (p Conclusion In vivo: Inactivation of Cav1.3 exacerbated the slowing of HR induced by agonists of the muscarinic signalling pathway in both Cav1.3-/- and Cav1.3-/-Kir3.4-/- compared to WT counterparts. In contrast, inactivation of Kir3.4 channels reduced the responsiveness of HR to the same agonists. Thus, Kir3.4 channels are possibly the predominant mechanism controlling HR under vagal input. In vitro: The spontaneous firing rate is strongly reduced under Ach stimulation in SAN WT cells, but is not affected in Cav1.3-/-Kir3.4-/- SAN cells. Moreover, there is a small but significant reduction on firing rate in Kir3.4-/- cells. These data seems to indicate Cav1.3 channels as a potential contributor in the muscarinic regulation of automaticity in isolated SAN cells.