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Sepiapterin reduces postischemic injury in the rat heart

  • Cardiovascular System
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Abstract

A reduced availability of tetrahydrobiopterin (BH4), an essential cofactor for NO-synthesis, is causally involved in the development of endothelial dysfunction associated with ischemia/reperfusion. We, therefore, investigated the effect of sepiapterin, a substrate for BH4 synthesis, on postischemic injury in myocardial infarction and myocardial stunning. In rats, myocardial stunning was induced by repetitive ischemia (5×10-min ligature of the left coronary artery, 5×20-min reperfusion) and myocardial infarction by 50-min ligature and 60-min reperfusion. Myocardial blood flow was determined by H2-clearance, regional myocardial function by pulsed Doppler and infarct size by tetrazolium staining. Myeloperoxidase (MPO) activity was measured as a marker of neutrophil extravasation. cGMP was determined in rat serum as an indicator of increased NO synthesis. In animals treated with sepiapterin, regional myocardial function was significantly improved in both myocardial stunning and infarction and infarct size was significantly reduced. MPO activity decreased with sepiapterin treatment in both models. The systemic level of cGMP was reduced both following myocardial stunning and myocardial infarction in the control group. Pretreatment with sepiapterin induced a significant increase of cGMP level at the end of the protocol in both models. Substitution of sepiapterin reduces postischemic injury both in myocardial stunning and infarction apparently by ameliorating the availability of NO, thereby attenuating the activation of neutrophils in ischemia/reperfusion.

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References

  1. Aukland K, Bower BF, Berliner RW (1964) Measurement of local blood flow with hydrogen gas. Circ Res 14:164–187

    CAS  Google Scholar 

  2. Bolli R (1990) Mechanism of myocardial "stunning". Circulation 82(3):723–738

    CAS  PubMed  Google Scholar 

  3. Cosentino F, Katusic ZS (1995) Tetrahydrobiopterin and dysfunction of endothelial nitric oxide synthase in coronary arteries. Circulation 91:139–144

    CAS  PubMed  Google Scholar 

  4. Flogel U, Decking UK, Godecke A, Schrader J (1999) Contribution of NO to ischemia reperfusion injury in the saline-perfused heart: a study in endothelial NO synthase knockout mice. J Mol Cell Cardiol 31(4):827–836

    Article  CAS  PubMed  Google Scholar 

  5. Hartley CJ, Latson LA, Michael LH, Seidel CL, Lewis RM, Entman ML (1983) Doppler measurement of myocardial thickening with a single epicardial transducer. Am J Physiol 245:H1066–H1072

    CAS  PubMed  Google Scholar 

  6. Heusch G, Post H, Michel MC, Kelm M, Schulz R (2000) Endogenous nitric oxide and myocardial adaptation to ischemia. Circ Res 87(2):146–152

    CAS  PubMed  Google Scholar 

  7. Ishii M, Shimizu S, Momose K, Yamamoto T (1999) SIN-1-induced cytotoxicity in cultured endothelial cells involves reactive oxygen species and nitric oxide: protective effect of sepiapterin. J Cardiovasc Pharmacol 33(2):295–300

    Article  CAS  PubMed  Google Scholar 

  8. Ishii M, Shimizu S, Nawata S, Kiuchi Y, Yamamoto T (2000) Involvement of reactive oxygen species and nitric oxide in gastric ischemia-reperfusion injury in rats: protective effect of tetrahydrobiopterin. Dig Dis Sci 45(1):93–98

    Article  CAS  PubMed  Google Scholar 

  9. Jones SP, Girod WG, Palazzo AJ, Granger DN, Grisham MB, Jourd'Heuil D, Huang PL, Lefer DJ (1999) Myocardial ischemia-reperfusion injury is exacerbated in absence of endothelial cell nitric oxide synthase. Am J Physiol 276(5 Pt 2):H1567–H1573

    CAS  PubMed  Google Scholar 

  10. Kakoki M, Hirata Y, Hayakawa H, Suzuki E, Nagata D, Tojo A, Nishimatsu H, Nakanishi N, Hattori Y, Kikuchi K, Nagano T, Omata M (2000) Effects of tetrahydrobiopterin on endothelial dysfunction in rats with ischemic acute renal failure. J Am Soc Nephrol 11(2):301–309

    CAS  PubMed  Google Scholar 

  11. Lefer J, Jones SP, Girod WG, Baines A, Grisham MB, Cockrell AS, Huang PL, Scalia R (1999) Leukocyte-endothelial cell interactions in nitric oxide synthase-deficient mice. Am J Physiol 276(6 Pt 2):H1943–H1950

    CAS  PubMed  Google Scholar 

  12. Liu YH, Yang XP, Sharov VG, Sigmon DH, Sabbah DN, Carretero OA (1996) Paracrine systems in the cardioprotective effect of angiotensin-converting enzyme inhibitors on myocardial ischemia/reperfusion injury in rats. Hypertension 27:7–13

    Google Scholar 

  13. Liu P, Hock CE, Nagele R, Wong PY (1997) Function of nitric oxide, superoxide, and peroxynitrite in myocardial ischemia-reperfusion injury in rats. Am J Physiol 272(5 Pt 2):H2327–H2336

    CAS  PubMed  Google Scholar 

  14. Mayer B, Werner ER (1995) In search of a function for tetrahydrobiopterin in the biosynthesis of nitric oxide. Naunyn Schmiedebergs Arch Pharmacol 351:453–463

    CAS  PubMed  Google Scholar 

  15. Mehta J, Dinerman J, Mehta P, Saldeen TG, Lawson D, Donnelly WH, Wallin R (1989) Neutrophil function in ischemic heart disease. Circulation 79(3):549–556

    CAS  PubMed  Google Scholar 

  16. Neumann FJ, Tiefenbacher C, Mohler T, Ott I, Parekh N, Steinhausen M, Tillmanns H (1991) Decreased myocardial blood flow after repetitive ischemia and reperfusion of the rat heart: Cause or consequence of myocardial stunning? Circulation 84 [Suppl. II]:656

  17. Patel VC, Yellon DM, Singh KJ, Neild GH, Woolfson RG (1993) Inhibition of nitric oxide limits infarct size in the in situ rabbit heart. Biochem Biophys Res Commun 194:234–238

    Article  CAS  PubMed  Google Scholar 

  18. Riddell DR, Owen JS (1999) Nitric oxide and platelet aggregation. Vitam Horm 57:25–48

    CAS  PubMed  Google Scholar 

  19. Romson JL, Hook BG, Kunkel SL, Abrams GD, Schork MA, Lucchesi BR (1983) Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog. Circulation 67(5):1016–1023

    CAS  PubMed  Google Scholar 

  20. Schmid RA, Hillinger S, Walter R, Zollinger A, Stammberger U, Speich R, Schaffner A, Weder W, Schoedon G (1999) The nitric oxide synthase cofactor tetrahydrobiopterin reduces allograft ischemia-reperfusion injury after lung transplantation. J Thorac Cardiovasc Surg 118(4):726–732

    CAS  PubMed  Google Scholar 

  21. Simpson PJ, Todd RF 3rd, Mickelson JK, Fantone JC, Gallagher KP, Lee KA, Tamura Y, Cronin M, Lucchesi BR (1990) Sustained limitation of myocardial reperfusion injury by a monoclonal antibody that alters leukocyte function. Circulation 81(1):226–237

    CAS  PubMed  Google Scholar 

  22. Sirsjö A, Nylander G, Lewis DH (1988) Myeloperoxidase as a measure of polymorphonuclear leukocyte (PMNL) content in ischaemic-reperfused rat sceletal muscle [Abstract]. Int J Microcirc Clin Exp 7:192

    Google Scholar 

  23. Stroes E, Kastelein J, Cosentino F, Erkelens W, Wever R, Koomans H, Luscher T, Rabelink T (1997) Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest 99(1):41–46

    CAS  PubMed  Google Scholar 

  24. Stroes E, Hijimering M, van Zandvoort M, Wever R, Rabelink TJ, van Faassen EE (1998) Origin of superoxide production by endothelial nitric oxide synthase. FEBS Lett 438(3):161–164

    CAS  PubMed  Google Scholar 

  25. Takeuchi K, McGowan FX, Danh HC, Glynn P, Simplaceanu E, del Nido PJ (1995) Direct detrimental effects of L-arginine upon ischemia-reperfusion injury to myocardium. J Mol Cell Cardiol 27:1405–1414

    Article  CAS  PubMed  Google Scholar 

  26. Tiefenbacher CP (2001) Tetrahydrobiopterin: a critical cofactor for eNOS and a strategy in the treatment of endothelial dysfunction? Am J Physiol 280:H2484–H2488

    Google Scholar 

  27. Tiefenbacher CP, Chilian WM, Mitchell M, Defily DV (1996) Restoration of endothelium-dependent vasodilation after reperfusion injury by tetrahydrobiopterin. Circulation 94:1423–1429

    CAS  PubMed  Google Scholar 

  28. Tiefenbacher CP, Ebert M, Niroomand F, Batkai S, Tillmanns H, Zimmermann R, Kübler W (1997) Inhibition of elastase improves myocardial function after repetitive ischaemia and myocardial infarction in the rat heart. Pflugers Arch 433:563–570

    Article  CAS  PubMed  Google Scholar 

  29. Vasquez-Vivar J, Kalyanamaran B, Martasek P, Hogg N, Siler Master BS, Karoui H, Tordos P, Pritchard KA Jr (1998) Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci USA 95:9220–9225

    CAS  PubMed  Google Scholar 

  30. Wang D, Yang XP, Liu YH, Carretero OA, LaPointe MC (1999) Reduction of myocardial infarct size by inhibition of inducible nitric oxide synthase. Am J Hypertens 12:174–182

    Article  CAS  PubMed  Google Scholar 

  31. Wang P, Zweier JL (1996) Measurement of nitric oxide and peroxynitrite generation in the postischemic heart. Evidence for peroxynitrite-mediated reperfusion injury. J Biol Chem15 271(46):29223–29230

    Article  CAS  Google Scholar 

  32. Wang QD, Morcos E, Wiklund P, Pernow J (1997)L-Arginine enhances functional recovery and Ca(2+)-dependent nitric oxide synthase activity after ischemia and reperfusion in the rat heart. J Cardiovasc Pharmacol 29(2):291–296

    Article  CAS  PubMed  Google Scholar 

  33. Wildhirt SM, Suzuki H, Wolf WP, Dudek R, Horstman D, Weismueller S, Reichart B (1996) S-Methylisothiourea inhibits inducible nitric oxide synthase and improves left ventricular performance after acute myocardial infarction. Biochem Biophys Res Commun 227:328–333

    Article  CAS  PubMed  Google Scholar 

  34. Xie YW, Wolin MS (1996) Role of nitric oxide and its interaction with superoxide in the suppression of cardiac muscle mitochondrial respiration. Involvement in response to hypoxia/reoxygenation. Circulation 15 94(10):2580–2586

    CAS  Google Scholar 

  35. Yasmin W, Strynadka KD, Schulz R (1997) Generation of peroxynitrite contributes to ischemia-reperfusion injury in isolated rat hearts. Cardiovasc Res 33(2):422–432

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by a grant from the Deutsche Forschungsgemeinschaft (C.P.T.).

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Correspondence to Christiane P. Tiefenbacher.

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Tiefenbacher, C.P., Lee, CH., Kapitza, J. et al. Sepiapterin reduces postischemic injury in the rat heart. Pflugers Arch - Eur J Physiol 447, 1–7 (2003). https://doi.org/10.1007/s00424-003-1131-y

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  • DOI: https://doi.org/10.1007/s00424-003-1131-y

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