Chelerythrine increases Na-K-ATPase activity and limits ischemic injury in isolated rat hearts

Jennifer L. Lundmark, Ravichandran Ramasamy, Philip R Vulliet, Saul Schaefer

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Myocardial ischemia results in an increase in intracellular sodium concentration ([Na](i)), which may lead to cellular injury via cellular swelling and calcium overload. Because protein kinase C (PKC) has been shown to reduce Na-K-ATPase activity, we postulated that pharmacological inhibition of PKC would directly increase Na-K-ATPase activity, reduce [Na](i) during ischemia, and provide protection from ischemic injury. Isolated rat hearts were subjected to 30 min of global ischemia with and without the specific PKC inhibitor chelerythrine. Intracellular pH, ATP, and [Na](i) were assessed using 31P and 23Na NMR spectroscopy, whereas Na-K-ATPase and PKC activity were determined using biochemical assays. Na/H exchanger activity was determined using the ammonium prepulse technique under nonischemic conditions. Chelerythrine increased Na-K-ATPase activity (13.76 ± 0.89 vs. 10.89 ± 0.80 mg ADP · h-1 · mg protein-1; P = 0.01), reduced PKC activity in both the membrane and cytosolic fractions (39% and 28% of control, respectively), and reduced creatine kinase release on reperfusion (48 ± 5 IU/g dry wt vs. 689 ± 63 IU/g dry wt; P = 0.008). The rise in [Na](i) during ischemia was significantly reduced in hearts treated with chelerythrine (peak [Na](i) chelerythrine: 21.5 ± 1.2 mM; control: 31.9 ± 1.2 mM; P < 0.0001), without an effect on either acidosis (nadir pH 6.16 ± 0.05 for chelerythrine vs. 6.08 ± 0.04 for control), the rate of ATP depletion or Na/H exchanger activity. These data support the hypothesis that pharmacological inhibition of PKC before ischemia induces cardioprotection by reducing intracellular sodium overload via an increase in Na-K-ATPase activity.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume277
Issue number3 46-3
StatePublished - Sep 1999

Keywords

  • Cardioprotection
  • Intracellular sodium
  • Protein kinase C

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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