Differential effects of ivabradine and ryanodine on pacemaker activity in canine sinus node and purkinje fibers

Effects of Ivabradine and Ryanodine on Cardiac Pacemakers . Introduction: It is generally accepted that at least 2 major mechanisms contribute to sinus node (SN) pacemaking: a membrane voltage (mainly I_f) clock and a calcium (Ca) clock (localized submembrane sarcoplasmic reticulum Ca²⁺ release during late diastolic depolarization). The aim of this study was to compare the contributions of each mechanism to pacemaker activity in SN and Purkinje fibers (PFs) exhibiting normal or abnormal automaticity. Methods and Results: Conventional microelectrodes were used to record action potentials in isolated spontaneously beating canine SN and free running PF in control and in the presence of 0.1 μM isoproterenol. Ryanodine (0.1–3 μM) and ivabradine (3 μM) were used to inhibit sarcoplasmic reticulum Ca²⁺ release or I_f, respectively. To induce automaticity at low membrane potentials, PFs were superfused with BaCl₂. In SN, ivabradine reduced the rate whereas ryanodine had no effect. Isoproterenol significantly accelerated automatic rate, which was decreased by ivabradine and ryanodine. In normally polarized PFs, ryanodine had no effects on the automatic rate in the absence or presence of isoproterenol, whereas ivabradine inhibited both control and isoproterenol‐accelerated automaticity. In PF depolarized with BaCl₂, ivabradine decreased BaCl₂‐induced automatic rate while ryanodine had no effect. Conclusion: In canine SN, I_f contributes to both basal automaticity and β‐adrenergic‐induced rate acceleration while the ryanodine‐inhibited Ca clock appears more involved in β‐adrenergic regulation of pacemaker rate. In PF, normal automaticity depends mainly on I_f. Inhibition of basal potassium conductance results in high automatic rates at depolarized membrane potentials with SN‐like responses to inhibition of membrane and Ca clocks. (J Cardiovasc Electrophysiol, Vol. 23, pp. 650–655, June 2012)