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Effectiveness of nicorandil in the preservation of myocardium stressed by transient ischemia and its influence on cardiac metabolism during coronary artery occlusion with subsequent reperfusion: a comparison with isosorbide dinitrate

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Summary

This study was designed to investigate the effects of nicorandil in comparison to isosorbide dinitrate (ISDN) on hemodynamics, on myocardial metabolism and on effectiveness in the preservation of ischemically stressed myocardium.

Repeated ischemia (3 min) was produced in anaesthetized open-chest mongrel dogs by proximal, intermittent left anterior descending artery occlusion with subsequent reperfusion. In each experiment 2–3 control occlusions were compared to 2–3 occlusions under nicorandil or ISDN. Application of both nicorandil (0.64 μmol·kg−1 body weight, i.v.) and ISDN (1.27 μmol·kg−1 body weight, i.v.) led to a significant afterload reduction and to a decrease of the coronary vascular resistance. The efficiency of the compounds in the protection of ischemic myocardium was examined by quantification of oxygen-debt and oxygen-repayment in the occlusion and reperfusion periods. Compared to control, premedication with nicorandil led to a significant increase of oxygen-debt, whereas ISDN reduced it significantly. Oxygen-repayment remained unchanged. The influence of the drugs on the metabolism of glucose, lactate and free fatty acids (FFA) was examined under basic conditions, in ischemia and during reperfusion. For all substrates, extraction, extraction ratio and oxygen extraction ratio were calculated. Under basic conditions, glucose metabolism was significantly enhanced in both groups but FFA metabolism was inhibited only by ISDN. In ischemia, FFA metabolism was enhanced by nicorandil and depressed by ISDN.

Data obtained in this study suggest that nicorandil may even aggravate the metabolic and energetic situation of ischemic myocardium and, on the other hand, clearly support the well documented protective effects of ISDN.

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Abbreviations

CO:

cardiac output

CVR:

coronary vascular resistance

Et :

myocardial energy demand

EX:

extraction

EXR:

extraction ratio

FFA:

free fatty acids

ISDN:

isosorbide dinitrate

LAD:

left anterior descending artery

MBF:

myocardial blood flow

MVO2 :

myocardial oxygen consumption

OER:

oxygen extraction ratio

PVR:

peripheral vascular resistance

References

  • Abiko Y, Nishimura T, Sakai K (1984) Nicorandil attenuates myocardial acidosis during coronary occlusion in dogs. Br J Pharmacol 81:409–411

    Google Scholar 

  • Baller D, Bretschneider HJ, Hellige G (1979) Validity of myocardial oxygen consumption parameters. Clin Cardiol 2:317–327

    Google Scholar 

  • Becker LC, Fortuin NJ, Pitt B (1971) Effect of ischemia and anti-anginal drugs on the distribution of radioactive microspheres in the canine left ventricle. Circ Res 28:263–269

    Google Scholar 

  • Bergmeyer HU (1974) Methoden der enzymatischen Analyse. Verlag Chemie, Weinheim/Bergstraße

    Google Scholar 

  • Bleifeld W, Wende W, Bussmann WD, Meyer J (1973) Influence of nitroglycerin on the size of experimental myocardial infarction. Naunyn-Schmiedeberg's Arch Pharmacol 277:387–400

    Google Scholar 

  • Capurro NL, Kent KM, Smith HJ, Aamodt R, Epstein SE (1977) Acute coronary occlusion: prolonged increase in collateral flow following brief administration of nitroglycerin and methoxamine. Am J Cardiol 39:679–683

    Google Scholar 

  • DeLeiris J, Opie LH, Lubbe WF (1975) Effects of free fatty acids and glucose on enzyme release in experimental myocardial infarction. Nature 253:746–747

    Google Scholar 

  • Fam WM, McGregor M (1964) Effect of coronary vasodilator drugs on retrograde flow in areas of chronic myocardial ischemia. Circ Res 15:355–362

    Google Scholar 

  • Furukawa K, Itoh T, Kajiwara M, Kitamura K, Suzuki H, Ito Y, Kuriyama H (1981) Vasodilating actions of 2-nicotinamidoethyl nitrate on porcine and guinea-pig coronary arteries. J Pharmacol Exp Ther 218:248–259

    Google Scholar 

  • Henderson HH, Most A, Parmley WW, Gorlin R, Sonnenblick EH (1970) Depression of myocardial contractility in rats by free fatty acids during hypoxia. Circ Res 26:439–449

    Google Scholar 

  • Hoeft A, Korb H, Baller D, Wolpers HG, Hellige G, Bretschneider HJ (1984) Quantification of ischemic stress during repeated coronary artery occlusion in the dog. A method for validation of therapeutic effects. I. Estimation of O2-debt and O2-repayment. Basic Res Cardiol 79:27–37

    Google Scholar 

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

    Google Scholar 

  • Hombach V, Jansen WC, Behrenbeck DW, Tauchert M, Höpp HW, Niehues B, Hilger HH (1982) Systemische und koronare Hämodynamik und Myokardstoffwechsel unter pharmakologischer und ergometrischer Belastung. Herz/Kreislauf 12:639–652

    Google Scholar 

  • Horwitz LD, Gorlin R, Taylor WJ, Kemp HG (1971) Effect of nitroglycerin on regional myocardial blood flow in coronary artery disease. J Clin Invest 50:1578–1584

    Google Scholar 

  • Imai S, Ushijima T, Nakazawa M, Nabata H, Sakai K (1983) Mechanism of relaxant effects of nicorandil on the dog coronary artery. Arch Int Pharmacodyn Ther 265:274–282

    Google Scholar 

  • Iwatsuki K, Ikeda K, Chiba S (1981) Effects of 2-nicotinamidoethyl nitrate (SG 75) on pancreatic secretion in the isolated, bloodperfused pancreas of the dog. Clin Exp Pharmacol Physiol 8:585–590

    Google Scholar 

  • Kajiwara M, Droogmans G, Casteels R (1984) Effects of 2-nicotinamidoethyl nitrate (Nicorandil) on excitation-contraction coupling in the smooth muscle cells of rabbit ear artery. J Pharmacol Exp Ther 230:462–468

    Google Scholar 

  • Korb H, Hoeft A, Baller D, Schräder R, Wolpers HG, Hellige G (1983) Improvement of the metabolic and energetic situation of ischemically stressed myocardium by verapamil after experimental coronary artery occlusion. Arzneimittelforsch/Drug Res 33:1546–1551

    Google Scholar 

  • Korb H, Hoeft A, Baller D, Wolpers HG, Hellige G, Bretschneider HJ (1984a) Quantification of ischemic stress during repeated coronary artery occlusion in the dog. A method for validation of therapeutic effects. II. Reproducibility of the release and uptake of electrolytes and substrates. Basic Res Cardiol 79:38–48

    Google Scholar 

  • Korb H, Hoeft A, Hunneman DH, Wolpers HG, Hellige G (1984b) Metabolic changes of glucose, lactate and free fatty acids during ischemia and subsequent reperfusion. In: Mohl W, Wolner E, Glogar D (eds): The coronary sinus. Steinkopff Verlag, Darmstadt, pp 153–159

    Google Scholar 

  • Korb H, Hoeft A, Hunneman DH, Schraeder R, Wolpers HG, Wober W, Hellige G (1984c) Changes in myocardial substrate utilisation and protection of ischemic stressed myocardium by oxfenicine ((S)-4-hydroxyphenylglycine). Naunyn-Schmiedeberg's Arch Pharmacol 327:70–74

    Google Scholar 

  • Lamping KA, Christensen CW, Pelc LR, Warltier DC, Gross GJ (1984) Effects of nicorandil and nifedipine on protection of ischemic myocardium. J Cardiovasc Pharmacol 6:536–542

    Google Scholar 

  • Lamping KA, Gross GJ (1984) Comparative effects of a new nicotinamide nitrate derivative, nicorandil (SG 75), with nifedipine and nitroglycerin on true collateral blood flow following an acute coronary occlusion in dogs. J Cardiovasc Pharmacol 6:601–608

    Google Scholar 

  • Mizukami M, Tomoike H, Inouh T, Watanabe K, Kikuchi Y, Nakamura M (1981) Effects of 2-nicotinamidoethyl nitrate (SG 75) and/or nitroglycerin on systemic hemodynamics and coronary blood flow in conscious dogs. Arzneimittelforsch/Drug Res 31:1244–1247

    Google Scholar 

  • Nakagawa Y, Takeda K, Katano Y, Tsukada T, Kitagawa T, Otorii T, Imai S (1979) Effects of 2-nicotinamidoethyl nitrate on the cardiovascular system. Jap Heart J 20:881–895

    Google Scholar 

  • Opie LH (1970) Effect of fatty acids on contractility and rhythm of the heart. Nature 227:1055–1056

    Google Scholar 

  • Sakai K, Gebhard MM, Spieckerman PG, Bretschneider HJ (1975) Enzyme release resulting from total ischemia and reperfusion in the isolated, perfused guinea pig heart. J Mol Cell Cardiol 7:827–840

    Google Scholar 

  • Sakai K, Akima M, Shiraki Y, Hoshino E (1983) Effects of a new antianginal agent, nicorandil, on the cardiovascular system of the miniature pig: with special reference to coronary vasospasm. J Pharmacol Exp Ther 227:220–228

    Google Scholar 

  • Sakanashi M, Tomomatsu E, Fukai R, Oyama Y, Ueda S, Takenaka F, Higuchi M (1979) Analysis of vasodilatory action of a new nitroester agent, 2-nicotinamidoethyl nitrate (nicorandil). Drug Res 29 10:1530–1533

    Google Scholar 

  • Sakanashi M, Rokutanda M, Takeo S, Higuchi M (1982) Effects of 4-aminopyridine and tetraethylammonium on relaxant responses of isolated dog coronary arteries to 2-nicotinamidoethyl nitrate (SG 75). Jpn Heart J 23:227–233

    Google Scholar 

  • Sakanashi M, Takeo S, Miyamoto Y, Aniya Y, Higuchi M (1983) Effects of 2-nicotinamidoethyl nitrate (SG 75; nicorandil) on indomethacin-induced contractions of isolated dog coronary arteries. Jpn Heart J 24:289–295

    Google Scholar 

  • Shibata S, Satake N, Tagaki T, Kerfoot F, Suh TK (1984) Relaxing effect of nicorandil (N-2-(hydroxyethyl)-nicotinamide nitrate), a new anti-angina agent, on the isolated vascular smooth muscle. Eur J Pharmacol 99:219–226

    Google Scholar 

  • Taira N, Satoh K, Yanagisawa T, Imai Y, Hiwatari M (1979) Pharmacological profile of a new coronary vasodilator drug: 2-nicotinamidoethyl nitrate (SG 75). Clin Exp Pharmacol Physiol 6:301–316

    Google Scholar 

  • Thorman J, Schlepper M, Kramer W, Gottwik M (1982) Effectiveness of Nicorandil (nicorandil), a new long-acting drug with nitro-properties, in patients with coronary artery disease: improvement in left ventricular function and regional wall motion without pacing-induced angina. Z Kardiol 71:747–753

    Google Scholar 

  • Uchida Y, Yoshimoto N, Murao S (1978) Effect of 2-nicotinamidoethyl nitrate (nicorandil) on coronary circulation. Jap Heart J 19:112–124

    Google Scholar 

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Authors and Affiliations

  1. Abteilung für Experimentelle Kardiologie, Zentrum 2, Physiologie und Pathophysiologie, Universität Göttingen, Humboldtallee 23, D-3400, Göttingen

    H. Korb, A. Hoeft, D. H. Hunneman, H. G. Wolpers & G. Hellige

  2. Zentrum der Inneren Medizin, Abteilung für Kardiologie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-6000, Frankfurt am Main 70, Federal Repulic of Germany

    R. Schraeder

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  1. H. Korb
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  2. A. Hoeft
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  3. D. H. Hunneman
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  4. R. Schraeder
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  5. H. G. Wolpers
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  6. G. Hellige
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Korb, H., Hoeft, A., Hunneman, D.H. et al. Effectiveness of nicorandil in the preservation of myocardium stressed by transient ischemia and its influence on cardiac metabolism during coronary artery occlusion with subsequent reperfusion: a comparison with isosorbide dinitrate. Naunyn-Schmiedeberg's Arch. Pharmacol. 329, 440–446 (1985). https://doi.org/10.1007/BF00496379

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  • DOI: https://doi.org/10.1007/BF00496379

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