Calpain is activated by beta-adrenergic receptor stimulation under hypoxic myocardial cell injury.
This study was undertaken to investigate the correlation between hypoxic cell injury and protease activity, as well as the effects of alpha 1-, and beta-adrenergic blocking agents and calcium antagonists during hypoxia. Cell death during hypoxia rose to 80% after 6h. Calpain activity increased to 4 units during hypoxia, much higher than the 0.7 units seen in aerobic condition at 6h. This activity was markedly inhibited by calpain-specific inhibitor I (n-acetyl-leucyle-leucyle-norleucinal). alpha 1-adrenergic blocking agents did not affect calpain activity and cell death under hypoxia. On the other hand, beta-adrenergic blocking agents and calcium antagonists suppressed the calpain activity and decreased cell death during hypoxia. These beta-adrenergic blocking agents and calcium antagonists also inhibited intracellular calcium-influx during hypoxia. These results suggest the beta-adrenergic receptor stimulation activates adenylate cyclase activity and enhances calcium-influx during hypoxia. The elevated intracellular calcium concentration then stimulates calpain activity under hypoxia. These results prove that beta-adrenergic blocking agents and calcium antagonists prevent protein degradation during hypoxic cell injury.
Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
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Iizuka
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Kawaguchi
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Yasuda
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D016009:Chi-Square Distribution; D004789:Enzyme Activation; D006023:Glycoproteins / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D006023:Glycoproteins; D011943:Receptors, Adrenergic, beta; C039304:calpain inhibitors; D002154:Calpain; D002118:Calcium