Introduction
Sympathetic nerve stimulation(SNS) shortens ventricular action potential duration(APD), ensuring diastolic filling despite increased heart rate(HR). This shortening has been reported to be driven by sympathetically sensitive IKs and IKr currents. SNS is known to increase the risk of sudden cardiac death through an increased incidence of ventricular fibrillation(VF) linked to the heterogenous effects of SNS on ventricular electrophysiology caused by regional differences in nerve and ion channel distribution. The effects of IKr and IKs blockade on this heterogeneity, and on the electrophysiological effects of SNS, have not been studied in detail in the rabbit ventricle.
Methods
An innervated isolated rabbit (NZW 3.38± 0.05kg, initial sedation (subcutaneous Sedator-0.2mg/kg, Ketavet-10mg/kg), followed by surgery under intravenous propofol before terminal anaesthesia (Dolethal – 160mg/kg)) was used to examine left ventricular (LV) APD responses to SNS during pacing. Protocols were run initially without drug, followed by pharmacological blockade of IKs (0.5μM HMR, n=6) or IKr(0.03μM E4031, n=7) and finally with blockade of both IKr and IKs combined(0.5μM HMR and 0.03μM E4031)
Results
Both LV apical and basal APDs were lengthened by E4031 (110±5ms to 133±5ms, p<0.001; 118±5ms to 146±10ms, p<0.05) and were modestly but not significantly lengthened with HMR (118±3ms to 127±5ms;119±7ms to 128±5ms). Similarly, both LV apical and basal APDs were lengthened significantly by the addition of E4031 to HMR (140±6ms, p<0.01; 163±8ms, p<0.01), and more modestly by the addition of HMR to E4031(150±11ms; 151±10ms). In all cases, SNS shortened both apical and basal APD, but the magnitude of this SNS-induced shortening was almost always greater in the base.
The effective refractory period (ERP) was also lengthening with HMR and to a greater extent with E4031(135±4ms to 146±4ms, p<0.01; 127±6 to 170±8ms, p<0.01). SNS significantly shortened ERP both in the absence and presence of HMR (120±4ms, p<0.001; 131±7ms, p<0.01) and E4031(116±3ms, p<0.05; 145±6ms, p<0.01). While the magnitude of this SNS-induced shortening was the same with or without HMR(-10.7% to -10.4%), it was significantly increased by E4031(-8.1% to -14.6%, p<0.5). ERP was not compared with both drugs combined, as the protocol often induced ventricular fibrillation(6/16 hearts).
Despite the high incidence of VF during ERP protocols with both drugs we saw no significant changes in VFT with HMR, E4031 or both drugs combined. In addition, the magnitude of the SNS-induced reduction in VFT was not significantly altered by these pharmacological blockades.
Conclusion
In this study, we observed greater APD and ERP lengthening with E4031 than with HMR and an increase in SNS-induced ERP shortening only with E4031. These results reflect the known variation in the roles of IKs and IKr in both the rabbit ventricle and in the sympathetic response. Despite a noticeable increase in the incidence of VF with both drugs combined during our ERP protocol, we didn’t observe any significant changes in VFT in this study, perhaps a result of the protocol used. In addition, when both IKr and IKs were pharmacologically blocked, the SNS-induced APD shortening and VFT reduction were still present, suggesting that in these experiments, some repolarisation reserve remains.