|Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1998: ¥300,000 (Direct Cost: ¥300,000)
Fiscal Year 1997: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1996: ¥1,200,000 (Direct Cost: ¥1,200,000)
The present study initially planed to examine whether induction of heat stress proteins, HSP70's, afford cardioprotection and whether the HSP-induced protection, if any, is mediated by ATP-sensitive K channels (KATP channels). Both heat stress and a transient ischemia induced expression of HSP70 and slight attenuated myocardial stunning. However, anti-infarct tolerance was not enhanced by HSP70 expression. Furthermore, there was a dissociation between the expression of HSP70 and the cardioprotection against myocardial stunning. Thus, we then assessed the role of KATP channels in cardioprotection by pre-ischemic activation of adenosine A1 and bradykinin B2 receptor activation. Infarct size limitation by A1 and B2 receptor activation was abolished by protein kinase C inhibitors and by a selective blocker of mitochondrial KATP channels, 5-hydroxydecanoate. In contrast, a selective blocker of sarcolemmal KATP channels, HMRl4098, did not affect cardioprotection by pre-ischemic stimulation of A1 and that by B2 receptors. Since protein kinase C activation facilitates opening of KATP channels, the present findings indicate that the mitochondrial KATP channel is an important effector downstream of protein kinase C in the A1 receptor-mediated and B2 receptor-mediated pathways of cardioprotection. The role of the mitochondrial KATP channel was also examined in another type of cardioprotection, inhibition of NaィイD1+ィエD1-HィイD1+ィエD1 exchanger type 1 (NHE1). Inhibition of this exchanger does not directly activate KATP channels in isolated cardiomyocytes. However, 5-hydroxydecanoate abolished anti-infarct and anti-stunning effects of NHE1 inhibitors (i.e., cariporide and ethyl-isopropyl amiloride), indicating requirement of mitochondrial KATP channel activity for protection by NHE1 inhibition. Taken together, the mitochondrial KATP channel may be an important effector downstream of various cardioprotective signals in the cardiomyocyte.