Aim: 

To determine the reduction of transient outward current (Ito) in a canine model of tachypacinginduced HF and assess the ability of the Ito activator NS5806 to recover Ito, phase 1 repolarization and contractility.

Methods: 

Action potentials (AP) were recorded from coronary-perfused left ventricular (LV) wedge preparations along with a pseudo-ECG. Ito were recorded in isolated Epi ventricular myocytes and unloaded cell shortening determined using a video edge detector.

Results: 

APs were recorded from LV Epi of wedges. In HF dogs, phase 1 amplitude was reduced to 53% of control. Application of NS5806 (10 mM) to HF wedges (3/4 HF wedges) restored the spike-and-dome morphology of the Epi AP and normalized the ECG. The Ito density was reduced in Epi moycytes from HF vs. control dogs (11.28±2.5 vs 23.13±2.9 pA/pF, at +50 mV). Application of NS5806 (10 mM) to HF Epi cells increased Ito (at +50 mV) from 11.28±2.5 to 17.0±2.9 pA/pF (p< 0.05). Using AP voltage-clamp techniques, application of a control Epi AP waveform with a prominent spike-and-dome morphology resulted in larger ICa compared to when an HF Epi AP waveform with no spike-and-dome morphology was applied to the same cell. On average, peak current and total charge were 26±11 and 47±10% (p< 0.05) larger (n=5), respectively, with a normal Epi vs. HF Epi AP clamp protocol. In addition, the magnitude of cell shortening was 19.7±6.8% larger when the control Epi AP waveform was applied to the cells.

Conclusion: 

Our results indicate that phase 1 repolarization is substantially reduced in HF dogs due to a reduction in Ito. Application of the Ito agonist NS5806 rescued Ito and restored the spike-and-dome morphology of the Epi AP. Using AP clamp techniques, we also show that ICa and unloaded cell shortening are greater when a control Epi waveform is applied to cells suggesting that both electrical and contractile remodelling encountered during the development of heart failure can be pharmacologically reversed.