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Endothelin receptors, localized in sympathetic nerve terminals of the heart, modulate norepinephrine release and reperfusion arrhythmias

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Abstract

Endothelin (ET)-1 is an endogenous vasoconstrictor which modulates norepinephrine (NE) release in myocardial ischemia reperfusion. Recent studies have demonstrated the pro- or anti-arrhythmic effects in reperfusion. The present studies were undertaken to test the hypothesis that ET receptors located in sympathetic nerve terminals modulate NE release associated with reperfusion arrhythmias (ventricular fibrillation; VF). Immunohistochemical studies showed that both ETA and ETB receptors exist in the sympathetic nerve varicosities, which were stained positive for tyrosine hydroxylase (TH) in the left ventricular wall in guinea pigs. Isolated guinea pig hearts were subjected to 20 min of normothermic global ischemia followed by 30 min reperfusion. Exogenously applied ET-1 (0.1 and 1 nM) dose-dependently increased NE release and the duration of VF, but these responses were significantly suppressed with the Na+/H+ exchanger inhibitor, 5-(N-ethyl-N-isopropyl)-amiloride (10 μM).

The ETA receptor antagonist (BQ123, 1 μM) and nonselective ET receptor antagonist (PD142893, 1 μM) significantly attenuated NE release and VF, whereas the ETB receptor antagonist (BQ788,300 nM) markedly elevated NE release but did not affect VF. These studies provide the first evidence that both ETA and ETB receptors, located in the sympathetic nerve varicosities, modulate NE release, at least in part, in association with reperfusion arrhythmias.

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References

  1. Armour JA (1999) Myocardial ischaemia and the cardiac nervous system. Cardiovasc Res 41:41–54

    Article  CAS  PubMed  Google Scholar 

  2. Bernier M, Hearse DJ, Manning AS (1986) Reperfusion-induced arrhythmias and oxygen-derived free radicals. Studies with “anti-free radical” interventions and a free radical-generating system in the isolated perfused rat heart. Circ Res 58:331–340

    CAS  PubMed  Google Scholar 

  3. Bremnes T, Oaasche JD, Mehlum A, Scandberg C, Bremnes B, Attramadal H (2000) Regulation and intracellular trafficking pathways of the endothelin receptors. J Biol Chem 275:17596–17604

    Article  CAS  PubMed  Google Scholar 

  4. Brunner F, Doherty AM (1996) Role of ET (B) receptors in local clearenace of endothelin-1 in rat heart: studies with the antagonists PD 155080 and BQ-788. FEBS Lett 396:238–242

    Article  CAS  PubMed  Google Scholar 

  5. Brunner F, Kukovetz WR (1996) Postischemic antiarrhythmic effects of angiotensin-converting enzyme inhibitors. Role of suppression of endogenous endothelin secretion. Circulation 94:1752–1761

    CAS  PubMed  Google Scholar 

  6. Brunner F, Opie LH (1998) Role of endothelin- A receptors in ischemic contracture and reperfusion injury. Circulation 97:391–398

    CAS  PubMed  Google Scholar 

  7. Crockett TR, Scott GA, McGowan NW, Kane KA, Wainwright CL (2001) Antiarrhythmic and electrophysiological effects of the endothelin receptor antagonists, BQ123 and PD161721. Eur J Pharmacol 432:71–77

    Article  CAS  PubMed  Google Scholar 

  8. Crockett TR, Sharif I, Kane KA,Wainwright CL (2000) Sarafotoxin 6c protects against ischaemia-induced cardiac arrhythmias in vivo and in vitro in the rat. J Cardiovasc Pharmacol 36: S297–S299

    CAS  PubMed  Google Scholar 

  9. Fernandes LB, Henry PJ, Spalding LJ, Cody SH, Pudney CJ, Goldie RG (1998) Immunocytochemical detection of endothelin receptors in rat cultured airway nerves. J Cardiovasc Pharmacol 31:S222–S224

    Article  CAS  PubMed  Google Scholar 

  10. Ferrier GR, Moffat MP, Lukas A (1985) Possible mechanisms of ventricular arrhythmias elicited by ischemia followed by reperfusion. Studies on isolated canine ventricular tissues. Circ Res 56:184–194

    CAS  PubMed  Google Scholar 

  11. Fliegel L (2001) Regulation of myocardial Na+/H+ exchanger activity. Basic Res Cardiol 96:301–305

    Article  CAS  PubMed  Google Scholar 

  12. Geshi E, Nomizo A, Arata Y, Nakatani M, Katagiri T (1999) Effect of non-selective endothelin blockade, TAK-044, on the ischemic cellular injury of rat heart. Basic Res Cardiol 94:94–101

    Article  CAS  PubMed  Google Scholar 

  13. Heuer HJ,Muller E, Bernauer W (1988) Differential effects of superoxide dismutase on high energy phosphates, creatine kinase release, and arrhythmias during post-ischaemic reperfusion in isolated rate hearts. Basic Res Cardiol 83:149–157

    Article  CAS  PubMed  Google Scholar 

  14. Imamura M, Lander HM, Levi R (1996) Activation of histamine H3-receptors inhibits carrier-mediated norepinephrine release during protracted myocardial ischemia. Comparison with adenosine A1-receptors and alpha2-adrenoceptors. Circ Res 78:475–481

    CAS  PubMed  Google Scholar 

  15. Jewitt DE, Reid D, Thomas M, Mercer CJ,Valori C, Shillingford JP (1969) Free noradrenaline and adrenaline excretion in relation to the development of cardiac arrhythmias and heart-failure in patients with acute myocardial infarction. Lancet 1:635–641

    Article  CAS  PubMed  Google Scholar 

  16. Khandoudi N,Ho J,Karmazyn M (1994) Role of Na(+)-H+ exchange in mediating effects of endothelin-1 on normal and ischemic/reperfused hearts. Circ Res 75:369–378

    CAS  PubMed  Google Scholar 

  17. Kloner RA (1993) Does reperfusion injury exist in humans? J Am Coll Cardiol 21:537–545

    Article  CAS  PubMed  Google Scholar 

  18. Leger J, Croll RP, Smith FM (1999) Regional distribution and extrinsic innervation of intrinsic cardiac neurons in the guinea pig. J Comp Neurol 407:303–317

    Article  CAS  PubMed  Google Scholar 

  19. Lewis MJ, Grey AC, Henderson AH (1982) Inotropic beta-blocking potency (pA2) and partial agonist activity of propranolol, practolol, sotalol and acebutolol. Eur J Pharmacol 86:71–76

    Article  CAS  PubMed  Google Scholar 

  20. Liu J, Chen R, Casley DJ, Nayler WG (1990) Ischemia and reperfusion increase 125I-labeled endothelin-1 binding in rat cardiac membranes. Am J Physiol 258:H829–H835

    CAS  PubMed  Google Scholar 

  21. Manning AS, Hearse DJ (1984) Reperfusion- induced arrhythmias: mechanisms and prevention. J Mol Cell Cardiol 16:497–518

    Article  CAS  PubMed  Google Scholar 

  22. Masaki T, Vane JR, Vanhoutte PM (1994) International Union of pharmacology nomenclature of endothelin receptors. Pharmacol Rev 46:137–142

    CAS  PubMed  Google Scholar 

  23. Millette E, de Champlain J, Lamontagne D (2003) Contribution of endogenous endothelin in the enhanced coronary constriction in DOCA-salt hypertensive rats. J Hypertens 21:115–123

    Article  CAS  PubMed  Google Scholar 

  24. Oka J, Imamura M, Hatta E,Maruyama R, Isaka M, Murashita T, Yasuda K (2002) Carrier-mediated norepinephrine release and reperfusion arrhythmias induced by protracted ischemia in isolated perfused guinea pig hearts: effect of presynaptic modulation by alpha( 2)-adrenoceptor in mild hypothermic ischemia. J Pharmacol Exp Ther 303:681–687

    Article  CAS  PubMed  Google Scholar 

  25. Penny WJ (1984) The deleterious effects of myocardial catecholamines on cellular electrophysiology and arrhythmias during ischaemia and reperfusion. Eur Heart J 5:960–973

    CAS  PubMed  Google Scholar 

  26. Rochette L, Didier JP, Moreau D, Bralet J, Opie LH (1984) Role of betaadrenoreceptor antagonism in the prevention of reperfusion ventricular arrhythmias: effects of acebutolol, atenolol, and d-propranolol on isolated working rat hearts subject to myocardial ischemia and reperfusion. Am Heart J 107:1132–1141

    Article  CAS  PubMed  Google Scholar 

  27. Rubanyi GM, Polokoff MA (1994) Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev 46:325–415

    CAS  PubMed  Google Scholar 

  28. Salvati P, Chierchia S, Dho L, Ferrario RG, Parenti P,Vicedomini G, Patrono C (1991) Proarrhythmic activity of intracoronary endothelin in dogs: relation to the site of administration and to changes in regional flow. J Cardiovasc Pharmacol 17:1007–1114

    Article  CAS  PubMed  Google Scholar 

  29. Schmitz-Spanke S, Schipke JD (2000) Potential role of endothelin-1 and endothelin antagonists in cardiovascular disease. Basic Res Cardiol 95:290–298

    Article  CAS  PubMed  Google Scholar 

  30. Schömig A (1990) Catecholamines in myocardial ischemia. Systemic and cardiac release. Circulation 82:II13–II22

    PubMed  Google Scholar 

  31. Schömig A, Richardt G (1990) Cardiac sympathetic activity in myocardial ischemia: release and effects of noradrenaline. Basic Res Cardiol 85(Suppl):9–30

    Article  PubMed  Google Scholar 

  32. Schömig A, Richardt G, Kurz T (1995) Sympatho-adrenergic activation of the ischemic myocardium and its arrhythmogenic impact. Herz 20:169–186

    PubMed  Google Scholar 

  33. Sharif I, Kane KA, Wainwright CL (1998) Endothelin and ischaemic arrhythmias- antiarrhythmic or arrhythmogenic? Cardiovasc Res 39:625–632

    Article  CAS  PubMed  Google Scholar 

  34. Swies, J,Omogbai EK, Smith GM (1990) Occlusion and reperfusion-induced arrhythmias in rats: involvement of platelets and effects of calcium antagonists. J Cardiovasc Pharmacol 15:816–825

    Article  CAS  PubMed  Google Scholar 

  35. Takimoto M, Inui T, Okada T, Urade Y (1993) Contraction of smooth muscle by activation of endothelin receptors on autonomic neurons. FEBS Lett 324:277–282

    Article  CAS  PubMed  Google Scholar 

  36. Tani M, Neely JR (1989) Role of intracellular Na+ in Ca2+ overload and depressed recovery of ventricular function of reperfused ischemic rat hearts. Possible involvement of H+-Na+ and Na+/Ca2+ exchange. Circ Res 65:1045–1056

    CAS  PubMed  Google Scholar 

  37. Tani M, Neely JR (1991) Deleterious effects of digitalis on reperfusion-induced arrhythmias and myocardial injury in ischemic rat hearts: possible involvements of myocardial Na+ and Ca2+ imbalance. Basic Res Cardiol 86:340–354

    Article  CAS  PubMed  Google Scholar 

  38. Torres GE, Gainetdinov RR, Caron MG (2003) Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci 4:13–25

    Article  CAS  PubMed  Google Scholar 

  39. Walker MJ, Curtis MJ, Hearse DJ, Campbell RW, Janse MJ, Yellon DM, Cobbe SM, Coker SJ, Harness JB, Harron DW, Higgins AJ, Julian DG, Lab MJ, Manning AS, Northover BJ, Parratt JR, Riemersma RA, Riva E, Russell DC, Sheridan DJ, Winslow E, Woodward B (1988) The Lambeth Conventions: guidelines for the study of arrhythmias in ischaemia, infarction, and reperfusion. Cardiovasc Res 22:447–455

    Article  CAS  PubMed  Google Scholar 

  40. Woodcock EA, Reyes N, Jacobsen AN, Du XJ (1999) Inhibition of inositol (1.4,5) trisphosphate generation by endothelin- 1 during postischemic reperfusion: A novel antiarrhythmic mechanism. Circulation 99:823–828

    CAS  PubMed  Google Scholar 

  41. Yamamoto S, Matsumoto N, Kanazawa M, Fujita M, Takaoka M, Gariepy CE, Yanagisawa M, Matsumura Y (2005) Different contributions of endothelin- A and endothelin-B receptors in postischemic cardiac dysfunction and norepinephrine release in rat hearts. Circulation 111:302–309

    Article  CAS  PubMed  Google Scholar 

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Author notes

  1. M. Isaka DVM, PhD

    Present address: Pediatric Cardiac Surgery, Arkansas Children’s Hospital, 800 Marshall Street, Slot 677, Little Rock, (AR) 72202, USA

Authors and Affiliations

  1. Pediatric Cardiac Surgery, Arkansas Children’s Hospital, 800 Marshall Street, Slot 677, Little Rock, (AR) 72202, USA

    M. Imamura MD, PhD

  2. Dept. of Anatomy, Kyorin University School of Medicine, Tokyo, Japan

    A. Kudo PhD & H. Kawakami PhD

  3. Dept. of Cardiovascular Surgery, Hokkaido University School of Medicine, Kita-14,Nishi-5,Kita-ku Sapporo, Hokkaido 060-8648, Japan

    M. Isaka DVM, PhD & K. Yasuda MD, PhD

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  2. A. Kudo PhD
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  3. M. Imamura MD, PhD
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  4. H. Kawakami PhD
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Correspondence to M. Isaka DVM, PhD.

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Isaka, M., Kudo, A., Imamura, M. et al. Endothelin receptors, localized in sympathetic nerve terminals of the heart, modulate norepinephrine release and reperfusion arrhythmias. Basic Res Cardiol 102, 154–162 (2007). https://doi.org/10.1007/s00395-006-0623-2

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  • DOI: https://doi.org/10.1007/s00395-006-0623-2

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