The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지

Nitric Oxide-cGMP-Protein Kinase G Pathway Contributes to Cardioprotective Effects of ATP-Sensitive $K^+$ Channels in Rat Hearts

  • Cuong, Cang Van (Department of Physiology & Biophysics, Molecular Cell Physiology Research Group, Biohealth Products Research Center, College of Medicine, Inje University) ;
  • Kim, Na-Ri (Department of Physiology & Biophysics, Molecular Cell Physiology Research Group, Biohealth Products Research Center, College of Medicine, Inje University) ;
  • Cho, Hee-Cheol (Department of Physiology & Biophysics, Molecular Cell Physiology Research Group, Biohealth Products Research Center, College of Medicine, Inje University) ;
  • Kim, Eui-Yong (Department of Physiology & Biophysics, Molecular Cell Physiology Research Group, Biohealth Products Research Center, College of Medicine, Inje University) ;
  • Han, Jin (Department of Physiology & Biophysics, Molecular Cell Physiology Research Group, Biohealth Products Research Center, College of Medicine, Inje University)
  • Published : 2004.04.21
Download PDF
⟨ Previous Next ⟩

Abstract

Ischemic preconditioning (IPC) has been accepted as a heart protection phenomenon against ischemia and reperfusion (I/R) injury. The activation of ATP-sensitive potassium $(K_{ATP})$ channels and the release of myocardial nitric oxide (NO) induced by IPC were demonstrated as the triggers or mediators of IPC. A common action mechanism of NO is a direct or indirect increase in tissue cGMP content. Furthermore, cGMP has also been shown to contribute cardiac protective effect to reduce heart I/R-induced infarction. The present investigation tested the hypothesis that $K_{ATP}$ channels attenuate DNA strand breaks and oxidative damage in an in vitro model of I/R utilizing rat ventricular myocytes. We estimated DNA strand breaks and oxidative damage by mean of single cell gel electrophoresis with endonuclease III cutting sites (comet assay). In the I/R model, the level of DNA damage increased massively. Preconditioning with a single 5-min anoxia, diazoxide $(100\;{\mu}M)$, SNAP $(300\;{\mu}M)$ and 8-(4-Chlorophenylthio)-guanosine-3',5'-cyclic monophosphate (8-pCPT-cGMP) $(100\;{\mu}M)$ followed by 15 min reoxygenation reduced DNA damage level against subsequent 30 min anoxia and 60 min reoxygenation. These protective effects were blocked by the concomitant presence of glibenclamide $(50\;{\mu}M)$, 5-hydroxydecanoate (5-HD) $(100\;{\mu}M)$ and 8-(4-Chlorophenylthio)-guanosine-3',5'-cyclic monophosphate, Rp-isomer (Rp-8-pCPT-cGMP) $(100\;{\mu}M)$. These results suggest that NO-cGMP-protein kinase G (PKG) pathway contributes to cardioprotective effect of $K_{ATP}$ channels in rat ventricular myocytes.

Keywords

References

  1. Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271: C1424 -1437, 1996 https://doi.org/10.1152/ajpcell.1996.271.5.C1424
  2. Buchwalow IB, Schulze W, Karczewski P, Kostic MM, Wallukat G, Morwinski R, Krause EG, Muller J, Paul M, Slezak J, Luft FC, Haller H. Inducible nitric oxide synthase in the myocard. Mol Cell Biochem 217: 73-82, 2001 https://doi.org/10.1023/A:1007286602865
  3. Carroll R, Gant VA, Yellon DM. Mitochondrial KATP channel opening protects a human atrial-derived cell line by a mechanism involving free radical generation. Cardiovasc Res 51: 691-700, 2001 https://doi.org/10.1016/S0008-6363(01)00330-3
  4. Collins A. R. Dusinska, M. Oxidation of cellular DNA measured with the comet assay. In: Donald Amstrong editor. Oxidative stress biomarkers and antioxidant protocols. New Jersey; Humana press p147-159, 2002
  5. Csonka C, Szilvassy Z, Fulop F, Pali T, Blasig IE, Tosaki A, Schulz R, Ferdinandy P. Classic preconditioning decreases the harmful accumulation of nitric oxide during ischemia and reperfusion in rat hearts. Circulation 100: 2260-2266, 1999 https://doi.org/10.1161/01.CIR.100.22.2260
  6. Crompton M, Virji S, Doyle V, Johnson N, Ward JM. The mitochondrial permeability transition pore. Biochem Soc Symp 66: 167-179, 1999 https://doi.org/10.1042/bss0660167
  7. Dos Santos P, Kowaltowski AJ, Laclau MN, Seetharaman S, Paucek P, Boudina S, Thambo JB, Tariosse L, Garlid KD. Mechanisms by which opening the mitochondrial ATP-sensitive K$^+$ channel protects the ischemic heart. Am J Physiol Heart Circ Physiol 283: H284-295, 2002 https://doi.org/10.1152/ajpheart.00034.2002
  8. Fryer RM, Patel HH, Hsu AK, Gross GJ. Stress-activated protein kinase phosphorylation during cardioprotection in the ischemic myocardium. Am J Physiol Heart Circ Physiol 281: H1184-92, 2001 https://doi.org/10.1152/ajpheart.2001.281.3.H1184
  9. Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio RB, D'Alonzo AJ, Lodge NJ, Smith MA, Grover GJ. Cardioprotective effect of diazoxide and its interaction with mitochondrial ATPsensitive K$^+$ channels. Possible mechanism of cardioprotection. Circ Res 81: 1072-1082, 1997 https://doi.org/10.1161/01.RES.81.6.1072
  10. Gross GJ. The role of mitochondrial KATP channels in the antiarrhythmic effects of ischaemic preconditioning in dogs. Br J Pharmacol 137: 939-940, 2002 https://doi.org/10.1038/sj.bjp.0704965
  11. Han J, Kim N, Joo H, Kim E, Earm YE. ATP-sensitive K$^+$ channel activation by nitric oxide and protein kinase G in rabbit ventricular myocytes. Am J Physiol Heart Circ Physiol 283: H1545-554, 2002 https://doi.org/10.1152/ajpheart.01052.2001
  12. Han J, Kim N, Cuong DV, Kim C, Kim E. Thiol-dependent redox mechanism in the modification of ATP-sensitive K$^+$ channels in rabbit ventricular myocytes. Korean J Physiol Pharmacol 7: 15- 23, 2003
  13. Hanley PJ, Mickel M, Loffler M, Brandt U, Daut J. K(ATP) channel-independent targets of diazoxide and 5-hydroxydecanoate in the heart. J Physiol 542: 735-741, 2002 https://doi.org/10.1113/jphysiol.2002.023960
  14. Hausenloy DJ, Duchen MR, Yellon DM. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury. Cardiovasc Res 60: 617- 625, 2003 https://doi.org/10.1016/j.cardiores.2003.09.025
  15. Ichinose M, Yonemochi H, Sato T, Saikawa T. Diazoxide triggers cardioprotection against apoptosis induced by oxidative stress. Am J Physiol Heart Circ Physiol 284: H2235-2241, 2003 https://doi.org/10.1152/ajpheart.01073.2002
  16. Ichinose M, Yonemochi H, Sato T, Saikawa T. Diazoxide triggers cardioprotection against apoptosis induced by oxidative stress. Am J Physiol Heart Circ Physiol 284: H2235-2241, 2003 https://doi.org/10.1152/ajpheart.01073.2002
  17. Lefer DJ, Granger DN. Oxidative stress and cardiac disease. Am J Med 109: 315-323, 2000 https://doi.org/10.1016/S0002-9343(00)00467-8
  18. Maejima Y, Adachi S, Ito H, Nobori K, Tamamori-Adachi M, Isobe M. Nitric oxide inhibits ischemia/reperfusion-induced myocardial apoptosis by modulating cyclin A-associated kinase activity. Cardiovasc Res 59: 308-320, 2003 https://doi.org/10.1016/S0008-6363(03)00425-5
  19. Martin C, Schulz R, Post H, Gres P, Heusch G. Effect of NO synthase inhibition on myocardial metabolism during moderate ischemia. Am J Physiol Heart Circ Physiol 284: H2320-2324, 2003 https://doi.org/10.1152/ajpheart.01122.2002
  20. McKelvey-Martin VJ, Green MH, Schmezer P, Pool-Zobel BL, De Meo MP, Collins A. The single cell gel electrophoresis assay (comet assay): a European review. Mutat Res 288: 47-63, 1993 https://doi.org/10.1016/0027-5107(93)90207-V
  21. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43: 109- 142, 1991
  22. Moncada S, Erusalimsky JD. Does nitric oxide modulate mitochondrial energy generation and apoptosis? Nat Rev Mol Cell Biol 3: 214-220, 2002 https://doi.org/10.1038/nrm762
  23. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium.Circulation 74:1124-1136, 1986 https://doi.org/10.1161/01.CIR.74.5.1124
  24. Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ, Schmidt U, Semigran MJ, Dec GW, Khaw BA. Apoptosis in myocytes in end-stage heart failure. N Engl J Med 335: 1182- 1189, 1996 https://doi.org/10.1056/NEJM199610173351603
  25. Oldenburg O, Qin Q, Krieg T, Yang XM, Philipp S, Critz SD, Cohen MV, Downey JM. Bradykinin induces mitochondrial ROS generation via NO, cGMP, PKG, and mKATP channel opening and leads to cardioprotection. Am J Physiol Heart Circ Physiol Sep 4, 2003
  26. Peart JN, Gross GJ. Sarcolemmal and mitochondrial KATP channels and myocardial ischemic preconditioning. J Cell Mol Med 6: 453 -464, 2002 https://doi.org/10.1111/j.1582-4934.2002.tb00449.x
  27. Radi R, Rodriguez M, Castro L, Telleri R. Inhibition of mitochondrial electron transport by peroxynitrite. Arch Biochem Biophys 308: 89-95, 1994 https://doi.org/10.1006/abbi.1994.1013
  28. Singh NP, McCoy MT, Tice RR, Schneider EL. A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175: 184-91, 1988 https://doi.org/10.1016/0014-4827(88)90265-0
  29. Taimor G, Hofstaetter B, Piper HM. Apoptosis induction by nitric oxide in adult cardiomyocytes via cGMP-signaling and its impairment after simulated ischemia. Cardiovasc Res 45: 588-594, 2000 https://doi.org/10.1016/S0008-6363(99)00272-2
  30. Vila-Petroff MG, Younes A, Egan J, Lakatta EG, Sollott SJ. Activation of distinct cAMP-dependent and cGMP-dependent pathways by nitric oxide in cardiac myocytes. Circ Res 84: 1020- 1031, 1999 https://doi.org/10.1161/01.RES.84.9.1020