Latar belakang: Antrasiklin diketahui dapat menimbulkan toksisitas pada jantung melalui mekanisme peningkatan pembentukan advanced glycation end-products (AGEs), yakni pentosidine dan Nε-(carboxylmethyl)lysine (CML).Penelitian ini bertujuan mengetahui efek telmisartan (TLM) suatu antagonis reseptor angiotensin II (ARB) terhadaptoksisitas jantung yang diinduksi oleh antrasiklin.Metode: Tikus galur Sprague Dawley dibagi secara acak menjadi 3 kelompok: kelompok pertama mendapat daunorubisin(DNR) 3 mg/kgBB dua hari sekali hingga mencapai dosis kumulatif 9 mg/kgBB. Kelompok kedua mendapat DNR ditambahTLM 10 mg/kgBB/hari, secara oral selama 6 minggu, sedangkan kelompok kontrol (CTL) hanya mendapat pelarut DNR.Rerata tekanan darah (MBP), tekanan ventrikel kiri (LVP), tekanan diastolik akhir ventrikel kiri (LVEDP), dan kontraktilitasventrikel (±dP/dt) diukur dengan menggunakan Powerlab. Sedangkan fraksi ejeksi (EF) dan fraksi pemendekan (FS) dinilaidengan ekokardiografi. Ekspresi reseptor AGE (RAGE), pentosidin, dan CML diperiksa dengan imunohistokimia danwestern blot.Hasil: DNR menyebabkan perburukan beberapa parameter hemodinamik yang dapat diperbaiki oleh TLM, yakni :LVP : 124,3 ± 6,0; 111 ± 7; dan 115,1 ± 5,4 mmHg, untuk kelompok CTL, DNR, dan DNR-TLM. LVEDP: 7,5 ± 0,9;10,7 ± 0,3; 8,7 ± 0,4 mmHg, dan ; +dP/dt: 6813 ± 541; 4800 ± 345; 5950 ± 398 mmHg/s. Hal yang sama juga terlihatpada parameter ekokardiografi, yakni: EF: 78,9 ± 1,8; 59.6 ± 1,4; 76,2 ± 2,75 %; FS: 42,8 ± 1,7; 29,1 ± 1,3; 41 ±2,7 % untuk kelompok CTL, DNR and DNR-TLM. Ekspresi protein RAGE, pentosidine dan CML meningkat padapemberian DNR yang kemudian dihambat dengan pemberian bersama TLM.Kesimpulan: AGE berperan pada toksisitas jantung akibat pemberian DNR. Telmisartan dapat menghambat efek tersebutdengan menurunkan ekspresi RAGE.
Abstract
Background: Anthracyclines have been reported to induce cardiotoxicity through mechanisms involving formation ofadvanced glycation end-products (AGEs), including pentosidine and Nє-(carboxymethyl) lysine (CML). We investigated thepotential 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 plusTLM at a dose10 mg/kgBW, by oral gavage for 6 weeks, and the third group served as control group (CTL) which onlyreceived 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. Ejectionfraction (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 couldbe reversed by TML (LVP: 124.3 ± 6.0; 111 ± 7; and 115.1 ± 5.4 mmHg, respectively in CTL, DNR and DNR-TLMgroups; LVEDP: 7.5 ± 0.9; 10.7 ± 0.3; 8.7 ± 0.4 mmHg, respectively; +dP/dt: 6813 ± 541; 4800 ± 345; 5950 ± 398mmHg/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 aswell 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 couldinhibit the progression of cardiac toxicity at least in part by reduction RAGE expressiom. |
