Delayed cardioprotection by isoflurane: role of K_ATP channels

Abstract

Isoflurane mimics the cardioprotective effect of acute ischemic preconditioning with an acute memory phase. We determined whether isoflurane can induce delayed cardioprotection, the involvement of ATP-sensitive potassium (KATP) channels, and cellular location of the channels. Neonatal New Zealand White rabbits at 7-10 days of age (n ϭ 5-16/group) were exposed to 1% isoflurane-100% oxygen for 2 h. Hearts exposed 2 h to 100% oxygen served as untreated controls. Twenty-four hours later resistance to myocardial ischemia was determined using an isolated perfused heart model. Isoflurane significantly reduced infarct size/area at risk (means Ϯ SD) by 50% (10 Ϯ 5%) versus untreated controls (20 Ϯ 6%). Isoflurane increased recovery of preischemic left ventricular developed pressure by 28% (69 Ϯ 4%) versus untreated controls (54 Ϯ 6%). The mitochondrial KATP channel blocker 5-hydroxydecanoate (5-HD) completely (55 Ϯ 3%) and the sarcolemmal KATP channel blocker HMR 1098 partially (62 Ϯ 3%) attenuated the cardioprotective effects of isoflurane. The combination of 5-HD and HMR-1098 completely abolished the cardioprotective effect of isoflurane (56 Ϯ 5%). We conclude that both mitochondrial and sarcolemmal KATP channels contribute to isoflurane-induced delayed cardioprotection. ischemia; heart; infarct size; volatile anesthetics; myocardial preconditioning BRIEF PERIODS OF ISCHEMIA lead to a reduced severity of cardiac injury following a second sustained period of ischemia. This cardioprotective effect has been termed ischemic preconditioning and has been demonstrated in all species studied. Certain pharmacological agents can mimic the cardioprotective effect of ischemic preconditioning. Recent clinical and experimental data indicate that volatile anesthetics also exert acute protective effects on the myocardium.The protective effects of volatile anesthetics on ischemic myocardium have been termed anesthetic-induced preconditioning because of its remarkable similarity to ischemic preconditioning. Isoflurane improves functional recovery of stunned myocardium in chronically or acutely instrumented dogs after brief periods of coronary artery occlusion and reperfusion (25,26,44). Low doses of the ATP-sensitive K (K ATP ) channel blocker glibenclamide completely abolished the cardioprotective effects of isoflurane (25). These results indicate that K ATP channels are activated by isoflurane and mediate the beneficial effects of isoflurane in stunned myocardium in animal models that respond to acute ischemic preconditioning in a similar fashion to the human heart (5, 45).K ATP channel openers mimic early ischemic preconditioning, whereas K ATP channel blockers prevent ischemic preconditioning. These effects were initially attributed to opening and closing of sarcolemmal K ATP channels, respectively. New evidence suggests, however, that mitochondrial K ATP channels might very well have even a greater influence on preconditioning (35, 37). For instance, diazoxide, an opener of mitochondrial K ATP channels, was demonstrated to exert ca...

General Anesthesia Delays the Inflammatory Response and Increases Survival for Mice with Endotoxic Shock

“…In fact, several reports have indicated that anesthetics offer cardioprotection (44) and neuroprotection (25,48) to subsequent ischemic events through a concept known as "anesthesia preconditioning" (15). The mechanism of this protective role of anesthetics has been attributed to adenosine A1 receptor activation and the opening of mitochondrial ATP-regulated potassium channels (39,44). These channels may have an antiapoptotic effect by inhibiting cytochrome c release and preventing the loss of mitochondrial membrane potential (2).…”

Volatile Anesthetic Preconditioning Attenuates Myocardial Apoptosis in Rabbits after Regional Ischemia and Reperfusion via Akt Signaling and Modulation of Bcl-2 Family Proteins

“…The number of apoptotic cells in the perinecrotic myocardium progressively increases during the extended period of reperfusion, which suggests the role of apoptosis in the development of infarction (Zhao et al, 2001b). Considering the reported delayed preconditioning effects of isoflurane (Tonkovic-Capin et al, 2002;Tanaka et al, 2004b), it would not be surprising if isoflurane also inhibits the extent of apoptosis in models of delayed preconditioning. This is an interesting question, which warrants future investigation.…”

Remote Limb Ischemic Preconditioning: A Neuroprotective Technique in Rodents

“…Isoflurane can participate in myocardium protection via opening of ATP-sensitive potassium channels, a similar protective mechanism reported in ischemic conditioning 37 . Although the size of the infarct in stroke models remains large in sham-treated animals given isoflurane, the molecular mechanism underlying remote ischemic conditioning may be masked by the effects of anesthetics.…”