Does ischemic preconditioning in the human involve protein kinase C and the ATP-dependent K+ channel? Studies of contractile function after simulated ischemia in an atrial in vitro model.
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)
Speechly-Dick
M E
ME
Hatter Institute, Department of Academic and Clinical Cardiology, University College London Hospitals, UK.
Grover
G J
GJ
Yellon
D M
DM
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000470:Alkaloids; D053119:Benzophenanthridines; D001578:Benzopyrans / Q000494:pharmacology; D019806:Cromakalim; D004075:Diglycerides / Q000494:pharmacology; D005260:Female; D006325:Heart Atria / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D010617:Phenanthridines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology; D011897:Random Allocation; D013997:Time Factors
D000470:Alkaloids; D053119:Benzophenanthridines; D001578:Benzopyrans; D004075:Diglycerides; D010617:Phenanthridines; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; C044295:1,2-dioctanoylglycerol; D000255:Adenosine Triphosphate; C016299:chelerythrine; D011493:Protein Kinase C