EFEK TELMISARTAN TERHADAP KADAR TGF-β1 DAN KETEBALAN DINDING AORTA TIKUS WISTAR (Rattus novergicus) YANG DIINDUKSI NaCl 8%

M. RICKY RAMADHIAN, Prof. Dr. Mustofa, M. Kes., Apt; Dr. Muhammad Ghufron

2015 | Tesis | S2 Ilmu Kedokteran Dasar dan Biomedis

Hubungan antara konsumsi garam, hipertensi, penyakit kardiovaskuler, dan penyakit ginjal sudah diteliti sejak lama, tetapi masih memberikan pertanyaan yang belum terjawab dan menimbulkan kontroversi terhadap peranan garam terhadap patogenesis hipertensi, kerusakan pada kardiovaskuler dan ginjal. Penyakit jantung kongestif dan fibrosis ginjal dikaitkan dengan asupan NaCl tinggi tetapi mekanisme yang tepat yang mendasari hubungan ini belum diketahui. Proses fibrosis berhubungan dengan sistem renin angiotensin-aldosteron, transforming growth factor-β (TGF-β), faktor pertumbuhan jaringan ikat (connective tissue growth factor (CTGF), matriks metalloproteinase dan peroxisome proliferator-activated receptor gamma (PPARγ). Telmisartan obat antihipetensi mempunyai fungis tidak hanya memblok reseptor angiotensin tetapi juga akan mengaktifkan proliferator activated receptor gamma (PPAR-γ) dan diduga menghambat transforming growth factor-β1 (TGF-β1). Apakah telmisartan menghambat peningkatan kadar TGF-β1, menghambat peningkatan fraksi volum kolagen, dan menghambat penebalan dinding aorta tikus Wistar yang diinduksi dengan NaCl 8% dalam percobaan ini. Dalam penelitian ini digunakan 25 ekor tikus Wistar jantan usia 2,5-3 bulan, berat 100-150 gram dibagi dalam 5 kelompok masing-masing 5 ekor. Kelompok I K I (kontrol negatif) tidak diberi NaCl, K II (kontrol positif) diberi NaCl 8% tiap hari, K III, IV dan V diberi NaCl 8% dan telmisartan berturut-turut 3, 6 dan 12 mg/kg BB tiap hari, selama 8 minggu. Pada minggu ke-8, tikus dikorbankan dengan cara dislokasi leher dan diambil organ aortanya. Pengukuran TGF-β1 diukur dengan teknik enzyme linked immunosorbent assay, ketebalan dinding aorta dan fraksi volum kolagen dilakukan pewarnaan picrosirius red dianalisis dengan ImageJ 1.49c. Data dinyatakan sebagai mean ± standar deviasi. Data dianalisis dengan uji parametrik (ANOVA) yang dilanjutkan dengan uji Post Hoc untuk perbandingan beberapa kelompok atau uji nonparametrik (Kruskal-Wallis). Sebuah nilai p<0,05 dianggap signifikan secara statistik. Hasil penelitian menunjukkan bahwa tekanan darah sistolik tidak meningkat dengan induksi NaCl 8%. Kadar TGF-β1 aorta pada tikus Wistar yang diberikan telmisartan bersama NaCl 8% lebih rendah dibandngkan tikus yang diinduksi NaCl 8% saja (p <0,05). Fraksi volume dinding kolagen aorta tidak mengalami peningkatan secara signifikan pada kelompok tikus yang diinduksi NaCl 8% (p>0,05). Rasio antara ketebalan dinding aorta dibandingkan diameter lumen pada tikus lebih rendah pada kelompok perlakuan telmisartan yang dibandingkan dengan kelompok NaCl 8% saja (p <0,05). Kesimpulan, konsentrasi TGF-β1 aorta lebih tinggi, fraksi volume kolagen dinding aorta tidak mengalami perubahan, rasio antara ketebalan dinding aorta dibandingkan diameter lumen lebih tinggi pada kelompok NaCl 8% saja dibandingkan dengan kelompok perlakuan telmisartan tikus Wistar jantan.

High salt intake is the main environmental factors that cause hypertension. The scientific literatures still debate that people should consume a low-salt diet.The relationship between salt intake, hypertension, cardiovascular, and kidney disease has been studied for a long time, but still provide unanswered questions. Congestive heart failure and renal fibrosis associated with high NaCl intake but the exact mechanism underlying this relationship has not been explained. The fibrotic process is associated with renin-angiotensin-aldosteron system, transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), matrix metalloproteinases and peroxisome proliferator-activated receptor gamma (PPARγ). Telmisartan is antihypertensive drug that not only blocks angiotensin receptor but also leads to the decrease of blood pressure, activates peroxisome proliferator activated receptor gamma (PPAR-γ) and presumeably inhibits expression of transforming growth factor beta-1 (TGF-β1). Does telmisartan inhibit TGF-β1 level, the aorta wall collagen volume fraction, and thickness of aortawall in excessive NaCl-induced Wistar rats are studied in this experiment. Twenty five male Wistar 2,5-3 months of age and 100 – 150 g BW rats were used in this experiment. They were grouped into 5, each contain of rats. Group I (G I) as placebo did not receive NaCl 8% nor telmisartan. G II received NaCl 8% only. G III, IV and V received NaCl 8% and telmisartan 3, 6 and 12 mg/ kg BW. The treatments were given every day for 8 weeks. At the day of 56 all rats were sacrificed by mean of neck dislocation and operated to take aorta. The concentration of TGF-β1 was measured by enzyme linked immunoabsorbent assay technique. Aorta stained with picrosirius red. Collagen volume fraction and thickness aortic wall were analyzed with imageJ 1.49c. Data were expressed as mean ± standard deviation. They were analyzed by parametric test (ANOVA) that followed by Post Hoc test for comparison of multiple groups or nonparametric test (Kruskal-Wallis). A value of p<0.05 was considered statistically significant. The result showed that systolic blood pressure not increased significantly on NaCl 8% induced rats in comparing to negative control (p>0.05). Aorta TGF-β1 concentration decreased significantly in telmisartan-given rat groups comparing NaCl 8% only and placebo (p<0.05). Aorta wall collagen volume fraction did not decrease significantly on telmisartan-given rat groups comparing NaCl 8% only (p>0,05). Ratio of aortawall thickness to lumen diameter in rat decreased significantly on telmisartan-given rat groups comparing NaCl 8% only (p<0,05). In conclusion, aorta TGF-β1 concentration were higher, aorta wall collagen volume fraction did not change, ratio of aortawall thickness ratio to lumen diameter were higher in aorta of NaCl 8% only male Wistar rats comparing to telmisartan-given male Wistar rats.

Kata Kunci : NaCl, telmisartan, TGF-β, kolagen, aorta