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

Abstract

Protein kinase C (PKC) and the ATP-dependent K+ channel (KATP channel) have been implicated in the mechanism of ischemic preconditioning in animal models. This study investigated the role of KATP channels and PKC in preconditioning in human myocardium and whether KATP 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 KATP 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 KATP channel blocker glibenclamide (%Rec, 17.8 +/- 3.5%). Preconditioning could be blocked by the PKC antagonist chelerythrine (%Rec, 24.1 +/- 5.0%) and the KATP blocker glibenclamide (%Rec, 24.8 +/- 3.1%). The effects of DOG could also be blocked by glibenclamide (%Rec, 23.1 +/- 2.3%).(ABSTRACT TRUNCATED AT 250 WORDS)

Activation of ɛ protein kinase C correlates with a cardioprotective effect of regular ethanol consumption

“…Chelerythrine decreased baseline LV developed pressure (LVDP) by 14% and increased coronary flow by 7% in both ethanol and control hearts ( Table 1). Similar changes in hemodynamics have been reported in previous studies with PKC inhibitors (28,31,32).…”

“…For example, treatment with chelerythrine did produce a small decrease of LVDP prior to ischemia. Similar changes in hemodynamics have been reported in prior ischemia-reperfusion studies with several PKC inhibitors (28,31,32) and are thought to be due to blocking PKC potentiation of adrenergic ␣1-associated slow Ca 2ϩ channels (57). A recent report in aortic rings suggests that chelerythrine can also affect cyclic nucleotide phosphodiesterases with an IC 50 ranging from 18 to 206 M (58) (we used 10 M).…”

“…After binding to their selective RACKs, activated PKC isozymes phosphorylate protein substrates which may ultimately mediate the cardioprotection against ischemiareperfusion injury (50). Potential mediators of ischemic preconditioning's first window of protection (up to 3 hr) include PKC activation of ATP-sensitive potassium channels causing reduced calcium influx (31,(51)(52)(53) and activation of vacuolar proton ATPase reducing intracellular acidification (54). Potential mediators of ischemic preconditioning's second window of protection (24-72 hr) include transcription factors activated via a PKC-mediated pathway which regulate expression of heat shock/stress proteins (55,56).…”

“…This concentration of chelerythrine, a potent and specific inhibitor of PKC (30), was used as described previously (28,31,32). Chelerythrine decreased baseline LV developed pressure (LVDP) by 14% and increased coronary flow by 7% in both ethanol and control hearts ( Table 1).…”

Medical and Cellular Implications of Stunning, Hibernation, and Preconditioning

“…237 Furthermore, the signaling pathways in human cardiac muscle appear to involve PKC, with supporting evidence for the role of the K ATP channel as a positive end effector. 238 Repeated coronary artery occlusions in the course of PTCA may simulate the preconditioning phenomenon. Several clinical studies have observed progressive decreases in chest pain, ST-segment elevation, and lactate production on subsequent compared with first 60-to 90-second intracoronary balloon inflation.…”