Submitted on June 21, 2004
Accepted on January 27, 2005
Fasudil prevents KATP channel-induced improvement in post-ischemic functional recovery
Kenya Nishizawa1, Paul E Wolkowicz2*, Tadashi Yamagishi1, Ling Ling Guo2, and Martin M Pike2
1 Medicine, National Defense Medical College, Saitama, Japan
2 Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
* To whom correspondence should be addressed. E-mail: wolk{at}uab.edu.
While the activation of ATP-dependent potassium (KATP) channels greatly improves postischemic myocardial recovery, the final effector mechanism for KATP channel-induced cardioprotection remains elusive. RhoA is a GTPase that regulates a variety of cellular processes which are known to be involved with KATP channel cardioprotection. Our goal was to determine if the activity of a key rhoA effector, rho kinase (ROCK), is required for KATP channel-induced cardioprotection. Four groups of perfused rat hearts were subjected to 36 min of zero-flow ischemia and 44 min of reperfusion with continuous measurements of mechanical function and 31P-NMR high-energy phosphate data: (i) untreated, (ii) pinacidil (10µM) to activate KATP channels, (iii) fasudil (15µM) to inhibit ROCK, and (iv) both pinacidil and fasudil. Pinacidil significantly improved postischemic mechanical recovery (39±16 vs 108±4mm Hg LVDP, untreated and pinacidil, respectively). Fasudil did not affect reperfusion LVDP (41±13mm Hg), but completely blocked the marked improvement in mechanical recovery that occurred with pinacidil treatment (54±15mm Hg). Substantial attenuation of the postischemic energetic recovery was also observed. These data support the hypothesis that ROCK activity plays a role in KATP channel-induced cardioprotection.
