Endothelin-1 (ET-1) has been implicated in many cardiovascular diseases, including acute heart failure (AHF) due to myocardial ischemia. Previously we described the oral endothelin-converting enzyme (ECE) inhibitor, PP36, and in this study, we investigated its cardioprotective effect in more detail, and examined the role of PP36 in the neurohormonal activation in rats that had been subjected to acute myocardial ischemia due to the microsphere embolization of coronary microcirculation. PP36 treatment (3.5 × 10−5 M/kg/day) led to a significant fourfold decrease in hypertensive response when big-ET-1 was administered to healthy, conscious rats. ECE inhibition did not affect mortality during the first 48 hours after ischemia initiation. Systemic hemodynamic, heart function, and neurohormonal activation were analyzed in the healthy control group, the AHF group, and the AHF+PP36 group two days after AHF induction. In conscious rats in the AHF+PP36 group, mean arterial pressure (MAP) was restored and became similar to that of the MAP of the control group. In anesthetized rats, in the AHF+PP36 group, MAP was not restored and was 22% lower than the MAP of the control group. Myocardial contractility was partially restored and cardiac relaxation significantly improved after PP36 application. Further analysis of cardiac output and peripheral resistance in anesthetized rats revealed no differences between the AHF group and the AHF+PP36 group. There were no differences in plasma ET-1 concentration, serum angiotensin converting enzyme activity, and in the adrenal glands’ catecholamine content between the AHF group and the AHF+PP36 group. However, rats in the AHF+PP36 group demonstrated a 60% decrease in cardiac endothelial nitric oxide synthase (eNOS) protein expression, and a 56% reduction of myocardial norepinephrine release, when compared with the AHF group’s animals. These results suggest that PP36 can preserve heart function during the recovery from acute ischemic injury, and may modulate the cardiac norepinephrine release and eNOS protein level.
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References
1.
De Luca L, Fonarow GC, Adams KF Jr, Mebazaa A, Tavazzi L, Swedberg K, Gheorghiade M. Acute heart failure syndromes: clinical scenarios and pathophysiologic targets for therapy. Heart Fail Rev12: 97–104, 2007.
2.
McNeill JR. Role of endothelin in regulation of resistance, fluid-exchange, and capacitance functions of the systemic circulation. Can J Physiol Pharmacol81:522–532, 2003.
3.
Cernacek P, Stewart DJ. Immunoreactive endothelin in human plasma: marked elevations in patients in cardiogenic shock. Biochem Biophys Res Commun161:562–567, 1989.
4.
Monge JC. Neurohormonal markers of clinical outcome in cardiovascular disease: is endothelin the best one? J Cardiovasc Pharmacol32 Suppl 2:S36–S42, 1998.
5.
Luscher TF, Barton M. Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation102:2434–2440, 2000.
6.
Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol41:851–876, 2001.
7.
Barton M, Yanagisawa M. Endothelin: 20 years from discovery to therapy. Can J Physiol Pharmacol86:485–498, 2008.
8.
Cernacek P, Stewart DJ, Monge JC, Rouleau JL. The endothelin system and its role in acute myocardial infarction. Can J Physiol Pharmacol81: 598–606, 2003.
9.
Tavares M, Rezlan E, Vostroknoutova I, Khouadja H, Mebazaa A. New pharmacologic therapies for acute heart failure. Crit Care Med36: S112–S120, 2008.
10.
Wada A, Tsutamoto T, Ohnishi M, Sawaki M, Fukai D, Maeda Y, Kinoshita M. Effects of a specific endothelin-converting enzyme inhibitor on cardiac, renal, and neurohumoral functions in congestive heart failure: comparison of effects with those of endothelin A receptor antagonism. Circulation99:570–577, 1999.
11.
Yanagisawa H, Hammer RE, Richardson JA, Emoto N, Williams SC, Takeda S, Clouthier DE, Yanagisawa M. Disruption of ECE-1 and ECE-2 reveals a role for endothelin-converting enzyme-2 in murine cardiac development. J Clin Invest105:1373–1382, 2000.
12.
Ikeda K, Emoto N, Raharjo SB, Nurhantari Y, Saiki K, Yokoyama M, Matsuo M. Molecular identification and characterization of novel membrane-bound metalloprotease, the soluble secreted form of which hydrolyzes a variety of vasoactive peptides. J Biol Chem274:32469–32477, 1999.
13.
Emoto N, Raharjo SB, Isaka D, Masuda S, Adiarto S, Jeng AY, Yokoyama M. Dual ECE/NEP inhibition on cardiac and neurohumoral function during the transition from hypertrophy to heart failure in rats. Hypertension45:1145–1152, 2005.
14.
Kwan AL, Lin CL, Chang CZ, Winardi D, Yen CP, Wu SC, Lee KS, Kassell NF, Howng SL, Savage P, Jeng AY. Oral administration of an inhibitor of endothelin-converting enzyme attenuates cerebral vaso-spasm following experimental subarachnoid haemorrhage in rabbits. Clin Sci (Lond)103 Suppl 48:414S–417S, 2002.
15.
Mellin V, Jeng AY, Monteil C, Renet S, Henry JP, Thuillez C, Mulder P. Triple ACE-ECE-NEP inhibition in heart failure: a comparison with ACE and dual ECE-NEP inhibition. J Cardiovasc Pharmacol46:390–397, 2005.
16.
Tikkanen I, Tikkanen T, Cao Z, Allen TJ, Davis BJ, Lassila M, Casley D, Johnston CI, Burrell LM, Cooper ME. Combined inhibition of neutral endopeptidase with angiotensin converting enzyme or endothelin converting enzyme in experimental diabetes. J Hypertens20:707–714, 2002.
17.
Daull P, Jeng AY, Battistini B. Towards triple vasopeptidase inhibitors for the treatment of cardiovascular diseases. J Cardiovasc Pharmacol50:247–256, 2007.
18.
Brands M, Erguden JK, Hashimoto K, Heimbach D, Krahn T, Schroder C, Siegel S, Stasch JP, Tsujishita H, Weigand S, Yoshida NH. Selective indole-based ECE inhibitors: synthesis and pharmacological evaluation. Chem Med Chem1:96–105, 2006.
19.
Umekawa K, Hasegawa H, Tsutsumi Y, Sato K, Matsumura Y, Ohashi N. Pharmacological characterization of a novel sulfonylureid-pyrazole derivative, SM-19712, a potent nonpeptidic inhibitor of endothelin converting enzyme. Jpn J Pharmacol84:7–15, 2000.
20.
Yamamoto S, Matsumoto N, Kanazawa M, Fujita M, Takaoka M, Gariepy CE, Yanagisawa M, Matsumura Y. Different contributions of endothelin-A and endothelin-B receptors in postischemic cardiac dysfunction and norepinephrine overflow in rat hearts. Circulation111:302–309, 2005.
21.
Isaka M, Kudo A, Imamura M, Kawakami H, Yasuda K. Endothelin receptors, localized in sympathetic nerve terminals of the heart, modulate norepinephrine release and reperfusion arrhythmias. Basic Res Cardiol102:154–162, 2007.
22.
Tawa M, Fukumoto T, Ohkita M, Matsumura Y. Role of endogenous endothelin-1 in post-ischemic cardiac dysfunction and norepinephrine overflow in rat hearts. Eur J Pharmacol591:182–188, 2008.
23.
Brunner F, Maier R, Andrew P, Wolkart G, Zechner R, Mayer B. Attenuation of myocardial ischemia/reperfusion injury in mice with myocyte-specific overexpression of endothelial nitric oxide synthase. Cardiovasc Res57:55–62, 2003.
24.
Hannan RL, John MC, Kouretas PC, Hack BD, Matherne GP, Laubach VE. Deletion of endothelial nitric oxide synthase exacerbates myocardial stunning in an isolated mouse heart model. J Surg Res93:127–132, 2000.
25.
Boli R. Cardioprotective function and role of nitric oxide in myocardial ischemia and preconditioning: an overview of a decade of research. J Mol Cell Cardiol33:1897–1918.
26.
Forstermann U, Munzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation113:1708–1714, 2006.
27.
Munzel T, Sinning C, Post F, Warnholtz A, Schulz E. Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction. Ann Med40:180–196, 2008.
28.
Baggia S, Perkins K, Greenberg B. Endothelium-dependent relaxation is not uniformly impaired in chronic heart failure. J Cardiovasc Pharmacol29:389–396, 1997.
29.
Vanin AF, Manukhina EB, Lapshin AV, Meerson FZ. [The intensification of nitric oxide synthesis in the aortic wall in experimental myocardial infarct]. Biull Eksp Biol Med116:142–144, 1993.
30.
Drummond GR, Cai H, Davis ME, Ramasamy S, Harrison DG. Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hydrogen peroxide. Circ Res86:347–354, 2000.
31.
Radin MJ, Holycross BJ, Hoepf TM, McCune SA. Salt-induced cardiac hypertrophy is independent of blood pressure and endothelin in obese, heart failure-prone SHHF rats. Clin Exp Hypertens30:541–552, 2008.
32.
Climent B, Fernandez N, Sanz E, Sanchez A, Monge L, Garcia-Villalon AL, Dieguez G. Enhanced response of pig coronary arteries to endothelin-1 after ischemia-reperfusion. Role of endothelin receptors, nitric oxide and prostanoids. Eur J Pharmacol524:102–110, 2005.
33.
Rossi GP, Sacchetto A, Cesari M, Pessina AC. Interactions between endothelin-1 and the renin-angiotensin-aldosterone system. Cardiovasc Res43:300–307, 1999.
Barton M, Carmona R, Krieger JE, Goettsch W, Morawietz H, d’Uscio LV, Lattmann T, Luscher TF, Shaw S. Endothelin regulates angiotensin-converting enzyme in the mouse kidney. J Cardiovasc Pharmacol36:S244–S247, 2000.
36.
Pozdnev VF, Gomazkov OA, Davydova MP, Medvedeva NA. [Synthesis and hemodynamic effects of the new inhibitor of endothelin converting enzyme]. Biull Eksp Biol Med126:526–529, 1998.
37.
Petrukhina VA, Medvedeva NA, Khropov I, Pozdnev VF, Gomazkov OA, Medvedev OS. [Correction of cardiac functions in rats with experimental myocardial ischemia by chronic administration of endothelin-converting enzyme inhibitor]. Vopr Med Khim46:361–369, 2000.
38.
Kalenikova EI, Gorodetskaya EA, Zacharova NV, Shechter AB, Medvedev OS. Perindopril effects on angiotensin I elimination in lung after experimental myocardial injury induced by intracoronary microembolization in rats. J Cardiovasc Pharmacol32:608–615, 1998.
39.
Gorodetskaya EA, Dugin SF, Medvedev OS, Allabergenova AE. Simple method to produce acute heart failure by coronary vessel embolization in closed chest rats with microspheres. J Pharmacol Methods24:43–51, 1990.
40.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem193:265–275, 1951.
41.
Gourine AV, Hu Q, Sander PR, Kuzmin AI, Hanafy N, Davydova SA, Zaretsky DV, Zhang J. Interstitial purine metabolites in hearts with LV remodeling. Am J Physiol Heart Circ Physiol286:H677–H684, 2004.
42.
de Diego AM, Gandia L, Garcia AG. A physiological view of the central and peripheral mechanisms that regulate the release of catecholamines at the adrenal medulla. Acta Physiol (Oxf)192:287–301, 2008.
43.
Kuzmin AI, Zaretsky DV, Kalenikova EI, Zaretskaja MV, Medvedev OS, Chazov EI. The effect of histamine receptor antagonists on stress-induced catecholamine secretion: an adrenomedullary microdialysis study in the rat. Eur J Pharmacol378:311–316, 1999.
44.
Kuzmin AI, Pogorelov VM, Zaretsky DV, Medvedev OS, Chazov EI. Comparison of the effects of 2-deoxyglucose and immobilization on secretion and synthesis rate of catecholamines in the adrenal gland: a microdialysis study in conscious rats. Acta Physiol Scand155:147–155, 1995.
45.
Simonova AI, Pozdneev VF, Gomazkov OA, Medvedeva NA. [Chronic treatment with an endothelin-converting enzyme inhibitor reduces the development of hypoxia-induced pulmonary hypertension in rat]. Ross Fiziol Zh Im I M Sechenova94:777–784, 2008.
46.
Kramer BK, Smith TW, Kelly RA. Endothelin and increased contractility in adult rat ventricular myocytes. Role of intracellular alkalosis induced by activation of the protein kinase C-dependent Na(+)-H+ exchanger. Circ Res68:269–279, 1991.
47.
Qi XL, Sia YT, Stewart DJ, Wei G, Nguyen QT, Cernacek P, Picard P, Sirois M, Rouleau JL. Myocardial contractile responsiveness to endothelin-1 in the post-infarction rat model of heart failure: effects of chronic quinapril. J Mol Cell Cardiol33:2023–2035, 2001.
48.
Sakurai K, Norota I, Tanaka H, Kubota I, Tomoike H, Endo M. Negative inotropic effects of angiotensin II, endothelin-1 and phenyl-ephrine in indo-1 loaded adult mouse ventricular myocytes. Life Sci70: 1173–1184, 2002.
49.
Konrad D, Oldner A, Wanecek M, Rudehill A, Weitzberg E, Biber B, Johansson G, Haggmark S, Haney M. Positive inotropic and negative lusitropic effects of endothelin receptor agonism in vivo. Am J Physiol Heart Circ Physiol289:H1702–H1709, 2005.
50.
Backs J, Bresch E, Lutz M, Kristen AV, Haass M. Endothelin-1 inhibits the neuronal norepinephrine transporter in hearts of male rats. Cardiovasc Res67:283–290, 2005.
51.
Zaretsky DV, Zaretskaia MV, Kalenikova EI, Grafov MA. Endothelin antagonism does not affect adrenal catecholamine secretion and system haemodynamics during acute stress in Wistar rats. J Cardiovasc Pharmacol36:S374–S376, 2000.
52.
Manukhina EB, Downey HF, Mallet RT. Role of nitric oxide in cardiovascular adaptation to intermittent hypoxia. Exp Biol Med (Maywood)231:343–365, 2006.
53.
Zhao X, Chen YR, He G, Zhang A, Druhan LJ, Strauch AR, Zweier JL. Endothelial nitric oxide synthase (NOS3) knockout decreases NOS2 induction, limiting hyperoxygenation and conferring protection in the postischemic heart. Am J Physiol Heart Circ Physiol292:H1541–H1550, 2007.
54.
Masano T, Kawashima S, Toh R, Satomi-Kobayashi S, Shinohara M, Takaya T, Sasaki N, Takeda M, Tawa H, Yamashita T, Yokoyama M, Hirata K. Beneficial effects of exogenous tetrahydrobiopterin on left ventricular remodeling after myocardial infarction in rats: the possible role of oxidative stress caused by uncoupled endothelial nitric oxide synthase. Circ J72:1512–1519, 2008.
55.
Jesmin S, Zaedi S, Maeda S, Yamaguchi I, Goto K, Miyauchi T. Effects of a selective endothelin A receptor antagonist on the expressions of iNOS and eNOS in the heart of early streptozotocin-induced diabetic rats. Exp Biol Med (Maywood)231:925–931, 2006.
56.
Han F, Shirasaki Y, Fukunaga K. Microsphere embolism-induced endothelial nitric oxide synthase expression mediates disruption of the blood-brain barrier in rat brain. J Neurochem99:97–106, 2006.
57.
Ryou MG, Sun J, Oguayo KN, Manukhina EB, Downey HF, Mallet RT. Hypoxic conditioning suppresses nitric oxide production upon myocardial reperfusion. Exp Biol Med (Maywood)233:766–774, 2008.
