Summary
Prolonged myocardial ischemia without reperfusion results in myocardial cell death. Early coronary artery reperfusion is important to minimize tissue injury. However, reperfusion itself exerts deleterious effects, that result in enhanced myocardial injury. Endothelin-1 (ET-1) is a powerful vasoconstrictor of coronary arteries, and several studies have suggested a role for ET in a number of cardiovascular disorders. The present study was designed to evaluate the potential of bosentan, a mixed ETA-ETB receptor antagonist and BMS 182874, a selective ETA receptor antagonist in limiting myocardial infarct size and to determine the hemodynamic and metabolic basis of such effects in a cat model of ischemia (MI) and reperfusion (R) induced myocardial injury. Twenty six adult mongrel cats of either sex (2.6–3.4kg; body weight) anesthetized with ether followed by alpha chloralose (80mg/kg), were tracheotomized and positive pressure ventilation was instituted. The animals were submitted to left anterior descending coronary artery (LAD) occlusion for 40 minutes; thereafter, reperfusion was instituted for a period of 3 h by untying the ligature. Animals were randomly assigned to either (i) saline-treated MI/R control group (CON), (ii) bosentan-treated MI/R group (BOS) or (iii) BMS 182874-treated MI/R group (BMS). Myocardial ischemia and reperfusion resulted in severe myocardial injury, profound hemodynamic alterations and marked metabolic derangements in the control group as assessed at the end of the experimental period (3h and 40 min). Administration of bosentan (3mg/kg; i.v.) and BMS 182874 (1mg/kg; i.v.) 20min after the onset of ischemia resulted in the salvage of 36% (BOS) and 22% (BMS) of the left ventricle at risk of infarction. Bosentan slightly increased heart rate, and affected a significant (p < 0.05) fall in systolic and diastolic arterial blood pressures. The sharp rise in LVEDP post-occlusion was significantly (p < 0.01) lowered by both BOS and BMS and the correction of this variable was sustained for the entire reperfusion period (3h). Administration of BOS and BMS afforded a modest correction of the LVdP/dtmax and attenuated reperfusion ectopy. Furthermore, administration of bosentan significantly decreased the level of lactate accumulation and corrected the myocardial energy profile as compared to the control group. These data highlight the possible role of endogenous endothelin-1 in exacerbating myocardial ischemia and reperfusion injury. It is further concluded that endothelin receptor blockade is expected to be an effective approach in the treatment of ischemic heart disease.
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References
Braunwald E. 1971. Control of myocardial oxygen consumption physiologic and clinical considerations. Am J Cardiol 27:416–432.
Hearse DJ, Yellon DM. 1984. Why are we still in doubt about infarct size limitation? The experimentalists viewpoint. In: Therapeutic approaches to myocardial infarct size limitations. Eds. DJ Hearse and DM Yellon, 17–41. New York: Raven Press.
Hearse DJ. 1990. Ischemia, reperfusion and the determinants of tissue injury. Cardiovasc Drug Ther 4:767–776.
Hearse DJ. 1988. Ischemia at the crossroads? Cardiovasc Drug Ther 2:9–15.
Heyndrickx GR, Millard RW, McRitchie RJ, et al. 1975. Regional myocardial functional and electrophysiological alterations after brief coronary artery occlusion in conscious dogs. J Clin Invest 56:975–978.
Kloner RA, Rude RE, Carlson N, et al. 1980. Ultrastructural evidence of microvascular damage and myocardial cell injury after coronary artery occlusion. Which comes first? Circulation 62:945–952.
Ellis SG, Menschke CI, Sandor T, et al. 1983. Time course of functional and biochemical recovery of myocardium salvaged by reperfusion. J Am Coli Cardiol 1:1047–1055.
Hansen PR. 1995. Myocardial reperfusion injury: experimental evidence and clinical relevance. Eur Heart J 16:734–740.
Pitarys CJ, Virmani R, Vildibill HD, et al. 1991. Reduction of myocardial reperfusion injury by intravenous adenosine administered during early reperfusion period. Circulation 83:237–247.
Narula J, Nicol PD, O’Donnell SM, et al. 1990. Documentation of experimental myocardial reperfusion injury by pre and post reperfusion antibody imaging. Circulation 82(Suppl III):III 288.
Bolli R. 1990. Mechanism of myocardial stunning. Circulation 82:723–728.
Forman MB, Kolodgie FD, Jenkins M, Virmani R. 1993. Endothelial and myocardial injury during ischemia and reperfusion: pathogenesis and therapeutic implications. J Am Coli Cardiol 21:1245–1253.
Park JL, Lucchesi BR. 1999. Mechanism of myocardial reperfusion injury. Ann Thorac Surg 68:1012–1905.
Ambrosio G, Tritto L. 1999. Reperfusion injury: experimental evidence and clinical implications. Am Heart J 138:S69–S75.
Rosenkranz ER, Buckberg GD. 1983. Myocardial protection during surgical coronary reperfusion. J Am Coli Cardiol 1:1235–1246.
Gray GA, Webb DJ. 1996. The endothelin system and its potential as a therapeutic target in cardiovascular disease. Pharmacol Ther 72:109–148.
Yorikane R, Koike H. 1990. The arrhythmogenic actions of endothelin in rats. Jpn J Pharmacol 53:259–263.
Salvati P, Chierchia S, Dho L, et al. 1991. Proarrhythmic activity of intracoronary endothelin in dogs: relation to the rate of administration and to change in regional flow. J Cardiovasc Pharmacol 17:107–114.
Toyo-Oka T, Aizawa T, Suzuki N, et al. 1991. Increased plasma level of endothelin-1 and coronary spasm induction in patients with vasospastic angina pectoris. Circulation 83:476–483.
Spielberg C, Schwenn K, Hensen J, Linderer T. 1991. Endothelin levels in the coronary sinus during PTCA of the left descending coronary artery. Circulation 84:11726–11731.
Grover GJ, Sleph PG, Fox M, Trippodo NC. 1992. Role of endothelin-1 and big endothelin-1 in modulating coronary vascular tone, contractile function and severity of ischemia in rat hearts. J Pharmacol Exp Ther 263:1074–1082.
Grover GJ, Dzwonczyk S, Parham CS. 1993. The endothelin-1 receptor angatonist BQ-123 reduces infarct size in a canine model of coronary occlusion and reperfusion. Cardiovasc Res 27:1613–1618.
Dagassan PH, Breu V, Clozel M, Clozel JP. 1994. Role of endothelin during reperfusion after ischemia in isolated perfused rat heart. J Cardiovasc Pharmacol 24:867–874.
Donckier J, Hanet C, Stoleru L, et al. 1994. Effects of endothelin-1 at pathophysiologic concentrations on coronary perfusion and mechanical function of normal and postischemic myocardium. J Cardiovasc Pharmacol 23:212–219.
Velasco C, Turner M, Inagami T, et al. 1994. Reperfusion enhances the local release of endothelin after regional myocardial ischemia. Am Heart J 128:441–451.
Illing B, Horn M, Han H, et al. 1996. Protective effect of the specific endothelin-1 antagonist BQ-610 on mechanical function and energy metabolism during ischemia/reperfusion injury in isolated perfused rat hearts. J Cardiovasc Pharmacol 27:487–494.
Roux S, Breu V, Ertel SI, Clozel M. 1999. Endothelin antagonism with bosentan: a review of potential applications. J Mol Med 77:364–376.
Ergul A. 2002. Endothelin-1 and endothelin receptor antagonists as potential cardiovascular therapeutic agents. Pharmacotherapy 22:54–65.
Opie LH. 1992. Where do we stand with respect to reperfusion in the 1990s? Clinical and experimental perspectives. In: Myocardial Protection: The Patho-physiology of Reperfusion Injury. Eds. DM Yellon and RB Jennings, 197–208. New York, Raven Press.
Opie LH. 1989. Reperfusion injury and its pharmacologic modification. Circulation 80:1049–1062.
Menasche P 1985. The inflammatory response to cardiopulmonary bypass and its impact on post-operative myocardial function. Curr Opin Cardiol 10:594–604.
Yanagisawa M, Kurihara H, Kimura S, et al. 1988. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–415.
Randall MD. 1991. Vascular activities of the endothelins. Pharmacol Ther 50:73–93.
Masaki T, Yanagisawa M. 1992. Physiology and pharmacology of endothelins. Med Res Rev 12:391–421.
Otsuka AH, Mikami H, Katahira K, et al. 1990. Haemodynamic effects of endothelin, a novel potent vasoconstrictor in dogs. Clin Exp Pharmacol Physiol 17:351–360.
LeMonnier de Gouville A-C, Lippton H, Cohen G, et al. 1990. Vasodilator activity of endothelin-1 and endothelin-3: rapid development of cross-tachyphylaxis and dependence on the rate of endothelin administration. J Pharmacol Exp Ther 254: 1024–1028.
Minkes RK, Bellan JA, Saroyan RM, et al. 1990. Analysis of cardiovascular and pulmonary responses to endothelin-1 and endothelin-3 in the anesthetized cat. J Pharmacol Exp Ther 253:1118–1125.
Reid AF, Parkes DG, Coghlan JP, et al. 1990. Haemodynamic effects of long-term endothelin infusion in conscious sheep. Clin Exp Pharmacol Physiol 17:241–245.
Siren AL, Feuerstein G. 1989. Hemodynamic effects of endothelin after systemic and central nervous system administration in the conscious rat. Neuropeptides 41:231–236.
Giannessi D, Delry S, Vitali RL. 2001. Role of endothelins and their receptors in heart failure. Pharmacol Res 43:111–126.
Ikegawa R, Matsumura Y, Tsukahara Y, et al. 1991. Phosphoramidon inhibits the generation of endothelin-1 from exogenously applied big endothelin-1 in cultured vascular endothelial cells and smooth muscle cells. FEBS Letts 293:45–48.
Inoue A, Yanagisawa M, Kimura S, et al. 1989. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Nad Acad Sci 86:2863–2867.
Kloog Y, Sokolovsky M. 1989. Similarities in mode and sites of action of sarafotoxins and endothelins. Trends Pharmacol Sci 10:212–215.
Sokolovsky M. 1992. Endothelins and sarafotoxins: physiological regulation; receptor subtypes and transmembrane signaling. Pharmacol Ther 54:129–149.
Sakurai T, Yanagisawa M, Masaki T. 1992. Molecular characterization of endothelin receptors. Trends Pharmacol Sci 13:103–108.
Arai H, Hori S, Aramori I, et al. 1990. Cloning and expression of cDNA encoding an endothelin receptor. Nature 348:730–732
Sakurai T, Yanagisawa M, Takuwa Y, et al. 1990. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature 348:732–735.
McMurdo L, Corder R, Thiemermann C, Vane JR. 1993. Incomplete inhibition of the pressor effects of endothelin-1 and related peptides in the anaesthetized rat with BQ-123 provides evidence for more than one vasoconstrictor receptor. Br J Pharmacol 108:557–561.
Bird JE, Waldron TL. 1993. Incomplete inhibition of endothelin-1 pressor effects by an endothelin ETA receptor antagonist. Eur J Pharmacol 240:295–298.
Seo B, Oemar BS, Siebenmann R, et al. 1994. Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels. Circulation 89:1203–1208.
Warner TD, Allcock GH, Corder R, Vane JR. 1993. Use of the endothelin antagonists BQ-123 and PD 142893 to reveal three endothelin receptors mediating smooth muscle contraction and the release of EDRF. Br J Pharmacol 110:777–782.
Gray GA, Clozel M. 1994. Three endothelin receptor subtypes suggested by the differential potency of bosentan, a novel endothelin receptor antagonist, in isolated tissues. Br J Pharmacol 112:U62.
Douglas SA, Vickery-Clark LM, Storer BL, et al. 1994. A role for endogenous endothelin-1 in neointima formation following rat carotid artery balloon angioplasty: antiproliferative effects of the non-peptide endothelin receptor antagonist SB 209670. Circ Res 75:190–197.
Ferrer P, Valentine M, Jenkins-West T, et al. 1995. Orally active endothelin receptor antagonist BMS-182874 suppresses neointimal deveploment in balloon-injured rat carotid arteries. J Cardiovasc Pharmacol 26:908–915.
Miyauchi T, Yanagisawa M, Tomizawa T, et al. 1989. Increased plasma concentrations of endothelin-1 and big endothelin-1 in acute myocardial infarction. Lancet 2:53–54.
Watanabe T, Suzuki N, Shimamoto N, et al. 1990. Endothelin in myocardial infarction. Nature 344:114.
Ando K, Hirata Y, Schichiri M, et al. 1989. Presence of immunoreactive endothelin in human plasma. FEBS Letts 245:164–166.
Suzuki N, Matsumoto H, Kitada C. 1989. Immunoreactive endothelin-1 in plasma detected by a sandwich-type enzyme immunoassay. J Cardiovasc Pharmacol 13:151–153.
Yasuda M, Kohno M, Tahara A, et al. 1990. Circulating immunoreactive endothelin in ischemic heart disease. Am Heart J 119:801–806.
Watanabe T, Suzuki N, Shimamoto N, et al. 1991. Contribution of endogenous endothelin to the extension of myocardial infarct size in rats. Circ Res 69:370–377.
Stewart DJ, Kubac G, Costello KB, Cernacek P. 1991. Increased plasma endothelin-1 in the early hours of acute myocardial infarction. J Am Coll Cardiol 18:38–43.
Tsuji S, Sawamura A, Watanabe H, et al. 1991. Plasma endothelin levels during myocardial ischemia and reperfusion. Life Sci 48:1745–1749.
Vemulapalli S, Rivelli M, Chiu PJ, et al. 1992. Phosphoramidon abolishes the increases in endothelin-1 release induced by ischemia-hypoxia in isolated perfused guinea-pig lungs. J Pharmacol Exp Ther 262: 1062–1069.
Qiu S, Theroux P, Marcil M, Solymoss BC. 1993. Plasma endothelin-1 levels in stable and unstable angina. Cardiology 82:12–19.
Shomisch Moravec C, Reynolds EE, Stewart RW, Bond M. 1989. Endothelin is a positive inotropic agent in human and rat heart in vitro. Biochem Biophys Res Commun 159:14–18.
Shah AM, Lewis MJ, Henderson AH. 1989. Inotropic effects of endothelin in ferret ventricular myocardium. Eur J Pharmacol 163:365–367.
Tippins JR, Antoniw JW, Maseri A. 1989. Endothelin a potent constrictor in conductive and resistive coronary arteries. J Cardiovasc Pharmacol 13(Suppl 5):S177–S179.
Ezra D, Goldstein RE, Czaja JF, Feuerstein GZ. 1989. Lethal ischemia due to intracoronary endothelin in pigs. Am J Physiol 257:H339–H343.
Larkin SW, Clarke JG, Keogh BE, et al. 1989. Intracoronary endothelin induces myocardial ischemia by small vessel constriction in the dog. Am J Cardiol 64:956–958.
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.
Neubauer S, Ertl G, Pulzer F, et al. 1990. Effects of endothelin-1 in the isolated heart under ischemic and cardioplegic conditions. J Cardiovasc Pharmacol 16:804–811.
Neubauer S, Zimmermann S, Hirsch A, et al. 1991. Effects of endothelin-1 in the isolated heart in ischemia/reperfusion and hypoxia/reoxygenation injury. J Mol Cell Cardiol 23:1397–1409.
Maguire JJ, Davenport AP. 2000. No alteration in vasoconstrictor endothelinB, receptor density or function in human coronary artery disease. J Cardiovasc Pharmacol 36(Suppl 1):S380–S381.
Watanabe T, Awane Y, Ikeda S, et al. 1995. Pharmacology of a non-selective ETA and ETB receptor antagonist, TAK-044 and the inhibition of myocardial infarct size in rats. Br J Pharmacol 144:949–954.
Tonnessen T, Giaid A, Saleh D, et al. 1995. Increased in vivo expression and production of endothelin-1 by porcine cardiomyocytes subjected to ischemia. Cir Res 76:767–772.
Ray SG, McMurray JJ, Morton JJ, et al. 1992. Circulating endothelin in acute ischaemic syndromes. Br Heart J 67:383–386.
Omland T, Lie RT, Aakvaag A, et al. 1994. Plasma endothelin determination as a prognostic indicator of 1-year mortality after acute myocardial infarction. Circulation 89:1573–1579.
Wieczorek I, Haynes WG, Webb DJ, et al. 1994. Raised plasma endothelin in unstable angina and non-Q wave myocardial infarction: relation to cardiovascular outcome. Br Heart J 72:436–441.
Lie JT, Pairolero PC, Holley KE, et al. 1975. Macroscopic enzyme mapping verification of large, homogenous, experimental myocardial infarcts of predictable size and location in dogs. J Thorac Cardiovas Surg 69:599–605.
Lamprecht W, Stan F, Weisser H, Heinz F. 1974. Determination of creatine phosphate and adenosine triphosphate with creatine kinase. In: Methods of enzymatic analysis. Ed. HU Bergmeyer, 1776–1778. New York: Academic Press.
Gawher K, Bergmeyer HU. 1974. Lactate determination. In: Methods of enzymatic analysis. Ed. HU Bergmeyer, 1492–1495. New York: Academic Press.
Miyauchi T, Doi T, Suzuki N, et al. 1992. Plasma endothelin-1 concentrations in the coronary sinus in dogs with artificially induced myocardial infarction. Peptides 13:1013–1015.
Luscher TF, Boulanger CM, Dohi Y, Yang Z. 1992. Endothelium-derived contracting factors. Hypertension 19:117–130.
Hillis J, Braunwald E. 1977. Myocardial ischemia. New Engl J Med 17:920–932.
Brezinski ME, Yanagisawa A, Darius H, Lefer AM. 1985. Antiischemic actions of a new thromboxane receptor antagonist during acute myocardial ischemia in cats. Am Heart J 110:1161–1167.
Greenfield RA, Swain JL. 1987. Disruption of myofibrillar energy use: Dual mechanisms that may contribute to post ischemic dysfunction in stunned myocardium. Circ Res 60:283–293.
Taegtmeyer H, Roberts AFC, Raine AEG. 1985. Energy metabolism in reperfused heart muscle: metabolic correlates to return of function. J Am Coll Cardiol 6:864–870.
Wang QD, Li XS, Pernow J. 1995b. The nonpeptide endothelin receptor antagonist bosentan enhances myocardial recovery and endothelial function during reperfusion of the ischemic rat heart. J Cardiovas Pharmacol 26(suppl 3):S445–S447.
Wang QD, Li XS, Lundberg JM, Pernow J. 1995a. Protective effects of the non-peptide endothelin receptor antagonist bosentan on myocardial ischaemic and reperfusion injury in pig. Cardiovasc Res 29:805–812.
Schaper W, George G, Winkler B, Schaper J. 1988. The collateral circulation of the heart. Prog Cardiovasc Dis 31:57–77.
Ma X-I, Tsao PS, Lefer AM. 1991. Antibody to CD-18 exerts endothelial and cardioprotective effects in myocardial ischemia and reperfusion. J Clin Invest 88:1237–1243.
Kloner R. 1989. No reflow revisited. J Am Coli Cardiol 14:1814–1815.
Richard V, Kaeffer N, Hogie M, et al. 1994. Role of endogenous endothelin in myocardial and coronary endothelial injury after ischaemia and reperfusion in rats: studies with bosentan, a mixed ETA-ETB antagonist. Br J Pharmacol 113:869–876.
Iimuro M, Kaneko M, Matsumoto Y, et al. 2000. Effects of an endothelin receptor antagonist TAK 044 on myocardial energy metabolism in ischemia/reperfused rat hearts. J Cardiovasc Pharmacol 35:403–409.
McMurdo L, Thiemermann C, Vane JR. 1994. The effects of the endothelin ETA receptor antagonist, FR 139317, on infarct size in a rabbit model of acute myocardial ischemia and reperfusion. Br J Pharmacol 112:75–80.
Bird JE, Moreland S, Waldron TL, Powell JR. 1995. Anti-hypertensive effects of a novel endothelin-A receptor antagonist in rats. Hypertension 25:1191–1195.
Persidis A, Harcombe AA, Davenport AP, et al. 1993. Isolation of human cardiac receptors by a peptide—receptor mobility shift assay. Clin Sci 85:169–173.
Lechleitner P, Genser N, Maier J, et al. 1993. Plasma immunoreactive endothelin in acute and subacute phases of myocardial infarction in patients undergoing fibrinolysis. Clin Chem 39:955–959.
Malatino L, Grassi R, Stancanelli B, et al. 1993. Release of immunoreactive endothelin from the heart during percutaneous transluminal coronary angioplasty. Am Heart J 126:700–702.
Komai H, Adatia IT, Elliot MJ, et al. 1993. Increased plasma levels of endothelin I after cardiopulmonary bypass in patients with pulmonary hypertension and congenital heart disease. J Thorac Cardiovasc Surg 106:473–478.
Bagnall A, Webb D. 2001. Are selective endothelin A receptor antagonists better than mixed antagonists? J Cardiovasc Pharmacol 30(Suppl 2):S43–S46.
Ohnishi M, Wada A, Tsutamoto T, et al. 1998. Comparison of the acute effects of a selective endothelin ET-A and a mixed ET-A/ET-B receptor antagonist in heart failure. Cardiovasc Res 39:617–624.
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Gupta, S.K., Singh, U. (2003). Myocardioprotection Against Ischemia and Reperfusion Injury by Endothelin Receptor Antagonists. In: Dhalla, N.S., Takeda, N., Singh, M., Lukas, A. (eds) Myocardial Ischemia and Preconditioning. Progress in Experimental Cardiology, vol 6. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0355-2_31
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