| BackgroundEmerging evidences indicate that SCN10A/NaV1.8is present in intrinsic cardiacneurons and associated with cardiac conduction and atrial fibrillation, but theexact role of NaV1.8in cardiac electrophysiology remains poorly understood.ObjectiveThe present study was designed to investigate the effects of blocking NaV1.8channels in cardiac ganglionated plexi (GP) on modulating cardiac conduction andatrial fibrillation inducibility in the canine model.MethodsThirteen mongrel dogs were randomly enrolled. NaV1.8channels blockerA-803467(1μmol/0.5mL per GP, n=7) or5%DMSO/95%polyethylene glycol(0.5mL per GP, n=6, control) was injected into the anterior right ganglionatedplexi (ARGP) and the inferior right ganglionated plexi (IRGP). Right cervicalvagus nerve stimulation (VNS,20Hz,0.1ms duration, square waves) was appliedto determine its effects on the sinus rate, ventricular rate during atrial fibrillation,PR interval, atrial effective refractory period, and the cumulative window of atrialvulnerability at baseline,10min,35min, and90min after drug injection. In order toverify the action of A-803467on the channels in cardiomyocytes, we also directlyinjected A-803467into right atrial free wall of the canine heart (2μmol/1ml, n=3).RT-PCR was used to detect the mRNA of NaV1.8channels in ARGP, IRGP, and isolated canine cardiomyocytes. We examined GP function at10min afterA-803467(1μmol/0.5mL, n=4) or5%DMSO/95%PEG (0.5ml, control, n=4)injection into the ARGP in separate experiments. Voltage-SR response curveswere constructed by applying HFS (20Hz,0.1ms duration, square waves) to theARGP with incremental voltages up to the voltage that induced AF. The slowingof the SR at each voltage level was determined.ResultsThe effects of VNS on the sinus rate, ventricular rate, PR interval, atrial effectiverefractory period and the cumulative window of atrial vulnerability weresignificantly eliminated at10min,35min, and90min after A-803467injection (p <0.05). The injection of A-803467into right atrium had no effects on theelectrophysiological characteristics of the atrium and AF inducibility (p>0.05).Results from RT-PCR indicated that SCN10A is expressed in ARGP and IRGP,but not in isolated canine cardiomyocytes. In separate experiments, A-803467blunted the slowing of sinus rate with increasing stimulation voltage of ARGP at10min after local injection (p=0.047).ConclusionsBlockade of NaV1.8channels suppresses the effects of VNS on the sinus rate,ventricular rate, PR interval, atrial effective refractory period and atrial fibrillationinducibility, most likely by inhibiting ganglionated plexi function. The underlyingmechanism for SCN10A modulating cardiac conduction and atrial fibrillationinducibility may be associated with the regulation of the neural activity of thecardiac ganglionated plexi. |
