Abstract
Background and PurposeThe exact mechanism of spontaneous pacemaking is not fully understood. Recent results suggest tight cooperation between intracellular Ca2+ handling and sarcolemmal ion channels. An important player of this crosstalk is the Na+/Ca2+ exchanger (NCX), however, direct pharmacological evidence was unavailable so far because of the lack of a selective inhibitor. We investigated the role of the NCX current in pacemaking and analyzed the functional consequences of the If-NCX coupling by applying the novel selective NCX inhibitor ORM-10962 on the sinus node (SAN).Experimental ApproachCurrents were measured by patch-clamp, Ca2+-transients were monitored by fluorescent optical method in rabbit SAN cells. Action potentials (AP) were recorded from rabbit SAN tissue preparations. Mechanistic computational data were obtained using the Yaniv et al. SAN model.Key ResultsORM-10962 (ORM) marginally reduced the SAN pacemaking cycle length with a marked increase in the diastolic Ca2+ level as well as the transient amplitude. The bradycardic effect of NCX inhibition was augmented when the funny-current (If) was previously inhibited and vice versa, the effect of If was augmented when the Ca2+ handling was suppressed.Conclusion and ImplicationsWe confirmed the contribution of the NCX current to cardiac pacemaking using a novel NCX inhibitor. Our experimental and modeling data support a close cooperation between If and NCX providing an important functional consequence: these currents together establish a strong depolarization capacity providing important safety factor for stable pacemaking. Thus, after individual inhibition of If or NCX, excessive bradycardia or instability cannot be expected because each of these currents may compensate for the reduction of the other providing safe and rhythmic SAN pacemaking.
Highlights
Computational modeling as well as experimental results established previously that the normal pacemaker function is regulated by the hyperpolarization-activated funny current (If) (DiFrancesco, 1981) but is regulated by the intracellular Ca2+ handling (Lakatta and DiFrancesco, 2009; Yaniv et al, 2013a; Yaniv et al, 2015; Sirenko et al, 2016)
In the computational SAN action potential model (Yaniv et al, 2013b), we identified the degree of Na+/Ca2+ exchanger (NCX) current suppression required to obtain a similar cycle length (CL) increase as was experimentally measured
We suggest that the observed NCX-If interplay is the consequence of the increased susceptibility of diastolic depolarization (DD) to any intervention when the DD was previously inhibited by another compound (Rocchetti et al, 2000; Zaza and Lombardi, 2001; Monfredi et al, 2014)
Summary
Computational modeling as well as experimental results established previously that the normal pacemaker function is regulated by the hyperpolarization-activated funny current (If) (DiFrancesco, 1981) but is regulated by the intracellular Ca2+ handling (Lakatta and DiFrancesco, 2009; Yaniv et al, 2013a; Yaniv et al, 2015; Sirenko et al, 2016). NCX may have crucial importance in the clock-like oscillator system since the NCX-mediated inward current is directly translated to membrane potential changes via the operation of forward mode of the exchanger. This hypothesis was repeatedly challenged and the pivotal role of Ca2+ clock was questioned by other authors (Noble et al, 2010; Himeno et al, 2011; DiFrancesco and Noble, 2012). The supposed crucial role of NCX in the normal pacemaker function of SAN could not be directly investigated experimentally so far due to the lack of a selective NCX inhibitor. Mechanistic computational data were obtained using the Yaniv et al SAN model
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