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Am J Physiol Heart Circ Physiol (February 4, 2005). doi:10.1152/ajpheart.01183.2004
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Submitted on November 29, 2004
Accepted on January 31, 2005

Temporary Blockade of Contractility during Reperfusion Elicits a Cardioprotective Effect of the p38 MAP Kinase Inhibitor SB203580

Tomohiko Sumida1, Hajime Otani1*, Shiori Kyoi1, Takayuki Okada1, Hiroyoshi Fujiwara1, Yoshihisa Nakao1, Masakuni Kido1, and Hiroji Imamura1

1 Cardiovascular Research Center, Kansai Medical University, Moriguchi, Japan

* To whom correspondence should be addressed. E-mail: otanih{at}takii.kmu.ac.jp.

p38 MAP kinase activation is known to be deleterious not only to mitochondria but also to contractile function. Therefore, p38 MAP kinase inhibition therapy represents a promising approach in preventing reperfusion injury in the heart. However, reversal of p38 MAP kinase-mediated contractile dysfunction may disrupt fragile sarcolemma of the ischemic/reperfused myocytes. We, therefore, hypothesized that the beneficial effect of p38 MAP kinase inhibition during reperfusion can be enhanced when contractility is simultaneously blocked. Isolated and perfused rat hearts were paced at 330 rpm and were subjected to 20 minutes ischemia followed by reperfusion. p38 MAP kinase was activated after ischemia and early during reperfusion (<30 minutes). Treatment with the p38 MAP kinase inhibitor SB203580 (10 µM) for 30 minutes during reperfusion but not the c-Jun NH2-terminal kinase inhibitor SP600125 (10 µM) improved contractility but increased creatine kinase (CK) release and infarct size. However, co-treatment with SB203580 and the contractile blocker, 2,3-butanedione monoxime (BDM; 20 mM), or the ultra-short acting {beta}-blocker, esmorol (0.15 mM), for the first 30 minutes during reperfusion significantly reduced CK release and infarct size. In vitro mitochondrial ATP generation and myocardial content of ATP were significantly increased in the heart co-treated with SB203580 and BDM during reperfusion. Dystrophin was translocated from the sarcolemma during ischemia and reperfusion. SB203580 increased the accumulation of Evans blue in myocytes depleted of sarcolemmal dystrophin during reperfusion, whereas co-treatment with BDM facilitated the restoration of sarcolemmal dystrophin and mitigated sarcolemmal damage after the withdrawal of BDM. These results suggest that treatment with SB203580 during reperfusion aggravates myocyte necrosis but concomitant blockade of contractile force unmasks cardioprotective effects afforded by SB203580.




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