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Nitric Oxide and Adenosine Triphosphate-Sensitive Potassium Channels

Their Different Properties But Analogous Effects on Cellular Protection

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Signal Transduction and the Gasotransmitters

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Summary

Myocardial protection by ischemic preconditioning is effective in experimental studies, and ischemic preconditioning can also prevent cellular damage in many tissues and organs. This has encouraged investigators in various fields to study ischemic preconditioning intensively. In search of the essential cardioprotective factors, they have begun to clarify the major events during brief periods of ischemia. Ca2+ overload, free radicals, catecholamines, cytokines, and hormones have been proposed as candidate causes of ischemic damage but have also been identified as triggers for ischemic preconditioningderived cardioprotection. Ischemic preconditioning leads to the activation of intracellular messengers, including nitric oxide (NO) and KATP channels, and other enzymes to produce a cardioprotective effect. These two agents have essentially different properties. However, they appear to use the analogous pathways to reduce the severity of both myocardial infarction and myocardial dysfunction such as stunning, hibernating myocardium, and remodeling. Because preconditioning ischemia must precede lethal ischemia for these effects to occur, the underlying mechanisms such as NO and the opening of KATP channel should be effectively applied to strategies for protection after ischemic insults. Here, we summarize previous and current investigations related to the interaction of NO and KATp channels, especially in cardioprotection including controversial issues, and discuss the future directions of investigation, including some successfully Proceeding clinical trials.

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References

  1. O’Neill WW. Primary percutaneous coronary angioplasty: a protagonist’s view. Am J Cardiol 1988;62:15K-20K.

    Article  PubMed  Google Scholar 

  2. Ganz W, Geft I, Maddahi J, et al. Nonsurgical reperfusion in evolving myocardial infarction. J Am Coll Cardiol 1983;1:1247–1253.

    Article  PubMed  CAS  Google Scholar 

  3. Kloner RA, Jennings RB. Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 1. Circulation 2001;104:2981–2989.

    Article  PubMed  CAS  Google Scholar 

  4. Tomai F. Warm up phenomenon and preconditioning in clinical practice. Heart 2002;87:99,100.

    Google Scholar 

  5. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124–1136.

    Article  PubMed  CAS  Google Scholar 

  6. Jaeschke H. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol 2003;284:G15-G26.

    PubMed  CAS  Google Scholar 

  7. Bonventre JV. Kidney ischemic preconditioning. Curr Opin Nephrol Hypertens 2002;11:43–48

    Article  PubMed  Google Scholar 

  8. Kirino T. Ischemic tolerance. J Cereb Blood Flow Metab 2002;22:1283–1296.

    Article  PubMed  Google Scholar 

  9. Pohlman TH, Harlan JM. Adaptive responses of the endothelium to stress. J Surg Res 2000;89:85–119.

    Article  PubMed  CAS  Google Scholar 

  10. Opie LH. The multifarious spectrum of ischemic left ventricular dysfunction: relevance of new ischemic syndromes. J Mol Cell Cardiol 1996;28:2403–2414.

    Article  PubMed  CAS  Google Scholar 

  11. Ishihara M, Sato H, Tateishi H, et al. Implications of prodromal angina pectoris in anterior wall acute myocardial infarction: acute angiographic findings and long-term prognosis. J Am Coll Cardiol 1997;30:970–975.

    Article  PubMed  CAS  Google Scholar 

  12. Liu GS, Thornton J, Van Winkle DM, et al. Protection against infarction afforded by preconditioning is mediated by Al adenosine receptors in rabbit heart. Circulation 1991;84:350–356.

    Article  PubMed  CAS  Google Scholar 

  13. Ytrehus K, Liu Y, Downey JM. Preconditioning protects ischemic rabbit heart by protein kinase C activation. Am J Physiol 1994;266:H1145-H1152.

    PubMed  CAS  Google Scholar 

  14. Kitakaze M, Hori M, Morioka T, et al. Alpha 1-adrenoceptor activation mediates the infarct sizelimiting effect of ischemic preconditioning through augmentation of 5′-nucleotidase activity. J Clin Invest 1994;93:2197–2205.

    Article  PubMed  CAS  Google Scholar 

  15. Node K, Kitakaze M, Sato H, et al. Role of intracellular Ca2+ in activation of protein kinase C during ischemic preconditioning. Circulation 1997;96:1257–1265.

    Article  PubMed  CAS  Google Scholar 

  16. Kitakaze M, Hori M, Morioka T, et al. Alpha 1-adrenoceptor activation increases ecto-5′-nucleotidase activity and adenosine release in rat cardiomyocytes by activating protein kinase C. Circulation 1995;91:2226–2234.

    Article  PubMed  CAS  Google Scholar 

  17. Kitakaze M, Node K, Minamino T, et al. 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.

    Article  PubMed  CAS  Google Scholar 

  18. Kitakaze M, Funaya H, Minamino T, et al. Role of protein kinase C-alpha in activation of ecto-5′nucleotidase in the preconditioned canine myocardium. Biochem Biophys Res Commun 1997;239:171–175.

    Article  PubMed  CAS  Google Scholar 

  19. Yoshida K, Kawamura S, Mizukami Y, et al. Implication of protein kinase C-alpha, delta, and epsilon isoforms in ischemic preconditioning in perfused rat hearts. J Biochem (Tokyo) 1997;122:506–511.

    Article  CAS  Google Scholar 

  20. Inagaki K, Kihara Y, Hayashida W, et al. Anti-ischemic effect of a novel cardioprotective agent, JTV519:is mediated through specific activation of delta-isoform of protein kinase C in rat ventricular myocardium. Circulation 2000;101:797–804.

    Article  PubMed  CAS  Google Scholar 

  21. Liu H, McPherson BC, Yao Z. Preconditioning attenuates apoptosis and necrosis: role of protein kinase C epsilon and -delta isoforms. Am J Physiol Heart Circ Physiol 2001;281:H404-H410.

    PubMed  CAS  Google Scholar 

  22. Ping P, Song C, Zhang J, et al. Formation of protein kinase C(epsilon)-Lck signaling modules confers cardioprotection. J Clin Invest 2002;109:499–507.

    PubMed  CAS  Google Scholar 

  23. Gray MO, Karliner JS, Mochly-Rosen D. A selective epsilon-protein kinase C antagonist inhibits protection of cardiac myocytes from hypoxia-induced cell death. J Biol Chem 1997;272:30945–30951.

    Article  PubMed  CAS  Google Scholar 

  24. Hori M, Kitakaze M. Adenosine, the heart, and coronary circulation. Hypertension 1991;18:565–574.

    Article  PubMed  CAS  Google Scholar 

  25. Kitakaze M, Hori M. It is time to ask what adenosine can do for cardioprotection. Heart Vessels 1998;13:211–228.

    Article  PubMed  CAS  Google Scholar 

  26. Kitakaze M, Hori M, Morioka T, et al. Infarct size-limiting effect of ischemic preconditioning is blunted by inhibition of 5′-nucleotidase activity and attenuation of adenosine release. Circulation 1994;89: 1237–1246.

    Article  PubMed  CAS  Google Scholar 

  27. Noma A. ATP-regulated K+ channels in cardiac muscle. Nature 1983;305:147–148.

    Article  PubMed  CAS  Google Scholar 

  28. Yokoshiki H, Sunagawa M, Seki T, et al. ATP-sensitive K+ channels in pancreatic, cardiac, and vascular smooth muscle cells. Am J Physiol 1998;274:C25-C37.

    PubMed  CAS  Google Scholar 

  29. Snyders DJ. Structure and function of cardiac potassium channels. Cardiovasc Res 1999;42:377–390

    Article  PubMed  CAS  Google Scholar 

  30. Matsuoka T, Matsushita K, Katayama Y, et al. C-terminal tails of sulfonylurea receptors control ADPinduced activation and diazoxide modulation of ATP-sensitive K(+) channels. Circ Res 2000;87:873–880.

    Article  PubMed  CAS  Google Scholar 

  31. Drain P, Li L, Wang J. KATP channel inhibition by ATP requires distinct functional domains of the cytoplasmic C terminus of the pore-forming subunit. Proc Natl Acad Sci USA 1998;95:13953–13958.

    Article  PubMed  CAS  Google Scholar 

  32. Gross GJ, Fryer RM. Sarcolemmal versus mitochondrial ATP-sensitive K+ channels and myocardial preconditioning. Circ Res 1999;84:973–979.

    Article  PubMed  CAS  Google Scholar 

  33. Gross GJ, Auchampach JA. Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circ Res 1992;70:223–233.

    Article  PubMed  CAS  Google Scholar 

  34. Grover GJ, Sleph PG, Dzwonczyk S. Role of myocardial ATP-sensitive potassium channels in mediating preconditioning in the dog heart and their possible interaction with adenosine Al-receptors. Circulation 1992;86:1310–1316.

    Article  PubMed  CAS  Google Scholar 

  35. Inoue I, Nagase H, Kishi K, et al. ATP-sensitive K+ channel in the mitochondrial inner membrane. Nature 1991;352:244–247.

    Article  PubMed  CAS  Google Scholar 

  36. Liu Y, Sato T, Seharaseyon J, et al. Mitochondrial ATP-dependent potassium channels: viable candidate effectors of ischemic preconditioning. Ann NY Acad Sci 1999;874:27–37.

    Article  PubMed  CAS  Google Scholar 

  37. Sato T, O’Rourke B, Marban E. Modulation of mitochondrial ATP-dependent K+ channels by protein kinase C. Circ Res 1998;83:110–114.

    Article  PubMed  CAS  Google Scholar 

  38. Pain T, Yang XM, Critz SD, et al. Opening of mitochondrial K(ATP) channels triggers the preconditioned state by generating free radicals. Circ Res 2000;87:460–466.

    Article  PubMed  CAS  Google Scholar 

  39. Suzuki M, Sasaki N, Miki T, et al. Role of sarcolemmal K(ATP) channels in cardioprotection against ischemia/reperfusion injury in mice. J Clin Invest 2002;109:509–516.

    PubMed  CAS  Google Scholar 

  40. Dzeja PP, Bast P, Ozcan C, et al. Targeting nucleotide-requiring enzymes: implications for diazoxideinduced cardioprotection. Am J Physiol Heart Circ Physiol 2003;284:H1048-H1056.

    PubMed  CAS  Google Scholar 

  41. Hanley PJ, Gopalan KV, Lareau RA, et al. Beta-oxidation of 5-hydroxydecanoate, a putative blocker of mitochondrial ATP-sensitive potassium channels. J Physiol 2003;547:387–393.

    Article  PubMed  CAS  Google Scholar 

  42. Sanada S, Kitakaze M, Asanuma H, et al. Role of mitochondrial and sarcolemmal K(ATP) channels in ischemic preconditioning of the canine heart. Am J Physiol Heart Circ Physiol 2001;280:H256-H263.

    PubMed  CAS  Google Scholar 

  43. Schwartz LM, Welch TS, Crago MS. Cardioprotection by multiple preconditioning cycles does not require mitochondrial K(ATP) channels in pigs. Am J Physiol Heart Circ Physiol 2002;283: H1538-H1544.

    PubMed  CAS  Google Scholar 

  44. Minamino T, Kitakaze M, Matsumura Y, et al. Impact of coronary risk factors on contribution of nitric oxide and adenosine to metabolic coronary vasodilation in humans. J Am Coll Cardiol 1998;31: 1274–1279.

    Article  PubMed  CAS  Google Scholar 

  45. Dawn B, Bolli R. Role of nitric oxide in myocardial preconditioning. Ann NY Acad Sci 2002;962: 18–41.

    Article  PubMed  CAS  Google Scholar 

  46. Kojda G, Kottenberg K. Regulation of basal myocardial function by NO. Cardiovasc Res 1999;41: 514–523.

    Article  PubMed  CAS  Google Scholar 

  47. Yoshida K, Mizukami Y, Kitakaze M. Nitric oxide mediates protein kinase C isoform translocation in rat heart during postischemic reperfusion. Biochim Biophys Acta 1999;1453:230–238.

    Article  PubMed  CAS  Google Scholar 

  48. Cohen MV, Yang XM, Liu GS, et al. Acetylcholine, bradykinin, opioids, and phenylephrine, but not adenosine, trigger preconditioning by generating free radicals and opening mitochondrial K(ATP) channels. Circ Res 2001;89:273–278.

    Article  PubMed  CAS  Google Scholar 

  49. Csonka C, Csont T, Onody A, et al. Preconditioning decreases ischemia/reperfusion-induced peroxynitrite formation. Biochem Biophys Res Commun 2001;285:1217–1219.

    Article  PubMed  CAS  Google Scholar 

  50. Altug S, Demiryurek AT, Kane KA, et al. Evidence for the involvement of peroxynitrite in ischaemic preconditioning in rat isolated hearts. Br J Pharmacol 2000:130:125–131.

    Article  PubMed  CAS  Google Scholar 

  51. Bell RM, Yellon DM. The contribution of endothelial nitric oxide synthase to early ischaemic preconditioning: the lowering of the preconditioning threshold. An investigation in eNOS knockout mice. Cardiovasc Res 2001;52:274–280.

    Article  PubMed  CAS  Google Scholar 

  52. Kitakaze M, Node K, Takashima S, Asanuma H, et al. Role of cellular acidosis in production of nitric oxide in canine ischemic myocardium. J Mol Cell Cardiol 2001;33:1727–1737.

    Article  PubMed  CAS  Google Scholar 

  53. Xie LH, Horie M, Takano M. Phospholipase C-linked receptors regulate the ATP-sensitive potassium channel by means of phosphatidylinositol 4,5-bisphosphate metabolism. Proc Natl Acad Sci USA 1999;96:15,292–15,297.

    CAS  Google Scholar 

  54. Merkus D, Haitsma DB, Fung TY, et al. Coronary blood flow regulation in exercising swine involves parallel rather than redundant vasodilator pathways. Am J Physiol Heart Circ Physiol 2003;285:H424-H433.

    PubMed  CAS  Google Scholar 

  55. Asanuma H, Kitakaze M, Funaya H, et al. Nifedipine limits infarct size via NO-dependent mechanisms in dogs. Basic Res Cardiol 2001;96:497–505.

    Article  PubMed  CAS  Google Scholar 

  56. Baxter GF. Role of adenosine in delayed preconditioning of myocardium. Cardiovasc Res 2002;55: 483–494.

    Article  PubMed  CAS  Google Scholar 

  57. Ambrosio G, Tritto I, Chiariello M. The role of oxygen free radicals in preconditioning. J Mol Cell Cardiol 1995;27:1035–1039.

    Article  PubMed  CAS  Google Scholar 

  58. 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.

    Article  PubMed  CAS  Google Scholar 

  59. Chen W, Gabel S, Steenbergen C, et al. A redox-based mechanism for cardioprotection induced by ischemic preconditioning in perfused rat heart. Circ Res 1995;77:424–429.

    Article  PubMed  CAS  Google Scholar 

  60. McPherson BC, Yao ZH. Morphine mimics preconditioning via free radical signals and mitochondrial KATP channels in myocytes. Circulation 2001;103:290–295.

    Article  PubMed  CAS  Google Scholar 

  61. Tritto I, D’ Andrea D, Eramo N, et al. Oxygen radicals can induce preconditioning in rabbit hearts. Circ Res 1997;80:743–748.

    Article  PubMed  CAS  Google Scholar 

  62. Vanden Hoek TL, Becker LB, Shao Z, et al. Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes. J Biol Chem 1998;273:18,092–18,098.

    Google Scholar 

  63. Yao Z, Tong J, Tan X, et al. Role of reactive oxygen species in acetylcholine-induced preconditioning in cardiomyocytes. Am J Physiol Heart Circ Physiol 1999;277:H2504-H2509.

    CAS  Google Scholar 

  64. Forbes RA, Steenbergen C, Murphy E. Diazoxide-induced cardioprotection requires signaling through a redox-sensitive mechanism. Circ Res 2001;88:802–809.

    Article  PubMed  CAS  Google Scholar 

  65. Vanden Hoek TL, Becker LB, Shao ZH, et al. Preconditioning in cardiomyocytes protects by attenuating oxidant stress at reperfusion. Circ Res 2000;86:541–548.

    Article  Google Scholar 

  66. Lochner A, Marais E, Genade S, et al. Nitric oxide: a trigger for classic preconditioning? Am J Physiol Heart Circ Physiol 2000;279:H2752–H2765.

    PubMed  CAS  Google Scholar 

  67. Ockaili R, Emani VR, Okubo S, et al. Opening of mitochondrial KATP channel induces early and delayed cardioprotective effect: role of nitric oxide. Am J Physiol Heart Circ Physiol 1999;277: H2425–H2434.

    CAS  Google Scholar 

  68. Rakhit RD, Edwards RJ, Mockridge JW, et al. Nitric oxide-induced cardioprotection in cultured rat ventricular myocytes. Am J Physiol Heart Circ Physiol 2000;278:H1211–H1217.

    PubMed  CAS  Google Scholar 

  69. Yao Z, Gross GJ. Role of nitric oxide, muscarinic receptors, and the ATP-sensitive K channel in mediating the effects of acetylcholine to mimic preconditioning in dogs. Circ Res 1993;73:1193–1201.

    Article  PubMed  CAS  Google Scholar 

  70. Lu HR, Remeysen P, De Clerck F. Does the antiarrhythmic effect of ischemic preconditioning in rats involve the L-arginine nitric oxide pathway? J Cardiovasc Pharmacol 1995;25:524–530.

    Article  PubMed  CAS  Google Scholar 

  71. Ping PP, Takano H, Zhang J, et al. Isoform selective activation of protein kinase C by nitric oxide in the heart of conscious rabbits: a signaling mechanism for both nitric oxide-induced and ischemia-induced preconditioning. Circ Res, 1999;84:587–604.

    Article  PubMed  CAS  Google Scholar 

  72. Nakano A, Liu GS, Heusch G, et al. Exogenous nitric oxide can trigger a preconditioned state through a free radical mechanism, but endogenous nitric oxide is not a trigger of classical ischemic preconditioning. J Mol Cell Cardiol 2000;32:1159–1167.

    Article  PubMed  CAS  Google Scholar 

  73. Liu H, McPherson BC, Zhu X, et al. Role of nitric oxide and protein kinase C in ACh-induced cardioprotection. Am J Physiol Heart Circ Physiol 2001;281:H191-H197.

    PubMed  CAS  Google Scholar 

  74. Lebuffe G, Schumacker PT, Shao ZH, et al. ROS and NO trigger early preconditioning: relationship to mitochondrial KATp channel. Am J Physiol Heart Circ Physiol 2003;284:H299-H308.

    PubMed  CAS  Google Scholar 

  75. Das DK, Engelman RM, Maulik N. Oxygen free radical signaling in ischemic preconditioning. Ann NY Acad Sci 1999;874:49–65.

    Article  PubMed  CAS  Google Scholar 

  76. Gross GJ, Auchampach JA. Role of ATP dependent potassium channels in myocardial ischaemia. Cardiovasc Res 1992;26:1011–1016.

    Article  PubMed  CAS  Google Scholar 

  77. Marber MS. Ischemic preconditioning in isolated cells. Circ Res 2000;86:926–931.

    Article  PubMed  CAS  Google Scholar 

  78. O’Rourke B. Myocardial KATP channels in preconditioning. Circ Res 2000;87:845–855.

    Article  PubMed  Google Scholar 

  79. Okubo S, Xi L, Bernardo NL, et al. Myocardial preconditioning: basic concepts and potential mechanisms. Mol Cell Biochem 1999;196:3–12.

    Article  PubMed  CAS  Google Scholar 

  80. Noda T, Minatoguchi S, Fujii K, et al. Evidence for the delayed effect in human ischemic preconditioning: prospective multicenter study for preconditioning in acute myocardial infarction. J Am Coll Cardiol 1999;34:1966–1974.

    Article  PubMed  CAS  Google Scholar 

  81. Mahaffey KW, Puma JA, Barbagelata NA, et al. Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction: results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial. J Am Coll Cardiol 1999;34:1711–1720.

    Article  PubMed  CAS  Google Scholar 

  82. Genda S, Miura T, Mild T, et al. K(ATP) channel opening is an endogenous mechanism of protection against the no-reflow phenomenon but its function is compromised by hypercholesterolemia. J Am Coll Cardiol 2002;40:1339–1346.

    Article  PubMed  CAS  Google Scholar 

  83. Ito H, Taniyama Y, Iwakura K, et al. Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction. J Am Coll Cardiol 1999;33:654–660.

    Article  PubMed  CAS  Google Scholar 

  84. Sakata Y, Kodama K, Komamura K, et al. Salutary effect of adjunctive intracoronary nicorandil administration on restoration of myocardial blood flow and functional improvement in patients with acute myocardial infarction. Am Heart J 1997;133:616–621.

    Article  PubMed  CAS  Google Scholar 

  85. Kotani J, Nanto S, Mintz GS, et al. Plaque gruel of atheromatous coronary lesion may contribute to the no-reflow phenomenon in patients with acute coronary syndrome. Circulation 2002;106:1672–1677.

    Article  PubMed  Google Scholar 

  86. Sato T, Sasaki N, O’Rourke B, et al. Nicorandil, a potent cardioprotective agent, acts by opening mitochondrial ATP-dependent potassium channels. J Am Coll Cardiol 2000;35:514–518.

    Article  PubMed  CAS  Google Scholar 

  87. IONA study group. Effect of nicorandil on coronary events in patients with stable angina: the Impact of Nicorandil in Angina (IONA) randomized trial. Lancet 2002;359:1269–1275.

    Article  Google Scholar 

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  1. Shoji Sanada
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  2. Jiyoong Kim
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  3. Masafumi Kitakaze
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Editors and Affiliations

  1. Department of Physiology, University of Saskatchewan, Saskatoon, SK, Canada

    Rui Wang MD, PhD, FAHA

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Sanada, S., Kim, J., Kitakaze, M. (2004). Nitric Oxide and Adenosine Triphosphate-Sensitive Potassium Channels. In: Wang, R. (eds) Signal Transduction and the Gasotransmitters. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-806-9_5

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  • DOI: https://doi.org/10.1007/978-1-59259-806-9_5

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