© 1995 American Heart Association, Inc.
Articles |
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
From the Hatter Institute (M.E.S.-D., D.M.Y.), Department of Academic and Clinical Cardiology, University College London (UK) Hospitals, and Bristol-Myers Squibb Pharmaceuticals Research Institute (G.J.G.), Princeton, NJ.
Correspondence to Prof D.M. Yellon, The Hatter Institute, Department of Academic and Clinical Cardiology, University College London Hospitals, Grafton Way, London WC1E 6DB, UK.
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%). These findings show that protection against contractile dysfunction after SI can be induced by activation of PKC and by the opening of the KATP channel and that the protection induced by PKC activation and preconditioning can be blocked by blocking the KATP channel. This suggests that the mechanism of preconditioning in humans may act via PKC and rely on the action of the KATP channel as the end effector.
Key Words: protein kinase C • ATP-dependent K+ channel • ischemic preconditioning • human atrium • contractile function
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I. Tritto, D. D'Andrea, N. Eramo, A. Scognamiglio, C. De Simone, A. Violante, A. Esposito, M. Chiariello, and G. Ambrosio Oxygen Radicals Can Induce Preconditioning in Rabbit Hearts Circ. Res., May 19, 1997; 80(5): 743 - 748. [Abstract] [Full Text]
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L. P. Perrault, P. Menasche, A. Bel, T. de Chaumaray, J. Peynet, A. Mondry, P. Olivero, R. Emanoil-Ravier, and J.-M. Moalic ISCHEMIC PRECONDITIONING IN CARDIAC SURGERY: A WORD OF CAUTION J. Thorac. Cardiovasc. Surg., November 1, 1996; 112(5): 1378 - 1386. [Abstract] [Full Text]
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R. L. Engler and D. M. Yellon Sulfonylurea KATP Blockade in Type II Diabetes and Preconditioning in Cardiovascular Disease: Time for Reconsideration Circulation, November 1, 1996; 94(9): 2297 - 2301. [Full Text]
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M. V. Cohen, Y. Liu, G. S. Liu, P. Wang, C. Weinbrenner, G. A. Cordis, D. K. Das, and J. M. Downey Phospholipase D Plays a Role in Ischemic Preconditioning in Rabbit Heart Circulation, October 1, 1996; 94(7): 1713 - 1718. [Abstract] [Full Text]
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P. E. Light, A. A. Sabir, B. G. Allen, M. P. Walsh, and R. J. French Protein Kinase C–Induced Changes in the Stoichiometry of ATP Binding Activate Cardiac ATP-Sensitive K+ Channels: A Possible Mechanistic Link to Ischemic Preconditioning Circ. Res., September 1, 1996; 79(3): 399 - 406. [Abstract] [Full Text]
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C. Vahlhaus, R. Schulz, H. Post, R. Onallah, and G. Heusch No Prevention of Ischemic Preconditioning by the Protein Kinase C Inhibitor Staurosporine in Swine Circ. Res., September 1, 1996; 79(3): 407 - 414. [Abstract] [Full Text]
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G. Brooks and D. J. Hearse Role of Protein Kinase C in Ischemic Preconditioning: Player or Spectator? Circ. Res., September 1, 1996; 79(3): 628 - 631. [Full Text]
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P. Menasche, C. Mouas, and C. Grousset Is Potassium Channel Opening an Effective Form of Preconditioning Before Cardioplegia? Ann. Thorac. Surg., June 1, 1996; 61(6): 1764 - 1768. [Abstract] [Full Text]
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