Extracellular proton depression of peak and late Na⁺ current in the canine left ventricle

Abstract

Cardiac ischemia reduces excitability in ventricular tissue. Acidosis (one component of ischemia) affects a number of ion currents. We examined the effects of extracellular acidosis (pH 6.6) on peak and late Na(+) current (I(Na)) in canine ventricular cells. Epicardial and endocardial myocytes were isolated, and patch-clamp techniques were used to record I(Na). Action potential recordings from left ventricular wedges exposed to acidic Tyrode solution showed a widening of the QRS complex, indicating slowing of transmural conduction. In myocytes, exposure to acidic conditions resulted in a 17.3 ± 0.9% reduction in upstroke velocity. Analysis of fast I(Na) showed that current density was similar in epicardial and endocardial cells at normal pH (68.1 ± 7.0 vs. 63.2 ± 7.1 pA/pF, respectively). Extracellular acidosis reduced the fast I(Na) magnitude by 22.7% in epicardial cells and 23.1% in endocardial cells. In addition, a significant slowing of the decay (time constant) of fast I(Na) was observed at pH 6.6. Acidosis did not affect steady-state inactivation of I(Na) or recovery from inactivation. Analysis of late I(Na) during a 500-ms pulse showed that the acidosis significantly reduced late I(Na) at 250 and 500 ms into the pulse. Using action potential clamp techniques, application of an epicardial waveform resulted in a larger late I(Na) compared with when an endocardial waveform was applied to the same cell. Acidosis caused a greater decrease in late I(Na) when an epicardial waveform was applied. These results suggest acidosis reduces both peak and late I(Na) in both cell types and contributes to the depression in cardiac excitability observed under ischemic conditions.

The late sodium current in heart failure: pathophysiology and clinical relevance

“…[96][97][98][99] An increased window current, and a shift of voltage dependency of activation and inactivation towards positive voltages were observed in Xenopus expression system. [97][98][99] In isolated canine ventricular myocytes, a rightward shift in voltage dependency of activation but not in SSI has been shown resulting in a reduction of I Na,late .…”

An Emerging Antiarrhythmic Target: Late Sodium Current

“…When INa,L is recorded under AP command, there are two major type of profiles observed. In the first case the current magnitude decays monotonically; this profile was observed in dog and predicted by some of the models [68][69][70]. In the second type, the decay of transient phase is followed by a slow current accumulation during the plateau, then it forms a peak before the terminal repolarization of AP and declines rapidly reaching zero when membrane potential returns to resting level.…”

“…Based on these data they predicted AP lengthening at low pH in a computer model [180]. Murphy et al reported depolarizing shift in voltage dependency of activation, but not in SSI in freshly isolated canine ventricular myocytes [68,179]. In agreement with Jones et al, they observed the prolongation of AP at low pH, but they found that INa,L was reduced at in both endocardial and epicardial cells [68].…”

“…Cardiac sodium channels has been shown sensitive to the metabolic state of the cell and modulated by pH, oxygen or metabolites. During myocardial hypoxia extracellular pH can drop as low as 6.0 [178], and cardiac sodium current is known to be modulated by these substantial increase in proton concentration [68,[179][180][181][182]. There is a consensus on that acidosis reduces the magnitude and the decay of the transient phase.…”

Modulation of ventricular transient outward K+ current by acidosis and its effects on excitation-contraction coupling

“…The resting membrane potential (CL ϭ 2 s) was slightly depolarized by extracellular acidosis (control ϭ Ϫ87.1 Ϯ 2.5 mV, acidosis ϭ Ϫ83.8 Ϯ 2.7 mV; n ϭ 5, P Ͻ 0.05, paired). The effects of extracellular acidosis on cardiac AP configuration are complex, with reports of inhibition of the rapid delayed-rectifier current I Kr (8), I Ca,L (8,41), and both peak and persistent sodium current (30). In addition, we have recently shown that the changes in rabbit ventricular repolarization induced by low pH o are largely mediated by a reduction in I Ca,L and are unlikely to involve I to (41).…”