Cardioprotection from ischemia-reperfusion injury due to Ras-GTPase inhibition is attenuated by glibenclamide in the globally ischemic heart.
The present study was designed to see if acute local inhibition of Ras-GTPase before or after ischemia (during perfusion) would produce protection against ischemia and reperfusion (I/R)-induced cardiac dysfunction. The effect of glibenclamide, an inhibitor of cardiac mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels, on Ras-GTPase-mediated cardioprotection was also studied. A 40 min episode of global ischemia followed by a 30 min reperfusion in perfused rat hearts produced significantly impaired cardiac function, measured as left ventricular developed pressure (P(max)) and left ventricular end-diastolic pressure (LVEDP). Perfusion with Ras-GTPase inhibitor FPT III before I/R [FPT(pre)], significantly enhanced cardiac recovery in terms of left ventricular contractility. P(max) was significantly higher at the end of 30 min reperfusion in FPT(pre)-treated hearts compared to pre-conditioned hearts. However, the degree of improvement in left ventricular contractility was significantly less when FPT III was given only after ischemia during reperfusion [FPT(post)]. Combination treatment with FPT III and glibenclamide before I/R resulted in significant reduction of FPT III-mediated cardioprotection. These data suggest that activation of Ras-GTPase signaling pathways during ischemia are critical in the development of left ventricular dysfunction and that opening of mitoK(ATP) channels, at least in part, contributes to cardioprotection produced by Ras-GTPase inhibition.
Al-Rashdan
Ibrahim
I
Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait.
Canatan
Halit
H
Al-Maghrebi
May
M
Yousif
Mariam H M
MH
Khan
Shah A
SA
Benter
Ibrahim F
IF
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology*; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D063065:Organophosphonates / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016277:Ventricular Function, Left / Q000187:drug effects; D018631:ras Proteins / Q000037:antagonists & inhibitors*
C436083:2-(2-oxo-2-((3,7,11-trimethyl-2,6,10-dodecatrienyl)oxy)aminoethyl)phosphonic acid, (2,2-dimethyl-1-oxopropoxy)methyl ester sodium; D002316:Cardiotonic Agents; D063065:Organophosphonates; D018631:ras Proteins; D005905:Glyburide