FUNCTIONAL IMPAIRMENT OF CARDIAC TRANSIENT OUTWARD K⁺ CURRENT AS A RESULT OF ABNORMALLY ALTERED CELLULAR ENVIRONMENT

Abstract

1. Physiological functions of cardiac cells require a normal cellular environment. Under pathological conditions, there is a loss of normal cellular environment due to metabolic perturbations and other abnormalities. To test the hypothesis that cellular environmental stresses can create an electrophysiological substrate for electrical disorders in the heart, we investigated the effects of hypoxia, acidosis and ischaemia on transient outward K+ current (I(to)) in single canine ventricular myocytes. 2. The I(to) was studied because it plays a critical role in initiating cardiac repolarization and, thereby, arrhythmias. It was found that I(to) was significantly depressed by some 30% under hypoxic conditions relative to that in a normal cellular environment with normal Tyrode's solution. 3. Acidosis created by lowering the pH of the external solution from 7.4 to 7.2 produced a substantial (approximately 35%) reduction of the I(to) amplitude. 4. A marked impairment of I(to) function was consistently observed in ischaemic hearts in the canine coronary artery ligation model, with an approximate 30% decrease in the size of I(to). 5. Importantly, the impairment of I(to) under these environmental stresses was largely reversible following restoration to normal conditions. 6. The results of the present study suggest that I(to) is susceptible to changes in the cellular environment and the functional impairment of I(to) under environmental stresses contributes to arrhythmias under relevant pathological conditions of the heart.

Humanin Attenuated the Change of Voltage‐Dependent Potassium Currents in Hippocampal Neurons Induced by Anoxia

“…Anoxia promoted excitability of neuron, while humanin antagonized this effect. Moreover, I to was significantly depressed under hypoxic conditions [9], and upregulation of I to protected neurons against cerebral ischemia [10]. Present result of humanin protecting decrease in I to amplitude due to anoxia suggested that humanin supported voltagedependent potassium channels by inhibiting the effects of anoxia.…”

Role of CaMKII in post acidosis arrhythmias: A simulation study using a human myocyte model

“…Reduced pH also produces an increased activity of the Na + -H + exchanger (NHE) [15] and reduced Na + -K + pump (NaK) activity [16], increasing intracellular Na + concentration [17]. Moreover, acidosis depresses numerous ion flows: Ca 2+ input through the voltage-dependent L-type Ca 2+ channel [18], Ca 2+ release through the SR ryanodine receptor (RyR2) [19], Ca 2+ reuptake by the sarco(endo)plasmic reticulum Ca 2+ ATPase2a (SERCA2a) [2], Ca 2+ extrusion through the Na + -Ca 2+ exchanger (NCX) [20], and K + efflux through the inward rectifier K + channel [21] and the transient outward current [22]. An increase in Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) activity has also been described during acidosis [6].…”