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

Abstract

Saegusa N, Garg V, Spitzer KW. Modulation of ventricular transient outward K ϩ current by acidosis and its effects on excitation-contraction coupling. Am J Physiol Heart Circ Physiol 304: H1680 -H1696, 2013. First published April 12, 2013 doi:10.1152/ajpheart.00070.2013.-The contribution of transient outward current (Ito) to changes in ventricular action potential (AP) repolarization induced by acidosis is unresolved, as is the indirect effect of these changes on calcium handling. To address this issue we measured intracellular pH (pHi), Ito, L-type calcium current (ICa,L), and calcium transients (CaTs) in rabbit ventricular myocytes. Intracellular acidosis [pHi 6.75 with extracellular pH (pHo) 7.4] reduced Ito by ϳ50% in myocytes with both high (epicardial) and low (papillary muscle) Ito densities, with little effect on steady-state inactivation and activation. Of the two candidate ␣-subunits underlying Ito, human (h)Kv4.3 and hKv1.4, only hKv4.3 current was reduced by intracellular acidosis. Extracellular acidosis (pHo 6.5) shifted Ito inactivation toward less negative potentials but had negligible effect on peak current at ϩ60 mV when initiated from Ϫ80 mV. The effects of low pHi-induced inhibition of Ito on AP repolarization were much greater in epicardial than papillary muscle myocytes and included slowing of phase 1, attenuation of the notch, and elevation of the plateau. Low pHi increased AP duration in both cell types, with the greatest lengthening occurring in epicardial myocytes. The changes in epicardial AP repolarization induced by intracellular acidosis reduced peak ICa,L, increased net calcium influx via ICa,L, and increased CaT amplitude. In summary, in contrast to low pHo, intracellular acidosis has a marked inhibitory effect on ventricular Ito, perhaps mediated by Kv4.3. By altering the trajectory of the AP repolarization, low pHi has a significant indirect effect on calcium handling, especially evident in epicardial cells. transient outward current; acidosis; excitation-contraction coupling; rabbit ventricular myocytes TRANSIENT OUTWARD K ϩ CURRENT (I to ) is the major repolarizing current flowing during the early repolarization phase of the cardiac action potential (AP) in a variety of cell types including human and rabbit ventricular myocytes and is largely responsible for phase 1 and the "spike-and-dome" configuration (4,12,17,20,22,31,48). By modulating the initial voltage trajectory of the AP, I to importantly influences the overall AP waveform through voltage-dependent effects on other ionic currents such as L-type calcium current (I Ca,L ), Na ϩ /Ca 2ϩ exchange (NCX) current, and delayed rectifier currents (34). In this regard, several studies have shown that inhibition of I to markedly affects excitation-contraction (E-C) coupling by altering transsarcolemmal Ca 2ϩ flux via I Ca,L and NCX, with secondary effects on calcium loading of the sarcoplasmic reticulum (SR) (5,6,11,13,27,42,43,53).The expression and magnitude of cardiac I to are regulated by a variety of factors and conditions ...

Cardiorenal Syndrome in Acute Kidney Injury

“…Acidosis reduces myocardial contractility via alterations in intracellular calcium handling and contractile protein sensitivity to calcium. 37 Furthermore, acidosis affects b-adrenergic−receptor expression, contributing to reduced contractility. 38 To assess the physiologic impact of different types of acidemia on cardiac function and systemic hemodynamics, mechanically ventilated pigs with respiratory and metabolic acidosis were studied.…”

Effects of Hypoxia and Acidosis on Cardiac Electrophysiology and Hemodynamics. Is NHE-Inhibition by Cariporide Still Advantageous?

“…Interestingly, Saegusa et al (2013) observed differential effects of intracellular and extracellular acidification on the action potential duration: intracellular pH reduction resulted in action potential prolongation while extracellular acidosis reduced action potential duration (Saegusa et al, 2013). These authors found that intracellular acidification reduced the transient outward current I(t.o.)…”

“…Extracellular acidification shifted I(t.o.) inactivation toward less negative potentials (Saegusa et al, 2013). Another important effect is that regarding the ATP-inhibited K + current I(K.ATP) (ATP-sensitive potassium current) it was described that hypoxia and ATP depletion can activate this current leading to action potential shortening (Wilde et al, 1990) and that -on the other hand-extracellular H + ions can inhibit I(K.ATP) (Moncada et al, 2000).…”

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“…It is to be noted that any change in AP waveform affects I CaL . Saegusa et al [85] performed experiments on rabbit ventricular myocytes and showed that intracellular acidosis strongly decreased I to , increasing AP plateau and decreasing peak I CaL . Their AP voltage clamp approach allowed them to determine that intracellular pH-induced changes in AP waveform (plateau elevation) per se, reduced I CaL , without the complicating effects of intracellular acidosis.…”