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

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.

• Authors: J L Lundmark, R Ramasamy, P R Vulliet, S Schaefer
• Journal: The American journal of physiology (Am J Physiol) Vol. 277 Issue 3 Pg. H999-H1006 (09 1999) ISSN: 0002-9513 [Print] United States
• PMID: 10484422 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Alkaloids
• Benzophenanthridines
• Enzyme Inhibitors
• Phenanthridines
• chelerythrine
• Protein Kinase C
• Sodium-Potassium-Exchanging ATPase

Topics

• Alkaloids
• Animals
• Benzophenanthridines
• Enzyme Activation
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Male
• Myocardial Ischemia (drug therapy, enzymology, physiopathology)
• Phenanthridines (pharmacology, therapeutic use)
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Rats
• Rats, Sprague-Dawley
• Sodium-Potassium-Exchanging ATPase (metabolism)