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

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 304; no. 12; p. H1680
• Main Authors: Saegusa, Noriko, Garg, Vivek, Spitzer, Kenneth W
• Format: Journal Article
• Language: English
• Published: Bethesda American Physiological Society 15.06.2013
• Subjects: Calcium; Cardiovascular system; Cells; Rabbits
• ISSN: 0363-6135; 1522-1539

The contribution of transient outward current (I...) 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), I..., 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 ~50% 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 α-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 +60 mV when initiated from -80 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 I..., increased net calcium influx via I..., 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. (ProQuest: ... denotes formulae/symbols omitted.)