Effect of hypernatremia on injury caused by energy deficiency: role of T-type Ca2+ channel.
Hypernatremia exerts multiple cellular effects, many of which could influence the outcome of an ischemic event. To further evaluate these effects of hypernatremia, isolated neonatal cardiomyocytes were chronically incubated with medium containing either normal (142 mM) or elevated sodium (167 mM) and then transferred to medium containing deoxyglucose and the electron transport chain inhibitor amobarbital. Chronic hypernatremia diminished the degree of calcium accumulation and reactive oxygen species generation during the period of metabolic inhibition. The improvement in calcium homeostasis was traced in part to the downregulation of the Ca(V)3.1 T-type calcium channel, as deficiency in the Ca(V)3.1 subtype using short hairpin RNA or treatment with an inhibitor of the Ca(V)3.1 variant of the T-type calcium channel (i.e., diphenylhydantoin) attenuated energy deficiency-mediated calcium accumulation and cell death. Although hyperosmotically stressed cells (exposed to 50 mM mannitol) had no effect on T-type calcium channel activity, they were also resistant to death during metabolic inhibition. Both hyperosmotic stress and hypernatremia activated Akt, suggesting that they initiate the phosphatidylinositol 3-kinase/Akt cytoprotective pathway, which protects the cell against calcium overload and oxidative stress. Thus hypernatremia appears to protect the cell against metabolic inhibition by promoting the downregulation of the T-type calcium channel and stimulating cytoprotective protein kinase pathways.
Pastukh
Viktor
V
Department of Pharmacology, University of South Alabama College of Medicine, Mobile, Alabama, USA.
Chen
Hairu
H
Wu
Songwei
S
Jong
Chian Ju
CJ
Alexeyev
Mikhail
M
Schaffer
Stephen W
SW
D000818:Animals; D000831:Animals, Newborn; D020747:Calcium Channels, T-Type / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology; D004579:Electron Transport / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology*; D006955:Hypernatremia / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
C500994:Cacna1g protein, rat; D020747:Calcium Channels, T-Type