Protein Kinase C And Ca2+-Calmodulin-Dependent Protein Kinase Ii Mediate The Enlarged Reverse I-Ncx Induced By Ouabain-Increased Late Sodium Current In Rabbit Ventricular Myocytes
EXPERIMENTAL PHYSIOLOGY（2015）
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更多- What is the central question of this study? What are the effects of protein kinaseC (PKC) and Ca2+-calmodulin-dependent protein kinaseII (CaMKII) on late sodium current (I-NaL), reverse Na+-Ca2+ exchange current (reverse I-NCX) or intracellular Ca2+ levels changed by ouabain?What is the main finding and its importance? Ouabain, even at low concentrations (0.5-8.0m), can increase I-NaL and reverse I-NCX, and these effects may contribute to the effect of the glycoside to increase Ca2+ transients and contractility. Both PKC and CaMKII activities may mediate or modulate these processes.It has been reported that the cardiac glycoside ouabain can increase the late sodium current (I-NaL), as well as the diastolic intracellular calcium concentration and contractile shortening. Whether an increase of I-NaL participates in a pathway that can mediate the positive inotropic response to ouabain is unknown. We therefore determined the effects of ouabain on I-NaL, reverse Na+-Ca2+ exchange current (reverse I-NCX), intracellular Ca2+ ([Ca2+](i)) levels and contractile shortening in rabbit isolated ventricular myocytes. Ouabain (0.1-8m) markedly increased I-NaL and reverse I-NCX in a concentration-dependent manner, with significant effects at concentrations as low as 0.5 and 1m. These effects of ouabain were suppressed by the I-NaL inhibitors TTX and ranolazine, the protein kinaseC inhibitor bisindolylmaleimide and the Ca2+-calmodulin-dependent protein kinaseII inhibitor KN-93. The enhancement by 0.5m ouabain of ventricular myocyte contractility and intracellular Ca2+ transients was suppressed by 2.0m TTX. We conclude that ouabain, even at low concentrations (0.5-8.0m), can increase I-NaL and reverse I-NCX, and these effects may contribute to the effect of the glycoside to increase Ca2+ transients and contractility. Both protein kinaseC and Ca2+-calmodulin-dependent protein kinaseII activities may mediate or modulate these processes.
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