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 language | English (US) |
|---|---|
| Journal | American Journal of Physiology - Heart and Circulatory Physiology |
| Volume | 277 |
| Issue number | 3 46-3 |
| State | Published - Sep 1999 |
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Keywords
- Cardioprotection
- Intracellular sodium
- Protein kinase C
ASJC Scopus subject areas
- Physiology
- Physiology (medical)
Cite this
Chelerythrine increases Na-K-ATPase activity and limits ischemic injury in isolated rat hearts. / Lundmark, Jennifer L.; Ramasamy, Ravichandran; Vulliet, Philip R; Schaefer, Saul.
In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 277, No. 3 46-3, 09.1999.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Chelerythrine increases Na-K-ATPase activity and limits ischemic injury in isolated rat hearts
AU - Lundmark, Jennifer L.
AU - Ramasamy, Ravichandran
AU - Vulliet, Philip R
AU - Schaefer, Saul
PY - 1999/9
Y1 - 1999/9
N2 - 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.
AB - 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.
KW - Cardioprotection
KW - Intracellular sodium
KW - Protein kinase C
UR - http://www.scopus.com/inward/record.url?scp=0032885623&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032885623&partnerID=8YFLogxK
M3 - Article
C2 - 10484422
AN - SCOPUS:0032885623
VL - 277
JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology
JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology
SN - 1931-857X
IS - 3 46-3
ER -