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Nicorandil Protects Against Lethal Ischemic Ventricular Arrhythmias and Up-regulates Endothelial Nitric Oxide Synthase Expression and Sulfonylurea Receptor 2 mRNA in Conscious Rats with Acute Myocardial Infarction

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Abstract

Nicorandil is an adenosine triphosphate sensitive K (K-ATP) channel opener and a nitric oxide donor. K-ATP channels and nitric oxide are important factors in ischemic preconditioning, which in turn suppresses reperfusion arrhythmias. The present study sought to evaluate whether nicorandil suppresses ischemic-induced ventricular arrhythmias and enhances sulfonylurea receptors (SUR 2; subunit of K-ATP channel), endothelial nitric oxide (eNOS), and inducible nitric oxide (iNOS) expression in the left ventricle after myocardial infarction without reperfusion. Thirty male Sprague-Dawley rats at 7 weeks of age were separated into three groups, as follows. Acute myocardial infarction was induced in twenty rats by ligating the left main coronary artery. Ten of these twenty rats were continuously administered nicorandil at 3 mg/kg/day i.p. The other ten rats were left untreated. The ten controls were untreated and sham-operated. After coronary ligation, ventricular arrhythmias were evaluated from stored ECG signals. At 24 hours after treatment, eNOS, iNOS, and SUR2 mRNA levels and eNOS, iNOS expression in the left ventricle were determined by reverse transcription polymerase chain reaction (RT-PCR) and by immunohistochemical staining, respectively. Nicorandil suppressed the total number of ventricular arrhythmias from 1 to 2 hours, the total duration of ventricular tachycardia from 2 to 3 hours, and that of ventricular fibrillation from 1 to 2 and from 4 to 5 hours after coronary ligation. Nicorandil improved the survival rate 24 hours after coronary ligation. Levels of SUR2 mRNA increased only in left ventricles treated with nicorandil, particularly in the non-ischemic myocardium. eNOS mRNA was enhanced 2.2-fold in the area at risk in infarcted controls compared to sham-operated rats. In the non-ischemic area and area at risk of rats treated with nicorandil compared to sham-operated rats, eNOS mRNA was enhanced 3.3- and 2.7-fold, respectively. Staining indicated that the highest concentrations of eNOS occurred in the endothelium and myocardium of the non-ischemic area of rats treated with nicorandil. iNOS mRNA was present in both the area at risk and the non-ischemic area only in infarcted rats, and levels thereof were higher in the area at risk than in the non-ischemic area. However, there was no difference in iNOS mRNA levels between nicorandil-treated rats and controls. iNOS exhibited stronger staining in the area at risk than in the non-ischemic area of both nicorandil-treated and infarcted controls, with no differences between these two groups of rats. The mechanisms of protection against lethal ventricular tachyarrhythmia in nicorandil may increase nitric oxide release by upregulated eNOS expression through the opening of K-ATP channels and/or a K-ATP channels opener itself after acute myocardial infarction.

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References

  1. Taira N. Nicorandil as a hybrid between nitrates and potassium channel activators. Am J Cardiol 1989;63:18J–24J.

    Article  CAS  PubMed  Google Scholar 

  2. Holzmann S. Cyclic GMP as possible mediator of coronary arterial relaxation by Nicorandil (SG-75). J Cardiovasc Pharmacol 1983;5:364–370.

    CAS  PubMed  Google Scholar 

  3. Grover GJ. Pharmacology of ATP-sensitive potassium channel (KATP) openers in models of myocardial ischemia and reperfusion. Can J Physiol Pharmacol 1997;75:309–315.

    Article  CAS  PubMed  Google Scholar 

  4. Ohno Y, Minatoguchi S, Uno Y, et al. Nicorandil reduces myocardial infarct size by opening the KATP channel in rabbits. Int J Cardiol 1997;62:181–190.

    Article  CAS  PubMed  Google Scholar 

  5. Schultz JE, Yao Z, Cavero I, et al. Glibenclamide-induced blockade of ischemic preconditioning is time dependent in intact rat heart. Am J Physiol 1997;272:H2607–H2615.

    CAS  PubMed  Google Scholar 

  6. Nakae I, Quan L, Hashimoto K, et al. Mechanism of the vasodilatory action of nicorandil on coronary circulation in dog. Cardiovasc Drug Ther 1994;8:137–145.

    Article  CAS  Google Scholar 

  7. Ashikawa K, Komaru T, Sekiguchi N, et al. Evaluation of coronary microcirculation in the beating canine left ventricle. J Jpn Coll Angiol 1989;29:337–341.

    Google Scholar 

  8. Di Diego JM, Antzelevitch C. Pinacidil-induced electrical heterogeneity and extrasystolic activity in canine ventricular tissues. Does activation of ATP-regulated potassium current promote phase 2 reentry? Circulation 1993;88:1177–1189.

    CAS  PubMed  Google Scholar 

  9. Lepran I, Baczko I, Varro A, et al. ATP-sensitive potassium channel modulators: Both pinacidil and glibenclamide produce antiarrhythmic activity during acute myocardial infarction in conscious rats. J Pharmacol Exp Ther 1996;277:1215–1220.

    CAS  PubMed  Google Scholar 

  10. 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.

    CAS  PubMed  Google Scholar 

  11. Horinaka S, Kobayashi N, Higashi T, et al. Nicorandil enhances cardiac endothelial NO synthase expression via activation of ATP sensitive K channel in rat. J Cardiovasc Pharmacol 2001;38:200–210.

    Article  CAS  PubMed  Google Scholar 

  12. Clark C, Foreman MI, Kane KA, et al. Coronary artery ligation in anesthetized rats as a method for the production of experimental dysrhythmias and for the determination of infarct size. J Pharmacol Methods 1980;3:357–368.

    Article  CAS  PubMed  Google Scholar 

  13. Song W, Furman BL, Parratt JR. Delayed protection against ischemia-induced ventricular arrhythmias and infarct size limitation by the prior administration of Escherichia coli endotoxin. Br J Pharmacol 1996;118:2157–2163.

    CAS  PubMed  Google Scholar 

  14. Chomezynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987;162:156–159.

    PubMed  Google Scholar 

  15. Hattori Y, Gross SS. GTP cyclohydrolase I mRNA is induced by LPS in vascular smooth muscle: Characterization, sequence and relationship to nitric oxide synthase. Biochem Biophys Res Commun 1993;195:435–441.

    Article  CAS  PubMed  Google Scholar 

  16. Seki T, Naruse M, Naruse K, et al. Gene expression of endothelial type isoform of nitric oxide synthase in various tissues of stroke-prone spontaneously hypertensive rats. Hypertens Res 1997;20:43–49.

    CAS  PubMed  Google Scholar 

  17. Nunokawa Y, Ishida N, Tanaka S. Cloning of inducible nitric oxide synthase in rat vascular smooth muscle cells. Biochem Biophys Res Commun 1993;191:89–94.

    Article  CAS  PubMed  Google Scholar 

  18. Akao M, Otani H, Horie M, et al. Myocardial ischemia induces differential regulation of K-ATP channel gene expression in rat hearts. J Clin Invest 1997;100:3053–3059.

    CAS  PubMed  Google Scholar 

  19. Terada Y, Tomita K, Nonoguchi H, et al. Polymerase chain reaction localization of constitutive nitric oxide synthase and soluble guanylate cyclase messenger RNAs in microdissected rat nephron segments. J Clin Invest 1992;90:659–665.

    CAS  PubMed  Google Scholar 

  20. Hattori Y, Akimoto K, Murakami Y, et al. Pyrrolidine dithiocarbamate inhibits cytokine-induced VCAM-1 gene expression in rat cardiac myocytes. Mol Cell Biochem 1997;177:177–181.

    Article  CAS  PubMed  Google Scholar 

  21. Kobayashi N, Kobayashi K, Hara K, et al. Benidipine stimulates nitric oxide synthase and improves coronary circulation in hypertensive rats. Am J Hypertens 1999;12:483–491.

    Article  CAS  PubMed  Google Scholar 

  22. Takanohashi A, Tojo A, Kobayashi N, et al. Effect of trichlormethiazide and captopril on nitric oxide synthase activity in the kidney of deoxycorticosterone acetate-salt hypertensive rats. Jpn Heart J 1996;37:251–259.

    CAS  PubMed  Google Scholar 

  23. Mizumura T, Nithipatikom K, Gross GL. Bimakalim, an ATP-sensitive potassium channel opener, mimics the effects of ischemic preconditioning to reduced infarct size, adenosine release, and neutrophil function in dogs. Circulation 1995;92:1236–1245.

    CAS  PubMed  Google Scholar 

  24. Das B, Sarker C, Karanth S. Selective mitochondrial KATP channel activation results in antiarrhythmic effect during experimental myocardial ischemia/reperfusion in anesthetized rabbits. Eur J Pharmacol 2002;5–71.

  25. Takimoto Y, Aoyama T, Keyamura R, et al. Differential expression of three types of nitric oxide synthase in both infarcted and non-infarcted left ventricles after myocardial infarction in the rat. Int J Cardiol 2000;76:135–145.

    Article  CAS  PubMed  Google Scholar 

  26. Gourine AV, Gonon AT, Pernow J. Involvement of nitric oxide in cardioprotective effect of endothelin receptor antagonist during ischemia-reperfusion. Am J Physiol Heart Circ Physiol 2001;280:H1105–H1112.

    CAS  PubMed  Google Scholar 

  27. Sumeray MS, Rees DD, Yellon DM. Infarct size and nitric oxide synthase in murine myocardium. J Mol Cell Cardiol 2000;32:35–42.

    Article  CAS  PubMed  Google Scholar 

  28. 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  CAS  PubMed  Google Scholar 

  29. The 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.

    Google Scholar 

  30. Shindo T, Yamada M, Isomoto S, et al. SUR2 subtype (A and B)-dependent differential activation of the cloned ATP-sensitive K+ channels by pinacidil and nicorandil. Br J Pharmacol 1998:124;985–991.

    Article  CAS  PubMed  Google Scholar 

  31. Palmer RMZ, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 1988;333:664–666.

    CAS  PubMed  Google Scholar 

  32. Kubes P, Suzuki M Granger DN. Nitric oxide: An endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 1991:88;4615–4655.

    Google Scholar 

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Authors and Affiliations

  1. Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi, 321-0293, Japan

    Shigeo Horinaka, Naohiko Kobayashi, Akihisa Yabe, Hiroshi Asakawa, Hiroshi Yagi, Yousuke Mori, Yusuke Tsubokou, Koutarou Yoshida, Shigefumi Nakano & Hiroaki Matsuoka

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  1. Shigeo Horinaka
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  2. Naohiko Kobayashi
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  3. Akihisa Yabe
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  4. Hiroshi Asakawa
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  5. Hiroshi Yagi
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  6. Yousuke Mori
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  7. Yusuke Tsubokou
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  9. Shigefumi Nakano
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  10. Hiroaki Matsuoka
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Horinaka, S., Kobayashi, N., Yabe, A. et al. Nicorandil Protects Against Lethal Ischemic Ventricular Arrhythmias and Up-regulates Endothelial Nitric Oxide Synthase Expression and Sulfonylurea Receptor 2 mRNA in Conscious Rats with Acute Myocardial Infarction. Cardiovasc Drugs Ther 18, 13–22 (2004). https://doi.org/10.1023/B:CARD.0000025751.82774.a9

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  • DOI: https://doi.org/10.1023/B:CARD.0000025751.82774.a9

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