Telmisartan inhibits the progression of cardiomyopathy in daunorubicin treated rats: the role of advanced glycation end products
Background: Anthracyclines have been reported to induce cardiotoxicity through mechanisms involving formation of advanced glycation end-products (AGEs), including pentosidine and Nє-(carboxymethyl) lysine (CML). We investigated the potential utility of telmisartan (TML), an angiotensin II receptor antagonists (ARB) on anthracycline-induced cardiotoxicity.
Methods: Three groups of Sprague-Dawley rats were treated as follows: The first group received daunorubicin (DNR) 3 mg/kgBW every alternating day to reach a cumulative dose of 9 mg/kg DNR . The second group received DNR plus TLM at a dose10 mg/kgBW, by oral gavage for 6 weeks, and the third group served as control group (CTL) which only received vehicle of DNR. Mean blood pressure (MBP) peak left ventricular pressure (LVP), LV end-diastolic pressure (LVEDP), and intra-ventricular contractility (±dP/dt) were recorded by using Powerlab instrumentation. Ejection fraction (EF), and fractional shortening (FS) were measured by echocardiography. Expression of receptor of AGE (RAGE), pentosidine and CML were measured by immunohistochemistry and Western blot in LV tissue.
Results: DNR treatment was associated with significant weakening of some hemodynamic parameters which could be reversed by TML (LVP: 124.3 ± 6.0; 111 ± 7; and 115.1 ± 5.4 mmHg, respectively in CTL, DNR and DNR-TLM groups; LVEDP: 7.5 ± 0.9; 10.7 ± 0.3; 8.7 ± 0.4 mmHg, respectively; +dP/dt: 6813 ± 541; 4800 ± 345; 5950 ± 398 mmHg/s, respectively). The same phenomenons were also observed on echocardiographic parameters (EF: 78.9 ± 1.8; 59.6 ± 1.4; 76.2 ± 2.75 %, resepectively; FS: 42.8 ± 1.7; 29.1 ± 1.3; 41 ± 2.7 %) respectively. Expression of RAGE as well as pentosidine and CML were increased in DNR-rats. TML treatment ameliorated these changes.
Conclusion: These results suggested the role of AGE formation in DNR-induced cardiotoxicity and telmisartan could inhibit the progression of cardiac toxicity at least in part by reduction RAGE expressiom. (Med J Indones 2011; 20:255-62)
Simunek T, Stirba M, Popelova O, Adamcova M, Hridina R, Gersl, V. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol Rep. 2009;61:154-71.
Gianni L, Herman EH, Lipshultz SE, Minotti G, Sarvazyan, Sawyer DB.. Anthracyline cardiotoxicity: from bench to bedside. J Clin Oncol. 2008;26: 3777-84.
Saad SY, Najjar TA, Arafah MM.. Cardioprotective effects of subcutaneous ebselen against daunorubicin-induced cardiomyopathy in rats. Basic Clin Pharmacol Toxicol. 2006;99: 412-7.
Yosihara K, Nagayama Y, Horiguchi H, Yoshida S, Tohyoh S, Takahashi, S., et al. Acceleration of pentosidine formation by medication. Int Congr Ser. 2002;1245: 425-6.
Moriyama T, Kemi M, Okumura C, Yoshihara K, Horie T. Involvement of advanced glycation end-products, pentosidine and N(epsilon)-(carboxymethyl)lysine, in doxorubicininduced cardiomyopathy in rats. Toxicology. 2010;268:89-97.
Benson SC, Pershadsingh HA, Ho CI, Chittiboyina A, Desai P, Pravenec M et al. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PARgammamodulating activity. Hypertension. 2004;43:993-1002.
Yamagishi S, Nakamura K, Matsui T.. Regulation of advanced glycation end product (AGE)-receptor (RAGE)
system by PPAR-gamma agonists and its implication in cardiovascular disease. Pharmacol Res. 2009;60:174-8.
Arozal W, Watanabe K, Veeraveedu PT, Thandavarayan RA, Harima M, Sukumaran, V et al. Effect of telmisartan
in limiting the cardiotoxic effect of daunorubicin in rats. J Pharm Pharmacol. 2010;62:1776-83.
Miyata T, van Ypersele de Strihou C, Ueda Y, Ichimiro K, Inagi R, Onogi H, et al. Angiotensin II receptor blockers and angiotensin converting enzyme inhibitors lower in vitro the formation of advanced glycation end products: biochemical mechanism. J Am Soc Nephrol. 2002;13:2478-87.
Nakamura, K., Yamagishi, S., Nakamura, Y., Takenaka, K., Matsui, T., Jinnouchi Y.Telmisartan inhibits expression of a receptor for advanced glycation end products (RAGE) in angiotensin-II-exposed endothelial cells and decreases serum levels of soluble RAGE in patients with essential hypertension. Microvasc Res. 2005;70:137-41.
Arozal W, Watanabe K, Veeraveedu PT, Ma M, Thandavarayan RA, Sukumaran V et al. Protective effect of carvedilol on daunorubicin-induced cardiotoxicity and nephrotoxicity in rats. Toxicology. 2010;274:18-26.
Soga M, Kamal FA, Watanabe, K, Ma, M, Palaniyandi S, Prakash P et al. Effects of angiotensin II receptor blocker (candesartan) in daunorubicin-induced cardiomyopathic rats. Int J Cardiol. 2005;110:378-85.
Ibrahim MA, Ashour OM, Ibrahim YF, El-Bitar HI, Gomaa W, Abdel-Rahim SR. Angiotensin-converting enzyme
inhibition and angiotensin AT(1)-receptor antagonism equally improve doxorubicin-induced cardiotoxicity and
nephrotoxicity. Pharmacol Res. 2009;60:378-81.
Giri SN, Al-Bayati MA, Du X, Schelegle E, Mohr FC, Margolin SB., Amelioration of doxorubicin-induced cardiac and renal toxicity by pirfenidone inrats. Cancer Chemother Pharmacol. 2004;53, 141-50.
Nakhaoul F, Ramada R, Khankin E, Yaccob A, Kositch Z, Lewin M, Assady S, Abassi Z. Glomerular abundance of nephrin and podocin in experimental nephritic syndrome: different effects of antiproteinuric therapies. Am J Physiol Renal Physiol. 2005;289:F880-90.
Watanabe K, OhtaY, Nakazawa M, Higuchi H, Hasegawa G, Naito M. et al . Low dose carvedilol inhibits progression of heart failure in rats with dilated cardiomyopathy. Br J Pharmacol. 2000;130:1489-95.
Yilmaz S, Atessahin A, Sahna E, Karaha I, Ozer S. Protective effect of lycopene on adriamycin-induced cardiotoxicity and nephrotoxicity. Toxicology. 2006;218;164-71.
Gurusamy N, Watanabe K, Ma M, Zhang S, Muslin AJ, Kodama, M et al. Dominant negative 14-3-3 promotes cardiomyocyte apoptosis in early stage of type I diabetes mellitus through activation of JNK. Biochem Biophys Res Commun. 2004;320:773-80.
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