Clinical and Experimental Pediatrics

대한소아청소년과학회 (The Korean Pediatric Society)
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Monocrotaline으로 유발한 백서 폐동맥 고혈압에서 Endothelin 수용체 차단제 투여의 효과

Effect of endothelin receptor blockade on monocrotaline-induced pulmonary hypertension in rats

  • 임경아 (포천중문의과대학 소아청소년과) ;
  • 심정연 (포천중문의과대학 병리과) ;
  • 조상호 (포천중문의과대학 병리과) ;
  • 김관창 (이화여자대학교 의과대학 흉부외과학교실) ;
  • 한재진 (이화여자대학교 의과대학 흉부외과학교실) ;
  • 홍영미 (이화여자대학교 의과대학 소아과학교실)
  • Lim, Kyoung Ah (Department of Pediatrics, College of Medicine, Pochon CHA University) ;
  • Shim, Jung Yun (Department of Pathology, College of Medicine, Pochon CHA University) ;
  • Cho, Sang Ho (Department of Pathology, College of Medicine, Pochon CHA University) ;
  • Kim, Kwan Chang (Department of Thoracic and Cardiovascular Surgery, School of Medicine, Ewha Womans University) ;
  • Han, Jae Jin (Department of Thoracic and Cardiovascular Surgery, School of Medicine, Ewha Womans University) ;
  • Hong, Young Mi (Department of Pediatrics, School of Medicine, Ewha Womans University)
  • 투고 : 2008.10.09
  • 심사 : 2008.12.05
  • 발행 : 2009.06.15
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초록

목 적 : 폐동맥 고혈압은 지속적인 폐혈관 저항의 증가로 우심실 부전에 이르게 되는 질병 상태를 일컫는다. 폐동맥 고혈압의 기전으로 폐혈관의 내피세포로부터 endothelin 분비가 증가되어 세포 증식 촉진, 세포 자멸 억제, 혈관 수축, 염증 반응을 통해 폐혈관의 재형성에 관여함이 제시되었다. Bosentan은 endothelin 수용체에 결합하여 효과를 차단시키는 약물로 개발되었다. 이에 monocrotaline으로 폐고혈압을 유발시킨 동물에서 non-selective endothelin receptor blocker인 bosentan을 투여하였을 때 폐동맥 고혈압 발생에 미치는 효과를 알아보고자 본 연구를 시행하였다. 방 법 : 체중 250 g 내외의 4주령 가량 된 자성 Sprague-Dawley 백서를 대조군, monocrotaline군, bosentan군으로 나누었다. Monocrotaline군과 bosentan군에는 monocrotaline 수용액 60 mg/kg를 배부에 1회 피하 주사하고 대조군에는 동량의 생리식염수를 주사하였다. Bosentan군에는 bosentan ($20mg{\cdot}kg^{-1}{\cdot}day^{-1}$)을 monocrotaline 투여 직후부터 매일 1일 2회 위관 영양법으로 투여하였다. 7일, 14일, 28일에 각각 동물을 희생시켜 심장의 무게를 우심실벽, 좌심실벽, 심실간벽으로 나누어 기관의 무게를 측정하고 조직 검사를 위해 양측 폐를 포르말린 수용액에 고정하였다. 결 과 : 7일, 14일, 28일째 평균 체중은 대조군에 비해 monocrotaline군과 bosentan군이 유의하게 적었다. 우심실/(좌심실＋심실간벽)의 무게 비율은 28일째 monocrotaline군($0.71{\pm}0.10mg/g$)에 비해 bosentan군($0.49{\pm}0.09mg/g$)이 유의하게 적었다(P<0.05). 폐세동맥의 조직형태학적 분석 결과 실험 28일째 monocrotaline투여에 의해 유발된 중막 비후 소견이 bosentan 투여에 의해 현저하게 저하된 것으로 나타났다(monocrotaline군 $49.94{\pm}10.06$ vs bosentan군 $47.09{\pm}10.48$, P<0.05). 또한 호흡성 세기관지 이하의 폐포에 분포하는 근육성 폐세동맥의 숫자도 monocrotaline 투여에 의해 증가되었으나 14, 28일째 bosentan군에서는 현저하게 적은 것으로 나타났다. 결 론 : Monocrotaline으로 유도한 백서의 폐고혈압에서 bosentan을 투여하고 초기 경과를 관찰한 결과, 2주째부터 우심실 비대가 억제되었고 4주 이내 사망률도 낮아 endothelin receptor에 대한 길항 작용의 효과로 해석될 수 있겠다.

Purpose : To examine the effect of bosentan, a dual endothelin receptor (ER) antagonist, on the development of monocrotaline (MCT)-induced pulmonary hypertension in rats by especially focusing on the pulmonary vascular morphology changes. Methods : Sprague-Dawley rats were treated as follows: controls received a subcutaneous saline injection, MCT-treated rats received a subcutaneous MCT injection, and bosentan-treated rats received a MCT injection followed by treatment with bosentan (20 mg/kg/day). To assess the effects of ER blockade on the time course, the animals were exsanguinated, and their hearts and lungs were dissected after 7, 14, or 28 days. Results : The mean body weights of the MCT- and bosentan-treated rats were significantly lower than that of the control rats on days 7, 14, and 28. Bosentan administration significantly inhibited the progression of right ventricular hypertrophy on day 28 (right ventricle/[left ventricle＋septum]: $0.71{\pm}0.10$ in MCT-treated rats vs. $0.49{\pm}0.09$ in bosentan-treated rats; P<0.05). Quantitative analysis of peripheral pulmonary arteries revealed that the increase in medial wall thickness after MCT injection was significantly attenuated in the bosentan-treated rats on day 28 ($49.96{\pm}10.06%$ in MCT-treated rats vs. $47.09{\pm}10.48%$ in bosentan-treated rats; P<0.05). In addition, the increase in the number of intra-acinar muscular arteries after MCT injection was reduced by bosentan on days 14 and 28. Conclusion : Bosentan administration in intermediate doses exerts inhibitory effects on lung vascular hypertrophy and right ventricular hypertrophy during the development of MCT-induced pulmonary hypertension in rats.

키워드

과제정보

연구 과제 주관 기관 : Il-dong Pharmaceutical Company, Korean Pediatric Society

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피인용 문헌

  1. Effects of Bosentan Treatment on Angiotensin Converting Enzyme in Monocrotaline Induced Pulmonary Hypertension Rats vol.17, pp.1, 2011, https://doi.org/10.5646/jksh.2011.17.1.28