Abstract
Ischemic preconditioning is a phenomenon in which exposure of the heart to a brief period of ischemia causes it to quickly adapt itself to become resistant to infarction from a subsequent ischemic insult. The mechanism is not fully understood but, at least in the rabbit, it is known to be triggered by occupation of adenosine receptors, opioid receptors, bradykinin receptors and the generation of free radicals during the preconditioning ischemia. All of these are thought to converge on and activate protein kinase C (PKC), which in turn activates a tyrosine kinase. This kinase cascade eventually terminates on some unknown effector, possibly a potassium channel or a cytoskeletal protein, which makes the cells resistant to infarction. If this process can be understood, it should be possible to devise a method for conferring this protection to patients with acute myocardial infarction.
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References
Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124–1136.
Maroko PR, Kjekshus JK, Sobel BE, Watanabe T, Covell JW, Ross J Jr, Braunwald E. Factors influencing infarct size following experimental coronary artery occlusions. Circulation 1971;43:67–82.
Hearse DJ, Yellon DM, Downey JM. Can beta blockers limit myocardial infarct size? Eur Heart J 1986;7:925–930.
Reimer KA, Murry CE, Richard VJ. The role of neutrophils and free radicals in the ischemic-reperfused heart: why the confusion and controversy? J Mol Cell Cardiol 1989;21:1225–1239.
Kloner RA, Braunwald E. Effects of calcium antagonists on infarcting myocardium. Am J Cardiol 1987;59:84B–94B.
Turrens JF, Thornton J, Barnard ML, Snyder S, Liu G, Downey JM. Protection from reperfusion injury by preconditioning hearts does not involve increased antioxidant defenses. Am J Physiol 1992;262:H585–H589.
Murry CE, Richard VJ, Jennings RB, Reimer KA. Myocardial protection is lost before contractile function recovers from ischemic preconditioning. Am J Physiol 1991;260:H796–H804.
Thornton J, Striplin S, Liu GS, Swafford A, Stanley AWH, Van Winkle DM, Downey JM. Inhibition of protein synthesis does not block myocardial protection afforded by preconditioning. Am J Physiol 1990;259:H1822–H1825.
Schott RJ, Rohmann S, Braun ER, Schaper W. Ischemic preconditioning reduces infarct size in swine myocardium. Circ Res 1990;66:1133–1142.
Van Winkle DM, Chien GL, Wolff RA, Soifer BE, Kuzume K, Davis RF. Cardioprotection provided by adenosine receptor activation is abolished by blockade of the KATP channel. Am J Physiol 1994;266:H829–H839.
Van Winkle DM, Thornton JD, Downey DM, Downey JM. The natural history of preconditioning: cardioprotection depends on duration of transient ischemia and time to subsequent ischemia. Coron Artery Dis 1991;2:613–619.
Yellon DM, Alkhulaifi AM, Browne EE, Pugsley WB. Ischaemic preconditioning limits infarct size in the rat heart. Cardiovasc Res 1992;26:983–987.
Li Y, Kloner RA. The cardioprotective effects of ischemic “preconditioning” are not mediated by adenosine receptors in rat hearts. Circulation 1993;87:1642–1648.
Liu Y, Downey JM. Ischemic preconditioning protects against infarction in rat heart. Am J Physiol 1992;263:H1107–H1112.
Deutsch E, Berger M, Kussmaul WG, Hirshfeld JW Jr, Herrmann HC, Laskey WK. Adaptation to ischemia during percutaneous transluminal coronary angioplasty: clinical, hemodynamic, and metabolic features. Circulation 1990;82:2044–2051.
Walker DM, Walker JM, Pugsley WB, Pattison CW, Yellon DM. Preconditioning in isolated superfused human muscle. J Mol Cell Cardiol 1995;27:1349–1357.
Yellon DM, Alkhulaifi AM, Pugsley WB. Preconditioning the human myocardium. Lancet 1993;342:276–277.
Ikonomidis JS, Shirai T, Weisel RD, Derylo B, Rao V, Whiteside CI, Mickle DAG, Li R-K. “Ischemic” or adenosine preconditioning of human ventricular cardiomyocytes is protein kinase C dependent. Circulation 1995;92 (Suppl I):I-12. Abstract.
Li GC, Vasquez JA, Gallagher KP, Lucchesi BR. Myocardial protection with preconditioning. Circulation 1990;82:609–619.
Miura T, Adachi T, Ogawa T, Iwamoto T, Tsuchida A, Iimura O. Myocardial infarct size-limiting effect of ischemic preconditioning: its natural decay and the effect of repetitive preconditioning. Cardiovasc Pathol 1992;1:147–154.
Liu GS, Thornton J, Van Winkle DM, Stanley AWH, Olsson RA, Downey JM. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation 1991;84:350–356.
Tsuchida A, Miura T, Miki T, Shimamoto K, Iimura O. Role of adenosine receptor activation in myocardial infarct size limitation by ischaemic preconditioning. Cardiovasc Res 1992;26:456–461.
Schulz R, Rose J, Post H, Heusch G. Involvement of endogenous adenosine in ischaemic preconditioning in swine. Pflügers Arch 1995;430:273–282.
Schwarz ER, Mohri M, Sack S, Anas M. The role of adenosine and its A1-receptor in ischemic preconditioning. Circulation 1991;84(Suppl II):II-191. Abstract.
Auchampach JA, Gross GJ. Adenosine A1 receptors, KATP channels and ischemic preconditioning in dogs. Am J Physiol 1993;264:H1327–H1336.
Kerensky RA, Kutcher MA, Braden GA, Applegate RJ, Soils GA, Little WC. The effects of intracoronary adenosine on preconditioning during coronary angioplasty. Clin Cardiol 1995;18:91–96.
Kohl C, Linck B, Schmitz W, Scholz H, Scholz J, Tóth M. Effects of carbachol and (-)-N6-phenyl-isopropyladenosine on myocardial inositol phosphate content and force of contraction. Br J Pharmacol 1990;101:829–834.
Cohen MV, Liu Y, Liu GS, Wang P, Weinbrenner C, Cordis GA, Das DK, Downey JM. Phospholipase D plays a role in ischemic preconditioning in rabbit heart. Circulation 1996;94:1713–1718.
Ytrehus K, Liu Y, Downey JM. Preconditioning protects ischemic rabbit heart by protein kinase C activation. Am J Physiol 1994;266:H1145–H1152.
Liu Y, Cohen MV, Downey JM. Chelerythrine, a highly selective protein kinase C inhibitor, blocks the antiinfarct effect of ischemic preconditioning in rabbit hearts. Cardiovasc Drugs Ther 1994;8:881–882.
Goto M, Liu Y, Yang X-M, Ardell JL, Cohen MV, Downey JM. Role of bradykinin in protection of ischemic preconditioning in rabbit hearts. Circ Res 1995;77:611–621.
Tsuchida A, Liu Y, Liu GS, Cohen MV, Downey JM. α1-Adrenergic agonists precondition rabbit ischemic myocardium independent of adenosine by direct activation of protein kinase C. Circ Res 1994;75:576–585.
Wang P, Gallagher KP, Downey JM, Cohen MV. Pretreatment with endothelin-1 mimics ischemic preconditioning against infarction in isolated rabbit heart. J Mol Cell Cardiol 1996;28:579–588.
Liu Y, Tsuchida A, Cohen MV, Downey JM. Pretreatment with angiotensin II activates protein kinase C and limits myocardial infarction in isolated rabbit hearts. J Mol Cell Cardiol 1995;27:883–892.
Miki T, Sato H, Cohen MV, Downey JM. Opioid receptor contributes to ischemic preconditioning through protein kinase C activation in rabbits. Circulation 1996;94(Suppl I):I-392–I-393. Abstract.
Natarajan V, Taher MM, Roehm B, Parinandi NL, Schmid HHO, Kiss Z, Garcia JGN. Activation of endothelial cell phospholipase D by hydrogen peroxide and fatty acid hydroperoxide. J Biol Chem 1993;268:930–937.
Gopalakrishna R, Anderson WB. Ca2+-and phospholipid-independent activation of protein kinase C by selective oxidative modification of the regulatory domain. Proc Natl Acad Sci 1989;86:6758–6762.
Baines CP, Goto M, Downey JM. Oxygen radicals released during ischemic preconditioning contribute to cardioprotection in the rabbit myocardium. J Mol Cell Cardiol 1997;29:207–216.
Schultz JEJ, Rose E, Yao Z, Gross GJ. Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts. Am J Physiol 1995;268:H2157–H2161.
Cohen MV, Walsh RS, Goto M, Downey JM. Hypoxia preconditions rabbit myocardium via adenosine and catecholamine release. J Mol Cell Cardiol 1995;27:1527–1534.
Yang X-M, Sato H, Downey JM, Cohen MV. Protection of ischemic preconditioning is dependent upon a critical timing sequence of protein kinase C activation. J Mol Cell Cardiol 1997; in press.
Thornton JD, Thornton CS, Downey JM. Effect of adenosine receptor blockade: preventing protective preconditioning depends on time of initiation. Am J Physiol 1993;265:H504–H508.
Cohen MV, Downey JM. Ischaemic preconditioning: can the protection be bottled? Lancet 1993;342:6.
Liu Y, Ytrehus K, Downey JM. Evidence that translocation of protein kinase C is a key event during ischemic preconditioning of rabbit myocardium. J Mol Cell Cardiol 1994;26:661–668.
Armstrong SC, Hoover DB, DeLacey MH, Ganote CE. Translocation of PKC, protein phosphatase inhibition and preconditioning of rabbit cardiomyocytes. J Mol Cell Cardiol 1996;28:1479–1492.
Brooks G, Hearse DJ. Role of protein kinase C in ischemic preconditioning: player or spectator? Circ Res 1996;79:627–630.
Van Wylen DGL. Effect of ischemic preconditioning on interstitial purine metabolite and lactate accumulation during myocardial ischemia. Circulation 1994;89:2283–2289.
Goto M, Cohen MV, Van Wylen DGL, Downey JM. Attenuated purine production during subsequent ischemia in preconditioned rabbit myocardium is unrelated to the mechanism of protection. J Mol Cell Cardiol 1996;28:447–454.
Gross GJ, Auchampach JA. Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circ Res 1992;70:223–233.
Auchampach JA, Gross GJ. Adenosine A1 receptors, KATP channels, and ischemic preconditioning in dogs. Am J Physiol 1993;264:H1327–H1336.
Grover GJ, Dzwonczyk S, Sleph PG. ATP-sensitive K+ channel activation does not mediate preconditioning in isolated rat hearts. Circulation 1992;86(Suppl I):I-341. Abstract.
Schultz JEJ, Hsu AK, Gross GJ. Morphine mimics the cardioprotective effect of ischemic preconditioning via a glibenclamide-sensitive mechanism in the rat heart. Circ Res 1996;78:1100–1104.
Thornton JD, Thornton CS, Sterling DL, Downey JM. Blockade of ATP-sensitive potassium channels increases infarct size but does not prevent preconditioning in rabbit hearts. Circ Res 1993;72:44–49.
Walsh RS, Tsuchida A, Daly JJF, Thornton JD, Cohen MV, Downey JM. Ketamine-xylazine anaesthesia permits a KATP channel antagonist to attenuate preconditioning in rabbit myocardium. Cardiovasc Res 1994;28:1337–1341.
Armstrong S, Ganote CE. Preconditioning of isolated rabbit cardiomyocytes: effects of glycolytic blockade, phorbol esters, and ischaemia. Cardiovasc Res 1994;28:1700–1706.
Murry CE, Richard VJ, Reimer KA, Jennings RB. Ischemic preconditioning slows energy metabolism and delays ultrastructural damage during a sustained ischemic episode. Circ Res 1990;66:913–931.
Kolocassides KG, Galiñanes M, Hearse DJ. Preconditioning accelerates contracture and ATP depletion in blood-perfused rat hearts. Am J Physiol 1995;269:H1415–H1420.
Kitakaze M, Hori M, Morioka T, Minamino T, Takashima S, Sato H, Shinozaki Y, Chujo M, Mori H, Inoue M, Kamada T. Alpha1-adrenoceptor activation mediates the infarct size-limiting effect of ischemic preconditioning through augmentation of 5′-nucleotidase activity. J Clin Invest 1994;93:2197–2205.
Speechly-Dick ME, Mocanu MM, Yellon DM. Protein kinase C: its role in ischemic preconditioning in the rat. Circ Res 1994;75:586–590.
Li Y, Kloner RA. Does protein kinase C play a role in ischemic preconditioning in rat hearts? Am J Physiol 1995;268:H426–H431.
Mitchell MB, Meng X, Ao L, Brown JM, Harken AH, Banerjee A. Preconditioning of isolated rat heart is mediated by protein kinase C. Circ Res 1995;76:73–81.
Hu K, Nattel S. Mechanisms of ischemic preconditioning in rat hearts: involvement of α1B-adrenoceptors, pertussis toxin-sensitive G proteins, and protein kinase C. Circulation 1995;92:2259–2265.
Cave AC, Apstein CS. Polymyxin B, a protein kinase C inhibitor, abolishes preconditioning-induced protection against contractile dysfunction in the isolated blood perfused rat heart. J Mol Cell Cardiol 1996;28:977–987.
Brew EC, Mitchell MB, Rehring TF, Gamboni-Robertson F, McIntyre RC Jr, Harken AH, Banerjee A. Role of bradykinin in cardiac functional protection after global ischemia-reperfusion in rat heart. Am J Physiol 1995;269:H1370–H1378.
Goto M, Miura T, Sakamoto J, Iimura O. Infarct size limitation by adenosine A1 receptor agonist was blocked by staurosporine. J Mol Cell Cardiol 1994;26:CLII. Abstract.
Armstrong S, Downey JM, Ganote CE. Preconditioning of isolated rabbit cardiomyocytes: induction by metabolic stress and blockade by the adenosine antagonist SPT and calphostin C, a protein kinase C inhibitor. Cardiovasc Res 1994;28:72–77.
Speechly-Dick ME, Grover GJ, Yellon DM. 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. Circ Res 1995;77:1030–1035.
Tsuchida A, Miura T, Miki T, Sakamoto J, Iimura O. Role of α1-adrenergic receptor and protein kinase C in infarct size limitation by ischemic preconditioning in rat heart. Circulation 1994;90 (Suppl I):I-647. Abstract.
Kolocassides KG, Galiñanes M. The specific protein kinase C inhibitor chelerythrine fails to inhibit ischemic preconditioning in the rat heart. Circulation 1994;90 (Suppl I):I-208. Abstract.
Mitchell MB, Brew EC, Harken AH, Banerjee A. Does protein kinase C mediate functional preconditioning? J Mol Cell Cardiol 1993;25(Suppl III):S.64. Abstract.
Moolman JA, Genade S, Tromp E, Lochner A. No evidence for mediation of ischemic preconditioning by alpha1-adrenergic signal transduction pathway or protein kinase C in the isolated rat heart. Cardiovasc Drugs Ther 1996;10:125–136.
Galinanes M, McGill C, Brooks G, Hearse DJ. Can the protein kinase C activator diacylglycerol precondition the rat heart? J Mol Cell Cardiol 1996;28:A73. Abstract.
Kitakaze M, Node K, Minammo T, Komamura K, Funaya H, Shinozaki Y, Chujo M, Mori H, Inoue M, Hori M, Kamada T. Role of activation of protein kinase C in the infarct size-limiting effect of ischemic preconditioning through activation of ecto-5′-nucleotidase. Circulation 1996;93:781–791.
Przyklenk K, Sussman MA, Simkhovich BZ, Kloner RA. Does ischemic preconditioning trigger translocation of protein kinase C in the canine model? Circulation 1995;92:1546–1557.
Vogt A, Barancik M, Weihrauch D, Arras M, Podzuweit T, Schaper W. Protein kinase C inhibitors reduce infarct size in pig hearts in vivo. Circulation 1994;90 (Suppl I):I-647. Abstract.
Vogt A, Barancik M, Weihrauch D, Arras M, Podzuweit T, Schaper W. Activation of protein kinase C fails to protect ischemic porcine myocardium from infarction in vivo. J Mol Cell Cardiol 1994;26:CXVIII. Abstract.
Vahlhaus C, Schulz R, Post H, Onallah R, Heusch G. No prevention of ischemic preconditioning by the protein kinase C inhibitor staurosporine in swine. Circ Res 1996;79:407–414.
Baines CP, Cohen MV, Downey JM. Protein tyrosine kinase inhibitor, genistein, blocks preconditioning in isolated rabbit hearts. Circulation 1996;94 (Suppl I):I-661. Abstract.
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Downey, J.M., Cohen, M.V. (1997). Signal Transduction in Ischemic Preconditioning. In: Sideman, S., Beyar, R. (eds) Analytical and Quantitative Cardiology. Advances in Experimental Medicine and Biology, vol 430. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5959-7_4
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DOI: https://doi.org/10.1007/978-1-4615-5959-7_4
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