KARYA TULIS AKHIR

PENGARUH EKSTRAK BIJI PINANG (Areca catechu) TERHADAP

REGRESI PLAK ENDOTEL VASKULAR PADA TIKUS PUTIH

MODEL ATEROSKLEROTIK

Oleh:

Vihara Dewi Mahendra

(09020071)

UNIVERSITAS MUHAMMADIYAH MALANG

FAKULTAS KEDOKTERAN

2013

i

HASIL PENELITIAN

PENGARUH EKSTRAK BIJI PINANG (Areca catechu) TERHADAP

REGRESI PLAK ENDOTEL VASKULAR PADA TIKUS PUTIH MODEL

ATEROSKLEROTIK

KARYA TULIS AKHIR

Diajukan kepada

Universitas Muhammadiyah Malang

untuk Memenuhi Salah Satu Persyaratan

Program Sarjana Fakultas Kedokteran

Oleh:

Vihara Dewi Mahendra

(09020071)

UNIVERSITAS MUHAMMADIYAH MALANG

FAKULTAS KEDOKTERAN

2013

ii

LEMBAR PENGESAHAN

LAPORAN HASIL PENELITIAN

Telah disetujui sebagai hasil penelitian

Untuk memenuhi persyaratan

Pendidikan Sarjana Fakultas Kedokteran

Universitas Muhammadiyah Malang

Tanggal : 28 Januari 2013

Pembimbing I

Prof.Dr.H.Djoni Djunaedi, dr,Sp.PD.,KPTI.,FINASIM

Pembimbing II

dr. Erdy Kuswandana

Mengetahui,

Fakultas Kedokteran

Dekan,

dr. Irma Suswati, M.Kes

iii

LEMBAR PENGUJIAN

Karya Tulis Akhir ini telah diuji dan dipertahankan di depan Tim Penguji pada tanggal 28

Januari 2013

Tim Penguji

Prof.Dr.H.Djoni Djunaedi, dr,Sp.PD.,KPTI.,FINASIM Ketua

dr. Erdy Kuswandana Anggota

dr.Fathiyah Safitri,Mkes Anggota

iv

KATA PENGANTAR

Assalamu’alaikum warahmatullahi wabarakatuh

Segala puji bagi Allah SWT atas segala rahmat,hidayah serta innayah –

Nya dan serta shalawat serta salam terlimpahkan bagi junjungan kita Nabi

Muhammad SAW. Syukur Alhamdulillah tak terhingga atas limpahan rahmat dan

karunia Allah serta doa dari kerabat dan rekan sehingga penulis dapat

menyelesaikan karya tulis akhir ini.

Dalam kesempatan ini penulis ingin mengucapkan terimakasih yang tak terhingga

kepada pihak- pihak yang turut membantu terselesaikannya tugas akhir ini, yaitu :

1. Ayah dan ibu tercinta, yang selalu tak henti-hentinya mendoakan dan memberi

semangat pada putri tercintanya.

2. Prof.Dr.H.Djoni Djunaedi, dr,Sp.PD.,KPTI.,FINASIM dan dr. Erdy

Kuswandana selaku dosen pembimbing, atas bimbingan dan saran yang telah

diberikan kepada penulis.

3. dr.Fathiyah Safithri,Mkes selaku dosen penguji atas bimbingan dan saran yang

telah diberikan kepada penulis.

4. dr. Thontowi Djauhari NS,Mkes, drg. Prasetyo Adi dan dr Indra Setiawan ,Sp

THT –KL atas bimbingan , saran , semangat serta ilmu – ilmu yang

bermanfaat yang telah diberikan kepada penulis .

5. dr. Soebarkah Basuki, Sp.PA selaku pembimbing Patologi Anatomi atas

bimbingan,semangat sertaa saran yang telah diberikan kepada penulis.

6. Fajar Akhmad Fauzi, seseorang yang dengan penuh kesabaran, perhatian,

kasih sayang serta doa yang tak henti-hentinya untuk penulis.

v

7. Adik- adikku tercinta, Clara Shinta, Seisa, Lyla, terimakasih banyak telah

memberikan warna baru dalam kehidupan penulis.

8. Rekan se – Timku, Fahmy,Erwin,Surya,Ana, terimakasih atas kerjasama,

bantuan dan semangat kalian. Semoga kita dapat menjadi dokter yang baik

kelak. Amin.

9. Mbak Emi, mbak Dilla, dan teman- teman Asisten lab Skill, terimakasih

banyak atas bantuan dan semangat yang selama ini diberikan kepada penulis.

10. Mbak siti, Mbak Vina,Mbak laela,mbak Iin,Mbak desy,mbak Rahma,Mas

heru dan seluruh staf dan karyawan UMC terimakasih banyak atas bantuan

dan semangat serta hari- hari yang sangat menyenangkan selama 2,5 tahun ini.

11. Teman – teman FK 09 , terimakasih atas bantuan dan hari- hari yang

menyenangkan selama 3,5 tahun ini.

12. Bapak Sujono dan seluruh Staf TU dan karyawan FK UMM atas bantuannya

selama masa kuliah hingga terselesaikannya tugas akhir ini.

13. Pak Aris Sandy terimakasih banyak atas bantuan selama penelitian yang

diberikan kepada penulis.

Karya tulis ini masih jauh dari kesempurnaan, dengan segala kerendahan

hati penulis memohon maaf yang sebesar-besarnya dan mengharapkan saran

kritik yang membangun. Semoga karya tulis ini dapat menambah wawasan dan

khasanah ilmu pengetahuan bagi semua pihak

Malang 11 Oktober 2012

Penulis

vi

ABSTRAK

Mahendra,Vihara Dewi.2013.Pengaruh Ekstrak Biji Pinang (Areca catechu)

terhadap Regresi Plak Endotel Vaskular Tikus Putih Model Aterosklerotik. Tugas

Akhir Fakultas Kedokteran Universitas Muhammadiyah Malang. Pembimbing :

(1) Djoni Djunaedi* (2) Erdy Kuswandana**.

Latar Belakang : Plak Ateroma merupakan salah satu indikasi adanya

aterosklerosis yang ditandai dengan penebalan dinding endotel vaskular dimana

salah satu penyebabnya adalah adanya respon inflamasi dan oksidan bebas dalam

darah serta kondisi hiperkolesterolemia. Biji pinang mempunyai komposisi

Proantosianidin yang berfungsi sebagai antioksidan dan anti inflamasi untuk

meregresi plak ateroma.

Tujuan : Untuk membuktikan pengaruh biji pinang (Areca Catechu ) terhadap

regresi plak endotel vaskular pada tikus putih model aterosklerotik

Metode : Penelitian ini merupakan penelitian eksperimental dengan menggunakan

metode The post test control group design. Masing-masing diberikan dengan

dosis 1,8 mg/200 g BB tikus /hari, 2,25 mg/200 g BB tikus /hari, dan 2,7 mg/200

g BB tikus /hari.

Hasil :Dari hasil uji anova menunjukkan bahwa nilai sig = 0,000 lebih kecil dari

pada p (0,01) yang berarti terdapat pengaruh perlakuan dosis yang sangat

bermakna pada ketebalan endotel arkus aorta tikus putih 3 bulan perlakuan. Uji

korelasi menunjukkan bahwa nilai sig (2-tailed) = 0,000 < p (0,01) yang berarti

terdapat hubungan yang berbanding lurus sangat bermakna yang berarti kenaikan

dosis ekstrak biji pinang menyebabkan kenaikan regresi plak aorta pada tikus

putih 3 bulan perlakuan. Hal ini ditunjukkan dengan nilai pearson correlation =

0,963.Dari hasil uji regresi menunjukkan bahwa Y = 22,961 (X) – 21,721 dimana

Y adalah besarnya regresi plak dan X adalah besarnya dosis. Terlihat ada

pengaruh yang sangat signifikan (sig 0,00 < p 0,01) . besar pengaruh dosis

ekstrak biji buah pinang terhadap penurunan plak endotel arkus aorta sebesar 92,8

% yang dapat dilihat dari R2= 0,928

Kesimpulan : Biji Pinang (Areca catechu ) dapat meregresi plak endotel vaskular

tikus putih model aterosklerotik.

Kata Kunci : Biji Pinang , Proantosianidin, Regresi plak ateroma

* Guru Besar Ilmu Penyakit Dalam konsultan Penyakit Tropis dan Infeksi FK

UMM

** Staf Ahli dan Dosen FK UMM

vii

ABSTRACT

Mahendra,Vihara Dewi.2013.The Effect of Betel Nut Seed Extract (Areca

catechu) as a Plaque Regression of Vascular Endothelium in Atherosclerotic Rat

Model. Final Project in medical Faculty of Muhammadiyah Malang . Advisors :

(1) Djoni Djunaedi *(2) Erdy Kuswandana**

Background : Atherosclerosis plaque is characterized by thickening of vascular

endothelial wall. The pathogenesis of atherosclerosis is inflammatory response to

endothelial injury and free oxidants in hypercholesterolemic condition. The main

composition of betel nut seed is proanthocyanidin has an antioxidant and anti

inflammatory effect to atherosclerotic plaque regression.

Objective : To demonstrate the effect of betel nut seed extract (Areca catechu) as

a plaque regression of vascular endothelium in atherosclerotic rat model.

Methods : This experimental research was using the post test control group

design. The doses in each group in this experiment were given by 1,8 mg/200g

/day, 2,25 mg/200 g/day, and 2,7 mg/200 g /day.

Results :The anova test showed that significancy value = 0,000 < p (0,01) which

means that there was a significant effect in vascular endothelial wall thickening

during 3 months experiments. Correlation test showed that significancy value (2-

tailed) = 0,000 < p (0,01) which means that there was a strong relationship

between increasing dose of betel nut seed extract versus plaque regression, it

showed in pearson correlation test = 0,963. The equation in regression test was Y

= 22,961 (X) – 21,721 where Y was vascular endothelial wall and X was the

dose of betel nut extract, and there’s a significant relationship (sig 0,00 < p 0,01) .

the percentage of the regression in vascular endothelial wall was 92,8 % , (it

showed in R2= 0,928 )

Conclusion : Betel nut seed (Areca catechu) could regress the endothelial

vascular plaque in Atherosclerosis Rat Model.

Keywords : Betel nut seed, Proanthocyanidin, Plaque regression,Vascular

atherosclerosis

*Lecturer and Professor in Internal Medicine,Tropical Infection Consultant in FK

UMM

* Staff and Lecturer in FK UMM

viii

DAFTAR ISI

HALAMAN JUDUL ........................................................................................ i

LEMBAR PENGESAHAN ............................................................................ ii

LEMBAR PENGUJIAN ................................................................................. iii

KATA PENGANTAR ..................................................................................... iv

ABSTRAK ....................................................................................................... vi

ABSTRACT ..................................................................................................... vii

DAFTAR ISI .................................................................................................... viii

DAFTAR TABEL ............................................................................................ xii

DAFTAR GAMBAR ....................................................................................... xiii

DAFTAR GRAFIK .......................................................................................... xiv

DAFTAR LAMPIRAN .................................................................................... xv

DAFTAR SINGKATAN ................................................................................. xvi

BAB 1 PENDAHULUAN .............................................................................. 1

1.1 Latar Belakang ............................................................................... 1

1.2 Rumusan Masalah .......................................................................... 4

1.3 Tujuan Penelitian ............................................................................ 4

1.3.1 Tujuan Umum ...................................................................... 4

1.3.2 Tujuan Khusus...................................................................... 4

1.4 Manfaat Penelitian .......................................................................... 5

1.5 Batasan Penelitian .......................................................................... 5

BAB 2 TINJAUAN PUSTAKA ..................................................................... 6

2.1 Pinang (A.catechu) ......................................................................... 6

2.1.1 Kandungan Kimia ................................................................ 8

ix

2.1.2 Proantosianidin ..................................................................... 8

2.1.3 Proantosianidin sebagai Antioksidan ................................... 10

2.1.4 Proantosianidin sebagai Anti Inflamasi................................ 14

2.1.4.1 Peranan HDL sebagai Anti Inflamasi ...................... 15

2.2 Pembuluh Darah ............................................................................. 18

2.2.1 Fisiologi Pembuluh Darah .................................................... 18

2.2.2 Histopatologi Pembuluh Darah ............................................ 19

2.2.3 Dinding Sel Pembuluh Darah dan Respon terhadap Jejas ... 21

2.2.3.1 Sel Endotel Pembuluh Darah ................................... 21

2.2.3.2 Sel Otot Polos Pembuluh Darah .............................. 24

2.2.3.3 Angiogenesis ............................................................ 25

2.3 Aterosklerosis ................................................................................. 27

2.3.1 Definisi Aterosklerosis ......................................................... 27

2.3.2 Faktor Resiko Aterosklerosis ............................................... 27

2.3.3 Hipotesis Terjadinya Aterosklerosis .................................... 28

2.3.4 Klasifikasi mekanisme Aterosklerosis ................................. 29

2.3.4.1 Cedera Endotel ......................................................... 29

2.3.4.2 Akumulasi Leukosit ................................................. 30

2.3.4.3 Pembentukan Foam Cell .......................................... 31

2.3.4.4 Regresi Plak Aterosklerosis ..................................... 33

BAB 3 KERANGKA KONSEP DAN HIPOTESIS .................................... 35

3.1 Kerangka Konsep ........................................................................... 35

3.2 Hipotesis ......................................................................................... 36

x

BAB 4 METODE PENELITIAN .................................................................. 37

4.1 Rancangan Penelitian ..................................................................... 37

4.2 Tempat dan Waktu Penelitian ........................................................ 37

4.3 Populasi dan Sampel ...................................................................... 37

4.3.1 Populasi.. .............................................................................. 37

4.3.2 Sampel .................................................................................. 37

4.3.3 Estimasi Besar Sampel ......................................................... 37

4.3.4 Teknik Sampling .................................................................. 39

4.3.5 Karakteristik Sampel Penelitian ........................................... 39

4.3.6 Variabel Penelitian ............................................................... 39

4.3.6.1 Variabel Bebas ......................................................... 39

4.3.6.2 Variabel Tergantung ................................................ 39

4.3.7 Definisi Operasional ............................................................. 39

4.4 Diet Aterosklerotik ......................................................................... 40

4.5 Dasar Penentuan Dosis Buah Pinang ............................................. 40

4.6 Bahan dan Instrumen Penelitian ..................................................... 41

4.7 Alur Penelitian ............................................................................... 43

4.8 Prosedur Penelitian ......................................................................... 44

4.8.1 Pembagian Kelompok Tikus ................................................ 44

4.8.2 Adaptasi ................................................................................ 45

4.8.3 Pemberian Diet Aterogenik .................................................. 45

4.8.4 Pemberian Ekstrak Buah Pinang .......................................... 45

4.9 Proses anestesi dan Pembedahan Hewan Coba .............................. 46

4.9.1 Proses Anestesi ..................................................................... 46

xi

4.9.2 Proses Pembedahan .............................................................. 46

4.10 Pembuatan Sediaan Histologi ....................................................... 46

4.11 Analisis Data ................................................................................ 47

BAB 5 HASIL PENELITIAN DAN ANALISIS DATA ............................. 48

5.1 Gambar sediaan histopatologis dinding arkus aorta ....................... 48

5.2 Pengaruh Dosis Ekstrak Biji Pinang Terhadap Ketebalan

Dinding Arkus Aorta.............................................................. ....... 52

5.3 Pengaruh dosis ekstrak biji pinang terhadap regresi plak endotel

vaskular pada tikus model aterosklerotik ...................................... 56

BAB 6 PEMBAHASAN ................................................................................ 58

BAB 7 KESIMPULAN DAN SARAN .......................................................... 64

7.1 Kesimpulan............................................................... ...................... 64

7.2 Saran ............................................................................................. 64

DAFTAR PUSTAKA ..................................................................................... 65

LAMPIRAN .................................................................................................... 69

xii

DAFTAR TABEL

Tabel 5.1 Pengaruh ekstrak biji pinang terhadap ketebalan dinding endotel

arkus aorta setelah 3 bulan perlakuan ............................................. 53

Tabel 5.2 Tebal plak endotel pada dinding arkus aorta ................................... 56

Tabel 5.3 Tabel hasil regresi plak dinding arkus aorta ................................. 57

xiii

DAFTAR GAMBAR

Gambar 2.1 Pohon pinang ................................................................................ 4

Gambar 2.2 Buah pinang.................................................................................. 6

Gambar 2.3 Mekanisme prontosianidin sebagai antioksidan .......................... 14

Gambar 2.4 Hambatan HDL terhadap sintesis adhesi protein ......................... 16

Gambar 2.5 Mekanisme HDL sebagai anti inflamasi ...................................... 17

Gambar 2.6 Arteriol,Venul,dan kapiler............................................................ 19

Gambar 2.7 Lapisan vaskular ........................................................................... 20

Gambar 2.8 Histologi penampag arteri ............................................................ 21

Gambar 2.9 Respon dinding pembuluh darah terhadap adanya jejas .............. 24

Gambar 2.10 Fatty streaks dan fibrous cap ..................................................... 29

Gambar 2.11 Proses terjadinya plak ateroma ................................................... 29

Gambar 2.12 Patogenesis terjadinya aterosklerosis ......................................... 30

Gambar 2.13 Proses terjadinya aterosklerosis ................................................. 32

Gambar 2.14 Gambaran histologi fibrous plak pada dinding pembuluh

Darah ........................................................................................... 32

Gambar 2.15 Patologi anatomi plak ateroma ................................................... 33

Gambar 2.16 Mekanisme regresi plak aterosklerosis pada sel endotel ............ 34

Gambar 5.1 Gambaran Mikroskopis ketebalan dinding arkus aorta tiap

Perlakuan .................................................................................... 49

xiv

DAFTAR GRAFIK

Grafik 5.1 Grafik persamaan regresi hubungan antara dosis ekstrak biji

pinang dengan ketebalan dinding arkus aorta ............................... 52

Grafik 5.2 Grafik persamaan regresi hubungan antara dosis ekstrak biji

pinang dengan regresi plak dinding arkus aorta ............................ 55

Grafik 5.3 Grafik gambaran regresi plak endotel arkus aorta ........................ 57

xv

DAFTAR LAMPIRAN

Lampiran 1 Ketebalan plak pada dinding endotel arkus aorta setelah

3 bulan perlakuan ........................................................................ 69

Lampiran 2 Regresi Plak 3 bulan perlakuan .................................................. 74

Lampiran 3 Diet Aterogenik ........................................................................... 79

Lampiran 4 Pelaksanaan Penelitian ................................................................ 80

Lampiran 5 Dokumentasi ............................................................................... 82

Lampiran 6 Surat Keterangan Penelitian ....................................................... 83

Lampiran 7 Surat Keterangan Konsultasi PA ............................................... 84

xvi

DAFTAR SINGKATAN

ABCA1 : ATP binding cassette transporter 1

AP – 1 : Activator protein 1

apoA-1 : Apolipoprotein A 1

CD -31 : Cluster disease 31

CERP : Cholesterol efflux regulatory protein

CSF : Colony stimulating factor

ECM : Extracellular matrix

FGF : Fibroblast growth factor

GPCR : G protein coupled receptor

HDL : High density lipoprotein

HUVECs : Human umbilical vein endothelial cells

ICAM – 1 : Intercellular adhesion molecule - 1

IHD : Ischaemic heart disease

IL-1 : Interleukin -1

IL-6 : Interleukin - 2

LDL : Low density lipoprotein

LPS : Lipopolysacharide

MCP – 1 : Monocyte chemoatractant protein 1

NF-κβ : Nuclear factor kappa β

NO : Nitric oxide

OPCs : Oligomeric Proantocyanidins

Ox LDL : Oxydized LDL

PAF : Platelet activating factor

PAI : Plasminogen activator inhibitor

PDGF : Platelet derived growth factor

PECAM – 1 : Platelet endothelial cell adhesion molecule - 1

PGI2 : Prostacyclin

rHDL : Reconstitued high density lipoprotein

ROS : Reactive oxygen spesies

S1P : Spingosine 1 phosphate

xvii

SMase : Sphingomyelinase

SMC : Smooth muscle cell

TF : Tissue factor

TGF β : Transforming growth factor β

TNF α : Tumor necrosis factor

UV : Ultraviolet

VCAM – 1 : Vascular cell adhesion molecule - 1

VE cadherin : Vascular endothelial cadherin

VLDL : Very low density lipoprotein

vWF : von Willebrand Factors

xviii

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