Antiarrhythmic effects and potential mechanism of WenXin KeLi in cardiac Purkinje cells

The transient receptor potential melastatin 4 channel inhibitor 9‐phenanthrol modulates cardiac sodium channel

“…Cardiac I NaL has recently been demonstrated as a promising antiarrhythmic target, inhibition of which can ameliorate abnormal Na + influx into cardiomyocytes, restore intracellular Ca 2+ homeostasis, enhance repolarization reserve, decrease transmural dispersion of repolarization and consequently terminate arrhythmias (Belardinelli et al, ; Rajamani et al, ). Our previous studies (Hou et al, ; Li et al, ) have demonstrated that I NaL in Purkinje cells (PCs) is usually larger than that in ventricular myocytes (VMs), consistent with a longer APD in PCs. Importantly, I NaL inhibitors, such as tetrodotoxin (TTX) and ranolazine , shorten the APD of PCs to a larger extent than that of VMs (Aomine, ).…”

“…In their study, the APD 90 of Purkinje fibres was reduced by about 15% in the presence of 30 μM 9‐phenanthrol. Nevertheless, I NaL also played a crucial role in modulating the APD of PCs, which has been demonstrated in various studies (Sicouri et al, ; Hou et al, ; Li et al, ) as well as in mathematical models (Corrias et al, ). In accordance with the results from Guinamard's lab, we observed that 30 μM 9‐phenanthrol significantly shortened the APD 90 of PCs (Figure A,C); however, this effect was diminished when PCs were pretreated with 1 μM GS967 (a selective inhibitor of I NaL ) (Figure B,C).…”

“…Cardiac Purkinje fibres play an important role in maintaining rapid impulse propagation from atrioventricular node to ventricle and in the genesis of various arrhythmias, such as catecholaminergic polymorphic ventricular tachycardia (Willis et al, ), idiopathic ventricular tachycardia (Xiao et al, ). Our previous studies indicated that I NaL in PCs displayed larger rate‐dependent property, slower decay and recovery kinetics compared with VMs (Li et al, ), and I NaL inhibition ameliorated rate‐dependent adaption of APD and effectively terminated related arrhythmias in PCs (Hou et al, ; Li et al, ). Therefore, we tested the effect of 9‐phenanthrol on PC‐related arrhythmias.…”

Oxidative Stress-Induced Afterdepolarizations and Protein Kinase C Signaling

“…As shown in Figure 4C, I Ca,L was elevated from −6.11 ± 0.47 to −8.82 ± 0.61 pA/pF after H 2 O 2 perfusion ( p < 0.01, control vs. H 2 O 2 , n = 5), and decreased to −6.21 ± 0.45 pA/pF after the addition of Gö 6983 ( p < 0.01, H 2 O 2 vs. Gö 6983, n = 5). In the control experiments, the run-down of I Ca,L was less than 5% [19]. …”

“…I Na,L plays a key role in H 2 O 2 -induced afterdepolarizations [19,20,21]. I Na,L curves averaged by five replicated depolarizing voltage steps from −120 to −30 mV of one representative cell are shown in Figure 5A.…”