Does Ischemic Preconditioning in the Human Involve Protein Kinase C and the ATP-Dependent K + Channel?

Abstract

Abstract Protein kinase C (PKC) and the ATP-dependent K + channel (K ATP channel) have been implicated in the mechanism of ischemic preconditioning in animal models. This study investigated the role of K ATP channels and PKC in preconditioning in human myocardium and whether K ATP channels are activated via a PKC-dependent pathway. Right atrial trabeculae were superfused with Tyrode’s solution and paced at 1 Hz. After stabilization, muscles underwent one of nine different protocols, followed by simulated ischemia (SI) consisting of 90 minutes of hypoxic substrate-free superfusion paced at 3 Hz and then by 120 minutes of reperfusion. Preconditioning consisted of 3 minutes of SI and 7 minutes of reperfusion. The experimental end point was recovery of contractile function after SI, presented here as percentage recovery (%Rec) of baseline function. %Rec was significantly improved by preconditioning by the K ATP channel opener cromakalim (CK), and by the PKC activator 1,2-dioctanoyl- sn -glycerol (DOG) compared with nonpreconditioned controls when these treatments were given before the SI insult (control group, 29.5±3.6%; preconditioned group, 63.5±5.4%, CK-treated group, 52.9±3.1%; and DOG-treated group, 48.0±3.5%; P <.01). The effects of CK could be blocked by the K ATP channel blocker glibenclamide (%Rec, 17.8±3.5%). Preconditioning could be blocked by the PKC antagonist chelerythrine (%Rec, 24.1±5.0%) and the K ATP blocker glibenclamide (%Rec, 24.8±3.1%). The effects of DOG could also be blocked by glibenclamide (%Rec, 23.1±2.3%). These findings show that protection against contractile dysfunction after SI can be induced by activation of PKC and by the opening of the K ATP channel and that the protection induced by PKC activation and preconditioning can be blocked by blocking the K ATP channel. This suggests that the mechanism of preconditioning in humans may act via PKC and rely on the action of the K ATP channel as the end effector.