Extracellular Proton Modulation of Peak and Late Sodium Current in the Canine Left Ventricle

Abstract

Background: Cardiac ischemia produces a reduction in excitability in ventricular tissue. Acidosis (one component of ischemia) affects a number of ion currents. We examined the effects of extracellular acidosis on Na+ current in canine ventricular cells. Methods: Epicardial (Epi) and endocardial (Endo) myocytes were isolated from the left ventricle. Voltage clamp methods were used to record INa. Peak INa was recorded in low external Na+ to ensure voltage control. Late INa was recorded in full external Na+ and defined as the TTX-sensitive current. Results: Action potential recordings from left ventricular wedges exposed to pH=6.6 showed a widening of the QRS complex indicating slowing of transmural conduction. In myocytes, exposure to acidic conditions caused a 17.3±0.9% reduction in upstroke velocity at pH=6.6 versus 7.4. Patch clamp analysis of fast INa showed current density was similar in Epi and Endo cells at normal pH (68.1±7.0 pA/pF versus 63.2±7.1 pA/pF respectively at −35 mV). Extracellular acidosis reduced fast INa magnitude by 22.7% in Epi cells and 23.1% in Endo cells. In addition, a slowing of the decay (τ) of fast INa was observed at pH=6.6. Acidosis did not affect steady state inactivation of INa or recovery from inactivation. Analysis of late INa during a 500 ms pulse showed acidosis reduced late INa at 250 and 500ms into the pulse but no reduction was observed 50ms into the pulse. Conclusions: We demonstrate that acidosis reduces the size of peak INa and slows the decay without affecting Na+ channel availability or recovery. Acidosis also reduced the TTX-sensitive late INa. The reduction in peak and late INa observed during acidosis may contribute to the depression in cardiac excitability observed under ischemia.