Abstract
Vasopeptidase inhibitors possess dual inhibitory actions on neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) and have beneficial effects on cardiac remodeling. However, the contribution of NEP inhibition to their effects is not yet fully understood. To address the role of cardiac NEP inhibition in the anti-remodeling effects of a vasopeptidase inhibitor, we examined the effects of omapatrilat on the development of cardiac remodeling in rats with left coronary artery ligation (CAL) and those on collagen synthesis in cultured fibroblast cells. In vivo treatment with omapatrilat (30 mg/kg/day for 5 weeks) inhibited cardiac NEP activity in rats with CAL, which was associated with a suppression of both cardiac hypertrophy and collagen deposition. In cultured cardiac fibroblasts, omapatrilat (10−7~10−5 M) inhibited NEP activity and augmented the ANP-induced decrease in [3H]-proline incorporation. ONO-BB, an active metabolite of the NEP selective inhibitor ONO-9902, also augmented the ANP-induced response, whereas captopril, an ACE inhibitor, did not. The angiotensin I-induced increase in [3H]-proline incorporation was prevented by omapatrilat and captopril, but not by ONO-BB. The results suggest that vasopeptidase inhibitor suppressed cardiac remodeling in the setting of chronic heart failure, possibly acting through the direct inhibition of cardiac NEP. Vasopeptidase inhibitors may have therapeutic advantages over the classical ACE and NEP inhibitors alone with respect to the regression of cardiac fibrosis.
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Schaper J, Speiser B: The extracellular matrix in the failing human heart. Basic Res Cardiol 87: 303-309, 1992
Sabbah HN, Sharov VG, Lesch M, Goldstein S: Progression of heart failure: A role for interstitial fibrosis. Mol Cell Biochem 147: 29-34, 1995
Pelouch V, Dixon IM, Golfman L, Beamish RE, Dhalla NS: Role of extracellular matrix proteins in heart function. Mol Cell Biochem. 129: 101-120, 1993
Dixon IM, Ju H, Jassal DS, Peterson DJ: Effect of ramipril and losartan on collagen expression in right and left heart after myocardial infarction. Mol Cell Biochem 165: 31-45, 1996
Nwogu JI, Geenen D, Bean M, Brenner MC, Huang X, Buttrick PM: Inhibition of collagen synthesis with prolyl 4-hydroxylase inhibitor improves left ventricular function and alters the pattern of left ventricular dilatation after myocardial infarction. Circulation 104: 2216-2221, 2001
Yamagishi H, Kim S, Nishikimi T, Takeuchi K, Takeda T: Contribution of cardiac renin-angiotensin system to ventricular remodeling in myocardial-infarcted rats. J Mol Cell Cardiol 25: 1369-1380, 1993
Sakai S, Miyauchi T, Sakurai T, Kasuya Y, Ihara M, Yamaguchi I, Goto K, Sugishita Y: Endogenous endothelin-1 participates in the maintenance of cardiac function in rats with congestive heart failure: Marked increase in endothelin-1 production in the failing heart. Circulation 93: 1214-1222, 1996
Bralet J, Schwartz JC: Vasopeptidase inhibitors: An emerging class of cardiovascular drugs. Trends Pharmacol Sci 22: 106-109, 2001
Corti R, Burnett JC Jr, Rouleau JL, Ruschitzka F, Luscher TF: Vasopeptidase inhibitors: A new therapeutic concept in cardiovascular disease? Circulation 104: 1856-1862, 2001
Trippodo NC, Fox M, Monticello TM, Panchal BC, Asaad MM: Vasopeptidase inhibition with omapatrilat improves cardiac geometry and survival in cardiomyopathic hamsters more than does ACE inhibition with captopril. J Cardiovasc Pharmacol 34: 782-790, 1999
Rouleau JL, Pfeffer MA, Stewart DJ, Isaac D, Sestier F, Kerut EK, Porter CB, Proulx G, Qian C, Block AJ: Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial. Lancet 356: 615-620, 2000
Packer M, Califf RM, Konstam MA, Krum H, Mcmurray JJ, Rouleau JL, Swedberg K: Comparison of omapatrilat and enalapril in patients with chronic heart failure: The omapatrilat vs. enalapril randomized trial of utility in reducing events (OVERTURE). Circulation 106: 920-926, 2002
Lapointe N, Blais C Jr, Adam A, Parker T, Sirois MG, Gosselin H, Clement R, Rouleau JL: Comparison of the effects of an angiotensin-converting enzyme inhibitor and a vasopeptidase inhibitor after myocardial infarction in the rat. J Am Coll Cardiol 39: 1692-1698, 2002
Cleutjens JP, Verluyten MJ, Smiths JF, Daemen MJ: Collagen remodeling after myocardial infarction in the rat heart. Am J Pathol 147: 325-338, 1995
Sun Y, Zhang JQ, Zhang J, Lamparter S: Cardiac remodeling by fibrous tissue after infarction in rats. J Lab Clin Med 135: 316-323, 2000
Sanbe A, Tanonaka K, Hanaoka Y, Katoh T, Takeo S: Regional energy metabolism of failing hearts following myocardial infarction. J Mol Cell Cardiol 25: 995-1013, 1993
Intengan HD, Schiffrin EL: Vasopeptidase inhibition has potent effects on blood pressure and resistance arteries in stroke-prone spontaneously hypertensive rats. Hypertension 35: 1221-1225, 2000
Maki T, Nasa Y, Yamaguchi F, Yoshida H, Mori M, Takada T, Horikawa E, Okano K, Takeo S: Long-term treatment with neutral endopeptidase inhibitor improves cardiac function and reduces natriuretic peptides in rats with chronic heart failure. Cardiovasc Res 51: 608-617, 2001
Tsai BS, Peach MJ: Angiotensin homologs and analogs as inhibitors of rabbit pulmonary angiotensin-converting enzyme. J Biol Chem 252: 4674-4681, 1977
Yoshida H, Takahashi M, Tanonaka K, Maki T, Nasa Y, Takeo S: Effects of ACE inhibition and angiotensin II type 1 receptor blockade on cardiac function and G proteins in rats with chronic heart failure. Br J Pharmacol 134: 150-160, 2001
Maki T, Horio T, Yoshihara F, Suga S, Takeo S, Matsuo H, Kangawa K: Effect of neutral endopeptidase inhibitor on endogenous atrial natriuretic peptide as a paracrine factor in cultured cardiac fibroblasts. Br J Pharmacol 131: 1204-1210, 2000
Burrell LM, Droogh J, Man in't Veld O, Rockell MD, Farina NK, Johnston CI: Antihypertensive and antihypertrophic effects of omapatrilat in SHR. Am J Hypertens 13: 1110-1116, 2000
Pu Q, Touyz RM, Schiffrin EL: Comparison of angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP) and dual ACE/NEP inhibition on blood pressure and resistance arteries of deoxycorticosterone acetate-salt hypertensive rats. J Hypertens 20: 899-907, 2002
Weber MA: Vasopeptidase inhibitors. Lancet 358: 1525-1532, 2001
Schoemaker RG, Debets JJ, Struyker-Boudier HA, Smits JF: Delayed but not immediate captopril therapy improves cardiac function in conscious rats, following myocardial infarction. J Mol Cell Cardiol 23: 187-197, 1991
Weber KT: Extracellular matrix remodeling in heart failure: A role for de novo angiotensin II generation. Circulation 96: 4065-4082, 1997
Sun Y, Cleutjens JP, Diaz-Arias AA, Weber KT: Cardiac angiotensin converting enzyme and myocardial fibrosis in the rat. Cardiovasc Res 28: 1423-1432, 1994
Weber KT, Sun Y, Katwa LC: Myofibroblasts and local angiotensin II in rat cardiac tissue repair. Int J Biochem Cell Biol 29: 31-42, 1997
Kim S, Ohta K, Hamaguchi A, Yukimura T, Miura K, Iwao H: Angiotensin II induces cardiac phenotypic modulation and remodeling in vivo in rats. Hypertension 25: 1252-1259, 1995
Linz W, Wiemer G, Schaper J, Zimmermann R, Nagasawa K, Gohlke P, Unger T, Scholkens BA: Angiotensin converting enzyme inhibitors, left ventricular hypertrophy and fibrosis. Mol Cell Biochem 147: 89-97, 1995
Monopoli A, Ongini E, Cigola E, Olivetti G: The neutral endopeptidase inhibitor, SCH 34826, reduces left ventricular hypertrophy in spontaneously hypertensive rats. J Cardiovasc Pharmacol 20: 496-504, 1992
Pu Q, Schiffrin EL: Effect of ACE/NEP inhibition on cardiac and vascular collagen in stroke-prone spontaneously hypertensive rats. Am J Hypertens 14: 1067-1072, 2001
Piedimonte G, Nadel JA, Long CS, Hoffman JI: Neutral endopeptidase in the heart neutral endopeptidase inhibition prevents isoproterenol-induced myocardial hypoperfusion in rats by reducing bradykinin degradation. Circ Res 75: 770-779, 1994
Fielitz J, Dendorfer A, Pregla R, Ehler E, Zurbrugg HR, Bartunek J, Hetzer R, Regitz-Zagrosek V: Neutral endopeptidase is activated in cardiomyocytes in human aortic valve stenosis and heart failure. Circulation 105: 286-289, 2002
Oliver PM, Fox JE, Kim R, Rockman HA, Kim HS, Reddick RL, Pandey KN, Milgram SL, Smithies O, Maeda N: Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. Proc Natl Acad Sci USA 94: 14730-14735, 1997
Li Y, Kishimoto I, Saito Y, Harada M, Kuwahara K, Izumi T, Takahashi N, Kawakami R, Tanimoto K, Nakagawa Y, Nakanishi M, Adachi Y, Garbers DL, Fukamizu A, Nakao K: Guanylyl cyclase-A inhibits angiotensin II type 1 A receptor-mediated cardiac remodeling, an endogenous protective mechanism in the heart. Circulation 106: 1722-1728, 2002
Harada K, Sugaya T, Murakami K, Yazaki Y, Komuro I: Angiotensin II type 1 A receptor knockout mice display less left ventricular remodeling and improved survival after myocardial infarction. Circulation 100: 2093-2099, 1999
Chen HH, Lainchbury JG, Matsuda Y, Harty GJ, Burnett JC Jr: Endogenous natriuretic peptides participate in renal and humoral actions of acute vasopeptidase inhibition in experimental mild heart failure. Hypertension 38: 187-191, 2001
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Maki, T., Nasa, Y., Tanonaka, K. et al. Direct inhibition of neutral endopeptidase in vasopeptidase inhibitor-mediated amelioration of cardiac remodeling in rats with chronic heart failure. Mol Cell Biochem 254, 265–273 (2003). https://doi.org/10.1023/A:1027337601863
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DOI: https://doi.org/10.1023/A:1027337601863