Glutamate protects against Ca(2+) paradox-induced injury and inhibits calpain activity in isolated rat hearts.
This study determined the effects of glutamate on the Ca(2+) paradoxical heart, which is a model for Ca(2+) overload-induced injury during myocardial ischaemia and reperfusion, and evaluated its effect on a known mediator of injury, calpain. An isolated rat heart was retrogradely perfused in a Langendorff apparatus. Ca(2+) paradox was elicited via perfusion with a Ca(2+) -free Krebs-Henseleit (KH) solution for 3 minutes followed by Ca(2+) -containing normal KH solution for 30 minutes. The Ca(2+) paradoxical heart exhibited almost no viable tissue on triphenyltetrazolium chloride staining and markedly increased LDH release, caspase-3 activity, cytosolic cytochrome c content, and apoptotic index. These hearts also displayed significantly increased LVEDP and a disappearance of LVDP. Glutamate (5 and 20 mmol/L) significantly alleviated Ca(2+) paradox-induced injury. In contrast, 20 mmol/L mannitol had no effect on Ca(2+) paradox. Ca(2+) paradox significantly increased the extent of the translocation of μ-calpain to the sarcolemmal membrane and the proteolysis of α-fodrin, which suggests calpain activation. Glutamate also blocked these effects. A non-selective inhibitor of glutamate transporters, dl-TBOA (10 μmol/L), had no effect on control hearts, but it reversed glutamate-induced cardioprotection and reduction in calpain activity. Glutamate treatment significantly increased intracellular glutamate content in the Ca(2+) paradoxical heart, which was also blocked by dl-TBOA. We conclude that glutamate protects the heart against Ca(2+) overload-induced injury via glutamate transporters, and the inhibition of calpain activity is involved in this process.
Department of Physiology, The Fourth Military Medical University, Xi'an, China.
Jian-Ying
JY
Zhang
Department of Physiology, The Fourth Military Medical University, Xi'an, China.|Institute of Basic Medical Science, Xi'an Medical College, Xi'an, China.
Ling-Heng
LH
Kong
Department of Physiology, The Fourth Military Medical University, Xi'an, China.
Dong
D
Lai
Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
Zhen-Xiao
ZX
Jin
Department of Physiology, The Fourth Military Medical University, Xi'an, China.
Xiao-Ming
XM
Gu
Department of Physiology, The Fourth Military Medical University, Xi'an, China.
Jing-Jun
JJ
Zhou
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000633:toxicity*; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018698:Glutamic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D006321:Heart / Q000187:drug effects / Q000502:physiology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
D002316:Cardiotonic Agents; D018698:Glutamic Acid; D002154:Calpain; D002118:Calcium
calcium; calpain; cardioprotection; glutamate; heart