Pengaruh doksisiklin dan lisinopril pada remodeling vaskular :: Studi histomorfometri pada tikus hipertensi dengan induksi glukokortikoid

JUNAIDI, Edy, Prof. dr. Ngatidjan, MSc., Sp.FK(K)

2009 | Tesis | S2 Ilmu Kedokteran Dasar dan Biomedis

Hipertensi merupakan faktor resiko utama dan independen terhadap penyakit kardiovaskular dengan prevalensi semakin meningkat yang menambah beban masalah kesehatan. Sebagai respons adaptif terhadap hipertensi, vasa mengalami remodeling yang mempengaruhi progresivitas hipertensi dan merupakan petanda awal kerusakan organ. Proses remodeling melibatkan perubahan komponen tunika media dan matriks ekstraseluler dimediasi aktivitas enzim matrix metalloproteinase (MMP). Penelitian ini bertujuan membuktikan apakah inhibisi MMP oleh doksisiklin dan lisinopril dapat menghambat remodeling vaskular tikus hipertensi yang diinduksi glukokortikoid dan asupan garam 1%. Empat puluh ekor tikus putih putih Wistar dibagi menjadi 5 kelompok meliputi 4 kelompok hipertensi (kelompok II – V) dan 1 kelompok normal sebagai kontrol. Induksi hipertensi dilakukan dengan penyuntikkan methylprednisolone 20 mg/kg/minggu subkutan dan asupan garam 1% ad libitum selama 28 hari. Perlakuan oral berupa normal saline (NS) diberikan pada kelompok I dan II bertindak sebagai kontrol, doksisiklin pada kelompok III, doksisiklin dan lisinopril pada kelompok IV, dan lisinopril pada kelompok V. Perlakuan diberikan selama 28 hari. Empat jam setelah perlakuan pada hari ke28, tekanan darah diukur dengan tailcuff NIBP model 31, kemudian dikorbankan dengan dislokasi servikal. Arteri renalis diambil melalui pembedahan dan dimasukkan formalin 10%, dipreparasi untuk pemeriksaan histomorfometri. Hasil penelitian ini menunjukkan bahwa proses remodeling berlangsung secara hipotrofi. Dibandingkan terhadap kelompok normal, penurunan ketebalan dinding vasa secara bermakna tampak pada kelompok tikus hipertensi, doksisiklin + lisinopril, dan lisinopril. Densitas kolagen kelompok doksisiklin juga lebih rendah dibandingkan kelompok perlakuan lainnya. Growth index doksisiklin hampir separuh lebih lambat dibandingkan kelompok hipertensi dan lisinopril. MAP kelompok doksisiklin lebih tinggi daripada kelompok lisinopril dan normal. Distensibilitas vasa kelompok doksisiklin lebih rendah daripada kelompok lisinopril. Oleh karena itu, berdasarkan nilai growth index, CSA, densitas kolagen, kekakuan vaskular dan penurunan relatif tekanan darah membuktikan bahwa doksisiklin mampu menghambat remodeling vaskular pada tikus putih hipertensi.

Hypertension is major risk factor and independent to cardiovascular diseases which the prevalence tend to increase with time adding more burden to health problems. Vascular remodeling which occur during the course of hypertension is a first sign of organ damage. Remodeling processes involve changes of tunica media components and extracellular matrices mediated by matrix metalloproteinase (MMP) activity. The goal of this research was to prove whether inhibition of MMP by doxycycline and lisinopril in inhibiting vascular remodeling on hypertensive rats induced by glucocorticoid and 1% salt loading. Forty Wistar rats were divided into 5 groups consist of 4 hypertensive groups (II – V) and 1 normal control group. Hypertension was induced by methylprednisolone 20 mg/kg/week subcutaneously and 1% salt intake ad libitum for 28 days. As control group, oral treatment of normal saline (NS) were given to group I and II, doxycycline, doxycycline + lisinopril, and lisinopril were given to group III – V, respectively and were administered for 28 days. Four hours of day of 28th, blood pressure were measured using tailcuff NIBP model 31. Then, rats were sacrified by cervical dislocation. Renal arteries were taken through otopsy and put into 10% formalin and prepared for histomorphometric analysis. The results showed that remodeling process occurred as hypotrophic remodeling. Vessel wall (CSA) reduced significantly on hypertensive group, doxycycline + lisinopril group, and lisinopril group. Collagen density were lower on doxycycline group compare to other treatment groups. Growth index on doxycycline group is almost twice lower than that of hypertensive or lisinopril groups. Doxycycline showed tendency to lower blood pressure to considerable degree. Vascular stiffness of doxycycline group is lower than other treatment groups. Therefore, based on growth index, CSA, collagen density, vascular stiffness, and relative reduction of blood pressure suggesting that doxycycline reduce vascular remodeling on hypertensive rats. Keywords : blood pressure – histomorphometry – doxycycline – lisinopril – MMP – remodeling

Kata Kunci : Tekanan darah,Histomorfetri,Doksisiklin,Lisinopril,MMP,Remodeling