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Br J Pharmacol. 2011 Jun;163(3):469-83. doi: 10.1111/j.1476-5381.2011.01244.x.

Pharmacological modulation of connexin-formed channels in cardiac pathophysiology.

Elke De Vuyst, Kerstin Boengler, Gudrun Antoons, Karin R Sipido, Rainer Schulz, Luc Leybaert

Affiliations

  1. Department of Basic Medical Sciences - Physiology group, Faculty of Medicine and Health Sciences, Ghent University, Belgium.

PMID: 21265827 PMCID: PMC3101610 DOI: 10.1111/j.1476-5381.2011.01244.x

Abstract

Coordinated electrical activity in the heart is supported by gap junction channels located at the intercalated discs of cardiomyocytes. Impaired gap junctional communication between neighbouring cardiomyocytes contributes to the development of re-entry arrhythmias after myocardial ischaemia. Current antiarrhythmic therapy is hampered by a lack of efficiency and side effects, creating the need for a new generation of drugs. In this review, we focus on compounds that increase gap junctional communication, thereby increasing the conduction velocity and decreasing the risk of arrhythmias. Some of these compounds also inhibit connexin 43 (Cx43) hemichannels, thereby limiting adenosine triphosphate loss and volume overload following ischaemia/reperfusion, thus potentially increasing the survival of cardiomyocytes. The compounds discussed in this review are: (i) antiarrythmic peptide (AAP), AAP10, ZP123; (ii) GAP-134; (iii) RXP-E; and (vi) the Cx mimetic peptides Gap 26 and Gap 27. None of these compounds have effects on Na(+) , Ca(2+) and K(+) channels, and therefore have no proarrhythmic activity associated with currently available antiarrhythmic drugs. GAP-134, RXP-E, Gap 26 and Gap 27 are pharmalogical agents with a favorable clinical safety profile, as already confirmed in phase I clinical trials for GAP-134. These agents show an excellent promise for treatment of arrhythmias in patients with ischaemic cardiomyopathy.

© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

References

  1. Cell Commun Adhes. 2009;16(1-3):29-38 - PubMed
  2. Circ Res. 2001 Jun 8;88(11):1159-67 - PubMed
  3. Arch Biochem Biophys. 2000 Dec 15;384(2):205-15 - PubMed
  4. Naunyn Schmiedebergs Arch Pharmacol. 2010 Mar;381(3):221-34 - PubMed
  5. Circulation. 1998 Nov 24;98(21):2334-51 - PubMed
  6. J Cardiovasc Pharmacol. 2006 Feb;47(2):236-42 - PubMed
  7. Antioxid Redox Signal. 2009 Feb;11(2):267-82 - PubMed
  8. Cell Calcium. 2009 Sep;46(3):176-87 - PubMed
  9. J Pharmacobiodyn. 1982 Jan;5(1):40-8 - PubMed
  10. J Biol Chem. 2006 Aug 11;281(32):23207-17 - PubMed
  11. Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1714-20 - PubMed
  12. J Cell Physiol. 2003 Nov;197(2):205-13 - PubMed
  13. J Pharmacol Exp Ther. 2006 Apr;317(1):236-43 - PubMed
  14. Circ Res. 2000 Feb 18;86(3):293-301 - PubMed
  15. Am J Physiol Heart Circ Physiol. 2006 Feb;290(2):H648-56 - PubMed
  16. Acta Physiol Scand. 2003 Sep;179(1):23-31 - PubMed
  17. Cell Commun Adhes. 2005 Jul-Dec;12(5-6):271-8 - PubMed
  18. Circ Arrhythm Electrophysiol. 2009 Apr;2(2):171-8 - PubMed
  19. Bioorg Med Chem Lett. 2009 Aug 15;19(16):4551-4 - PubMed
  20. Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1425-31 - PubMed
  21. J Cardiovasc Electrophysiol. 2003 May;14(5):510-20 - PubMed
  22. Exp Clin Cardiol. 2006 Winter;11(4):286-93 - PubMed
  23. J Pharmacol Exp Ther. 2009 Jun;329(3):1127-33 - PubMed
  24. Circ Res. 2006 Jun 23;98(12):1498-505 - PubMed
  25. Pflugers Arch. 2010 Aug;460(3):583-92 - PubMed
  26. Br J Pharmacol. 2006 Jan;147 Suppl 1:S172-81 - PubMed
  27. J Cell Biol. 2007 Dec 17;179(6):1301-9 - PubMed
  28. Physiol Rev. 2004 Apr;84(2):431-88 - PubMed
  29. Endocrinology. 2005 Nov;146(11):4745-54 - PubMed
  30. Cell Calcium. 2003 Jan;33(1):37-48 - PubMed
  31. Med Clin North Am. 2001 Mar;85(2):321-41 - PubMed
  32. J Pharmacol Exp Ther. 2003 Sep;306(3):1191-9 - PubMed
  33. Cardiovasc Res. 2002 Aug 15;55(3):456-65 - PubMed
  34. J Mol Cell Cardiol. 2000 Oct;32(10):1859-72 - PubMed
  35. J Cell Biol. 1991 Dec;115(5):1357-74 - PubMed
  36. J Cardiovasc Pharmacol Ther. 2009 Sep;14(3):207-14 - PubMed
  37. Am J Physiol. 1999 Jun;276(6):H1911-7 - PubMed
  38. Peptides. 2001 Jul;22(7):1011-21 - PubMed
  39. Brain Res Brain Res Rev. 2000 Apr;32(1):308-15 - PubMed
  40. Eur Heart J. 2003 Jan;24(1):13-5 - PubMed
  41. J Am Coll Cardiol. 2010 Jun 1;55(22):2435-45 - PubMed
  42. Am J Physiol Heart Circ Physiol. 2003 Jul;285(1):H10-6 - PubMed
  43. Expert Opin Ther Targets. 2010 Jul;14(7):681-92 - PubMed
  44. Cell Regul. 1990 Dec;1(13):989-1002 - PubMed
  45. Am J Physiol Heart Circ Physiol. 2009 Feb;296(2):H396-403 - PubMed
  46. Experientia. 1987 Oct 15;43(10):1075-9 - PubMed
  47. Mol Cell Biol. 1990 Apr;10(4):1754-63 - PubMed
  48. Naunyn Schmiedebergs Arch Pharmacol. 1994 Aug;350(2):174-84 - PubMed
  49. Chem Pharm Bull (Tokyo). 1983 Feb;31(2):612-9 - PubMed
  50. Circ Res. 1987 Aug;61(2):271-9 - PubMed
  51. Naunyn Schmiedebergs Arch Pharmacol. 1997 Jul;356(1):76-82 - PubMed
  52. Zhonghua Xin Xue Guan Bing Za Zhi. 2006 Sep;34(9):825-8 - PubMed
  53. J Pharmacol Exp Ther. 2005 Sep;314(3):1386-92 - PubMed
  54. Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9726-31 - PubMed
  55. Peptides. 1998;19(10):1725-9 - PubMed
  56. Cardiovasc Res. 2008 Oct 1;80(1):9-19 - PubMed
  57. Cell Commun Adhes. 2003 Jul-Dec;10(4-6):251-7 - PubMed
  58. J Cardiovasc Electrophysiol. 2005 May;16(5):537-45 - PubMed
  59. Circulation. 2003 Dec 23;108(25):3157-63 - PubMed
  60. N Engl J Med. 2003 Nov 13;349(20):1893-906 - PubMed
  61. Eur J Pharmacol. 2009 Mar 1;605(1-3):9-14 - PubMed
  62. Circ Res. 2006 Jun 9;98(11):1365-72 - PubMed
  63. Cardiovasc Res. 2009 Jul 15;83(2):405-15 - PubMed
  64. Cardiovasc Res. 2006 May 1;70(2):374-83 - PubMed
  65. Adv Cardiol. 2006;42:198-212 - PubMed
  66. Br J Pharmacol. 2009 Sep;158(1):198-208 - PubMed
  67. Circulation. 1997 Feb 18;95(4):988-96 - PubMed
  68. Adv Cardiol. 2006;42:132-149 - PubMed
  69. J Membr Biol. 2007 Aug;218(1-3):93-100 - PubMed
  70. FASEB J. 2002 Jul;16(9):1114-6 - PubMed
  71. Circulation. 2000 Feb 8;101(5):547-52 - PubMed
  72. Circulation. 1995 Nov 15;92(10):3051-60 - PubMed
  73. Heart Rhythm. 2010 Oct;7(10):1491-8 - PubMed
  74. Circulation. 2002 Feb 5;105(5):589-94 - PubMed
  75. Curr Opin Cardiol. 2000 Jan;15(1):64-72 - PubMed
  76. Eur Heart J. 1991 Oct;12(10):1112-31 - PubMed
  77. Biochem J. 2006 Mar 15;394(Pt 3):527-43 - PubMed
  78. J Mol Cell Cardiol. 1979 Jul;11(7):619-30 - PubMed
  79. Cell Commun Adhes. 2001;8(4-6):257-64 - PubMed
  80. Trends Neurosci. 2008 May;31(5):243-50 - PubMed
  81. Am J Physiol Heart Circ Physiol. 2004 Jan;286(1):H214-21 - PubMed
  82. Biochem J. 2006 Jul 1;397(1):1-14 - PubMed
  83. Cardiovasc Res. 1999 May;42(2):309-17 - PubMed
  84. Chem Pharm Bull (Tokyo). 1987 Sep;35(9):3928-30 - PubMed
  85. J Cardiovasc Pharmacol. 2002 Nov;40(5):770-9 - PubMed
  86. Curr Opin Cardiol. 2006 Jul;21(4):361-7 - PubMed
  87. Cell Commun Adhes. 2003 Jul-Dec;10(4-6):371-8 - PubMed
  88. Expert Opin Investig Drugs. 2009 Jul;18(7):875-85 - PubMed
  89. Biochem Soc Trans. 2001 Aug;29(Pt 4):606-12 - PubMed
  90. Cell Death Differ. 2009 Apr;16(4):524-36 - PubMed
  91. Mol Cell Biochem. 2003 Jan;242(1-2):129-34 - PubMed
  92. Chem Pharm Bull (Tokyo). 1980 Nov;28(11):3332-9 - PubMed
  93. Circ Res. 2008 Aug 29;103(5):519-26 - PubMed
  94. Circ Res. 2006 Nov 10;99(10):1100-8 - PubMed
  95. J Clin Invest. 2010 May;120(5):1441-53 - PubMed
  96. J Med Chem. 2009 Feb 26;52(4):908-11 - PubMed
  97. Biol Chem. 2002 May;383(5):725-37 - PubMed
  98. Nat Neurosci. 1998 Oct;1(6):494-500 - PubMed
  99. Circ Res. 2004 Oct 1;95(7):726-33 - PubMed
  100. Circ Res. 2001 Oct 26;89(9):807-14 - PubMed
  101. Am J Cardiol. 1993 Dec 1;72(17):1243-8 - PubMed
  102. Cardiovasc Res. 2010 Aug 1;87(3):406-23 - PubMed
  103. Basic Res Cardiol. 2009 May;104(3):321-32 - PubMed
  104. Biochem J. 2009 Apr 15;419(2):261-72 - PubMed
  105. Circ Res. 2009 Jul 17;105(2):176-84 - PubMed
  106. Circulation. 1997 Nov 18;96(10):3579-86 - PubMed
  107. J Cell Sci. 2006 Aug 15;119(Pt 16):3435-42 - PubMed
  108. Cardiovasc Res. 2009 Sep 1;83(4):747-56 - PubMed
  109. Am J Physiol Heart Circ Physiol. 2010 Apr;298(4):H1115-25 - PubMed
  110. Circ Res. 2000 Dec 8;87(12):1103-7 - PubMed
  111. Jpn Heart J. 2004 Nov;45(6):1007-19 - PubMed
  112. Peptides. 2002 Sep;23(9):1701-9 - PubMed
  113. Biophys J. 2004 Jul;87(1):574-81 - PubMed
  114. Naunyn Schmiedebergs Arch Pharmacol. 2008 Nov;378(5):459-70 - PubMed
  115. Basic Clin Pharmacol Toxicol. 2007 Oct;101(4):215-30 - PubMed
  116. Pharmacology. 2010;85(4):203-10 - PubMed
  117. Exp Cell Res. 2006 May 1;312(8):1277-88 - PubMed
  118. J Mol Cell Cardiol. 2006 Jun;40(6):790-8 - PubMed
  119. Circulation. 2001 Sep 25;104(13):1544-9 - PubMed
  120. Cardiovasc Pathol. 2002 May-Jun;11(3):158-65 - PubMed
  121. Cardiovasc Pathol. 2001 Jan-Feb;10(1):13-7 - PubMed
  122. Cell Death Differ. 2009 Jan;16(1):151-63 - PubMed
  123. J Neurosci. 2008 Apr 30;28(18):4702-11 - PubMed
  124. Circulation. 2002 May 28;105(21):2537-42 - PubMed
  125. Cardiovasc Res. 2005 Aug 1;67(2):234-44 - PubMed
  126. Eur J Pharmacol. 1997 May 26;327(1):65-72 - PubMed
  127. Circ Res. 2000 Oct 13;87(8):656-62 - PubMed
  128. Proc Natl Acad Sci U S A. 1962 Dec 15;48:2026-34 - PubMed
  129. Am J Physiol Heart Circ Physiol. 2001 Jun;280(6):H2563-71 - PubMed
  130. Cell Commun Adhes. 2006 Jan-Apr;13(1-2):21-7 - PubMed
  131. J Membr Biol. 2007 Jun;217(1-3):35-41 - PubMed
  132. N Engl J Med. 2008 Mar 27;358(13):1397-8 - PubMed

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