Key result
Fasudil blocks pinacidil-induced cardioprotection, cutting postischemic LVDP recovery by ~50%.
Why the study?
The final effector mechanism for ATP-dependent potassium channel-induced cardioprotection remains elusive, and it was unknown whether activity of the RhoA effector rho kinase is required.
Does Rho kinase inhibition with fasudil prevent KATP channel-induced improvement in postischemic myocardial recovery in perfused rat hearts?
Does Rho kinase inhibition with fasudil prevent KATP channel-induced improvement in postischemic myocardial recovery in perfused rat hearts?
Answers are grounded in this paper and cite their sources.
Demonstrates in an ex vivo rat heart model that Rho kinase (ROCK) activity is required as a downstream effector for KATP channel-mediated cardioprotection against ischemia-reperfusion injury.
Whereas activation of ATP-dependent potassium (K(ATP)) channels greatly improves postischemic myocardial recovery, the final effector mechanism for K(ATP) channel-induced cardioprotection remains elusive. RhoA is a GTPase that regulates a variety of cellular processes known to be involved with K(ATP) channel cardioprotection. Our goal was to determine whether the activity of a key rhoA effector, rho kinase (ROCK), is required for K(ATP) 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 (31)P NMR high-energy phosphate data: 1) untreated, 2) pinacidil (10 microM) to activate K(ATP) channels, 3) fasudil (15 microM) to inhibit ROCK, and 4) both fasudil and pinacidil. Pinacidil significantly improved postischemic mechanical recovery [39 +/- 16 vs. 108 +/- 4 mmHg left ventricular diastolic pressure (LVDP), untreated and pinacidil, respectively]. Fasudil did not affect reperfusion LVDP (41 +/- 13 mmHg) but completely blocked the marked improvement in mechanical recovery that occurred with pinacidil treatment (54 +/- 15 mmHg). Substantial attenuation of the postischemic energetic recovery was also observed. These data support the hypothesis that ROCK activity plays a role in K(ATP) channel-induced cardioprotection.
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Nishizawa et al. (2005) studied Myocardial ischemia-reperfusion injury. Fasudil + Pinacidil vs. Pinacidil (10 microM) alone, Fasudil (15 microM) alone, or untreated was evaluated on Postischemic mechanical recovery measured by left ventricular diastolic pressure (LVDP) in mmHg. Fasudil (15 microM) completely blocked pinacidil-induced improvement in postischemic LVDP recovery in perfused rat hearts (54 ± 15 vs. 108 ± 4 mmHg).
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