Sumatriptan protects against myocardial ischaemia–reperfusion injury by inhibition of inflammation in rat model

Abstract

Ischemic heart disease is a leading cause of death on a global scale, placing major socio-economic burdens on health systems worldwide. Myocardial ischaemia and reperfusion (I/R)-induced tissue injury is associated with alteration in activity of inflammatory system and nitric oxide pathway. Sumatriptan, which is mainly used to relieve migraine headache, has recently been shown to exert anti-inflammatory properties. In this study, we aimed to assess the possible cardioprotective effect of sumatriptan in a rat model of I/R injury. Male Wistar rats were subjected to 30-min ligation of left anterior descending coronary artery and 120-min reperfusion. Animals were randomly divided into five groups: (1) Sham (2) I/R (3) I/R treated with sumatriptan (0.3 mg/kg i.p.) 20 min after induction of I/R rats, (4) GR127935 (a selective antagonist of 5-HT1B/D serotonin receptors; 0.3 mg/kg) 20 min after induction of I/R, and (5) GR127935 (0.3 mg/kg) 15 min before administration of sumatriptan. Post-infarct treatment with sumatriptan increased left ventricular function, which was damaged in I/R animal’s heart. Sumatriptan (0.3 mg/kg) decreased lipid peroxidation, CK-MB and lactate dehydrogenase levels; tumor necrosis factor concentration; and Nf-ҡB’ protein production. Treatment with sumatriptan significantly increased the endothelial nitric oxide synthase (eNOS) expression consequences nitric oxide metabolites’ level in I/R rats. Also, injection of sumatriptan remarkably decreased myocardial tissue injury assessed by histopathological study. These findings suggest that sumatriptan may attenuate I/R injury via modulating the inflammatory responses and endothelial NOS activity. But therapeutic index of sumatriptan is narrow according to the result of this study.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

taken from a sham-operated rat (a); a heart tissue of rat subjected to myocardial ischaemia/reperfusion (I/R) (b); a heart section taken from a rat subjected to myocardial I/R administered sumatriptan (c); a heart section taken from a rat subjected to myocardial I/R administered GR-127935 (d); and I/R co-administered GR-127935 with sumatriptan (e). Hematoxylin and eosin, original magnification × 150

References

  1. Ambrose JA, Singh M (2015) Pathophysiology of coronary artery disease leading to acute coronary syndromes. F1000Prime Rep 7:08

  2. Araldi D, Ferrari LF, Levine JD (2016) Gi-protein coupled 5-HT1B/D receptor agonist sumatriptan induces type I hyperalgesic priming. Pain 157(8):1773

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. Azizi Y, Faghihi M, Imani A et al (2013) Post-infarct treatment with [Pyr1]-apelin-13 reduces myocardial damage through reduction of oxidative injury and nitric oxide enhancement in the rat model of myocardial infarction. Peptides 46:76–82

    CAS  PubMed  Article  Google Scholar 

  4. Barnes NM, Neumaier JF (2011) Neuronal 5-HT receptors and SERT. Tocris Biosci Sci Rev Ser 34:1–16

    Google Scholar 

  5. Brahadeesh M, Suresha RN (2016) Screening of the drug amiodarone for its antiinflammatory potential in albino rats. IJPLS:7(5):5042–5046

    Google Scholar 

  6. Buja LM (2005) Myocardial ischaemia and re perfusion injury. Cardiovasc Pathol 14(4):170–175

    CAS  PubMed  Article  Google Scholar 

  7. De Felice M, Ossipov MH, Wang R et al (2010) Triptan-induced enhancement of neuronal nitric oxide synthase in trigeminal ganglion dural afferents underlies increased responsiveness to potential migraine triggers. Brain 133(8):2475–2488

    PubMed  PubMed Central  Article  Google Scholar 

  8. Dhalla NS, Golfman L, Takeda S et al (1999) Evidence for the role of oxidative stress in acute ischaemic heart disease: a brief review. Can J Cardiol 15(5):587–593

    CAS  PubMed  Google Scholar 

  9. Dobutović B, Smiljanić K, Soskić S et al (2011) Nitric oxide and its role in cardiovascular diseases. Open Nitric Oxide J 3(3):65–71

    Article  Google Scholar 

  10. Förstermann U (2010) Nitric oxide and oxidative stress in vascular disease. Pflugers Arch 459(6):923–939

    PubMed  Article  Google Scholar 

  11. Frangogiannis NG, Smith CW, Entman ML (2002) The inflammatory response in myocardial infarction. Cardiovascular res 53(1):31–47

    CAS  Article  Google Scholar 

  12. Grønholdt M, Dalager-Pedersen S, Falk E (1998) Coronary atherosclerosis: determinants of plaque rupture. Eur Heart J 19:C24–C29

    PubMed  Google Scholar 

  13. Haddadi NS, Foroutan A, Shakiba S et al (2018) Attenuation of serotonin-induced itch by sumatriptan: possible involvement of endogenous opioids. Arch Dermatol Res 310(2):165–172

    CAS  PubMed  Article  Google Scholar 

  14. Humphrey P, Goadsby P (1994) The mode of action of sumatriptan is vascular? A debate. Cephalalgia 14(6):401–410

    CAS  PubMed  Article  Google Scholar 

  15. Ibáñez B, Heusch G, Ovize M et al (2015) Evolving therapies for myocardial ischaemia/re perfusion injury. J Am Coll Cardiol 65(14):1454–1471

    PubMed  Article  Google Scholar 

  16. Ikeda Y, Jimbo H, Shimazu M et al (2002) Sumatriptan scavenges superoxide, hydroxyl, and nitric oxide radicals: in vitro electron spin resonance study. Headache 42(9):888–892

    PubMed  Article  Google Scholar 

  17. Oyama J-i, Blais C, Liu X et al (2004) Reduced myocardial ischaemia–re perfusion injury in toll-like receptor 4-deficient mice. Circulation 109(6):784–789

    CAS  PubMed  Article  Google Scholar 

  18. Kaminski KA, Bonda TA, Korecki J et al (2002) Oxidative stress and neutrophil activation—the two keystones of ischaemia /re perfusion injury. Int J Cardiol 86(1):41–59

    PubMed  Article  Google Scholar 

  19. Khalilzadeh M, Panahi G, Rashidian A et al (2018) The protective effects of sumatriptan on vincristine-induced peripheral neuropathy in a rat model. Neurotoxicology 67:279–286

    CAS  PubMed  Article  Google Scholar 

  20. Mohammad-Zadeh L, Moses L, Gwaltney-Brant S (2008) Serotonin: a review. J Vet Pharmacol Ther 31(3):187–199

    CAS  PubMed  Article  Google Scholar 

  21. Murphy E, Steenbergen C (2008) Mechanisms underlying acute protection from cardiac ischaemia -re perfusion injury. Physiol Rev 88(2):581–609

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Nazari A, Sadr SS, Faghihi M, Azizi Y et al (1999) Evidence for the role of oxidative stress in acute ischaemic heart disease: a brief review. Can J Cardiol 15(5):587–593

    Google Scholar 

  23. Nikai T, Basbaum AI, Ahn AH (2008) Profound reduction of somatic and visceral pain in mice by intrathecal administration of the anti-migraine drug, sumatriptan. Pain 139(3):533–540

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Rawlins J, Wilkinson J, Curzen N (2014) Evidence for benefit of percutaneous coronary intervention for chronically occluded coronary arteries (CTO)–clinical and health economic outcomes. Interv Cardiol 9(3):190

    PubMed  PubMed Central  Google Scholar 

  25. Roberts C, Price GW, Middlemiss DN (2001) Ligands for the investigation of 5-HT autoreceptor function. Brain Res Bull 56(5):463–469

    CAS  PubMed  Article  Google Scholar 

  26. Rutz S, Riegert C, Rothmaier AK et al (2006) Presynaptic serotonergic modulation of 5-HT and acetylcholine release in the hippocampus and the cortex of 5-HT1B-receptor knockout mice. Brain Res Bull 70(1):81–93

    CAS  PubMed  Article  Google Scholar 

  27. Schulz R, Kelm M, Heusch G (2004) Nitric oxide in myocardial ischaemia /re perfusion injury. Send to Cardiovasc Res 61(3):402–413

    CAS  Article  Google Scholar 

  28. Siegfried MR, Erhardt J, Rider T et al (1992) Cardioprotection and attenuation of endothelial dysfunction by organic nitric oxide donors in myocardial ischaemia-re perfusion. J Pharmacol Exp Ther 260(2):668–675

    CAS  PubMed  Google Scholar 

  29. Skingle M, Beattie DT, Scopes DI et al (1995) GR127935: a potent and selective 5-HT1D receptor antagonist. Behav Brain Res 73(1–2):157–161

    CAS  Article  Google Scholar 

  30. Turer AT, Hill JA (2010) Pathogenesis of myocardial ischaemia-re perfusion injury and rationale for therapy. Am J Cardiol 106(3):360–368

    PubMed  PubMed Central  Article  Google Scholar 

  31. Vanhoutte PM (1987) Serotonin and the vascular wall. Int J Cardiol 14(2):189–203

    CAS  PubMed  Article  Google Scholar 

  32. Vera-Portocarrero LP, Ossipov MH, King T et al (2008) Reversal of inflammatory and noninflammatory visceral pain by central or peripheral actions of sumatriptan. Gastroenterology 135(4):1369–1378

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Wang J, Huang W, Xu R et al (2012) MicroRNA-24 regulates cardiac fibrosis after myocardial infarction. J Cell Mol Med 16(9):2150–2160

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Yang J, Jiang H, Yang J et al (2009) Valsartan preconditioning protects against myocardial ischaemia-re perfusion injury through TLR4/NF-κB signalling pathway. Mol Cell Biochem 330(1–2):39

    CAS  PubMed  Article  Google Scholar 

  35. Yeh C-H, Chen T-P, Wu Y-C et al (2002) The inflammatory response in myocardial infarction. Cardiovascular Res 53(1):31–47

    Article  Google Scholar 

  36. Yin Y, Guan Y, Duan J et al (2013) Cardioprotective effect of Danshensu against myocardial ischaemia/re perfusion injury and inhibits apoptosis of H9c2 cardiomyocytes via Akt and ERK1/2 phosphorylation. Eur J Pharmacol 699(1–3):219–226

    CAS  PubMed  Article  Google Scholar 

  37. Zhao Z-Q, Corvera JS, Halkos ME et al (2003) Inhibition of myocardial injury by ischaemic postconditioning during re perfusion: comparison with ischaemic preconditioning. Am J Physiol Heart Circ Physiol 285(2):H579–H588

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

This study was funded by Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; grant no. 97-01-158-37318, and by a grant (96002757) from Iran National Science Foundation (INSF).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Ahmad Reza Dehpour.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sheibani, M., Faghir-Ghanesefat, H., Dehpour, S. et al. Sumatriptan protects against myocardial ischaemia–reperfusion injury by inhibition of inflammation in rat model. Inflammopharmacol 27, 1071–1080 (2019). https://doi.org/10.1007/s10787-019-00586-5

Download citation

Keywords

  • Sumatriptan
  • ischaemia/reperfusion
  • Cardioprotective
  • Inflammation