Fasudil prevents KATP channel-induced improvement in postischemic functional recovery.
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.
Nishizawa
Kenya
K
Dept. of Medicine, Univ. of Alabama at Birmingham, Birmingham, AL 35294, USA.
Wolkowicz
Paul E
PE
Yamagishi
Tadashi
T
Guo
Ling-Ling
LL
Pike
Martin M
MM
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D006321:Heart / Q000502:physiology* / Q000503:physiopathology; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology* / Q000517:prevention & control; D020110:Pinacidil / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D014665:Vasodilator Agents; D020110:Pinacidil; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C049347:fasudil