Original Articles Korean Circulation J 2002;32 8 : 당뇨쥐에서안지오텐신전환효소억제제에 의한미세관상동맥재형성개선 장기육 1 백상홍 1 고승현 1 윤건호 1 김기영 2 승기배 1 채장성 1 김재형 1 홍순조 1 최규보 1

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1 Original Articles Korean Circulation J 2002;328: 당뇨쥐에서안지오텐신전환효소억제제에 의한미세관상동맥재형성개선 장기육 1 백상홍 1 고승현 1 윤건호 1 김기영 2 승기배 1 채장성 1 김재형 1 홍순조 1 최규보 1 Angiotensin-Converting Enzyme Inhibitor Ramipril Improves Coronary Microvascular Remodeling in Type II Diabetic Rats Kiyuk Chang, MD 1, Sang Hong Baek, MD, PhD 1, Seung-Hyun Ko, MD 1, Kun-Ho Yoon, MD, PhD 1, Ki-Young Kim, PhD 2, Ki-Bae Seung, MD, PhD 1, Jang-Seong Chae, MD, PhD 1, Jae-Hyung Kim, MD, PhD 1, Soon-Jo Hong, MD, PhD 1 and Kyu-Bo Choi, MD, PhD 1 1 Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, 2 Department of Pathology, College of Medicine, Wonkwang University, Iksan, Korea ABSTRACT Background and ObjectivesCoronary microvascular remodeling is one of the complications associated with diabetic cardiovascular disease. We investigated the effect of long-term treatment with ramipril, an angiotensin converting enzyme inhibitor, on coronary microvascular remodeling on a type II diabetic model, the Otsuka Long-Evans Tokushima Fatty OLETF rat. Materials and MethodsTwenty OLETF diabetic, and twenty LETO non-diabetic rats at twenty-four weeks old, were randomized into 4 equal groups for treatment with either an aqueous solution of ramipril 5 mg/kg, n10 for two groups or saline n10 for two groups for 24 weeks on a daily basis. The blood glucose levels, body weights and blood pressures of the rats were checked on a regular basis. Masson s trichrome and picrosirius red stains were used for the morphometric analysis of the thickening of the coronary arterial wall and the degree of perivascular fibrosis. The myocardial collagen content was determined by measuring the levels of myocardial hydroxyproline. ResultsMarked thickening of the coronary microvascular wall and prominent perivascular fibrosis were detected in the hearts of OLETF rats to a greater extent than in the LETO rats p0.01. Ramipril significantly prevented coronary microvascular remodeling in OLETF rats p0.01, but there was no significant difference in the collagen content/dry heart weight ratio between the groups. ConclusionLong-term treatment with ramipril has an antifibrotic effect, and improves the coronary microvascular remodeling in diabetic OLETF rats. Korean Circulation J 2002;328: KEY WORDSDiabetes mellitusrats, inbred OLETFCoronary circulationmicrocirculationangiotensin-converting enzyme inhibitors. 680

2 서론 방법 실험동물 - - 라미프릴 (Ramipril) 투여 - 체중, 혈압측정및경구당부하검사 - 조직학적검사

3 심장조직의 hydroxyproline과콜라겐의정량 p 조직형태학적분석 통계적분석 결과 라미프릴투여후체중과심장무게의변화 Table 1. The body weight, heart weight, and heart weight per body weight ratio of 48 week-old OLETF and LETO rats Group n BW g Heart wt mg Heart wt/bw mg/g OL-RMP * * * OL-CON * * * LT-RMP * * * LT-CON * * * OLETFindicates Otsuka Long-Evans Tokushima Fatty, LETOLong-Evans Tokushima Otsuka, BWindicates body weightheart wt, heart weight. OL-RMPOLETF rats treated with ramipril, OL-CONOLETF rats not treated with ramipril, LT-RMPLETO rats treated with ramipril, LT-CONLETO rats not treated with ramipril. Values are mean SD. p0.05 vs each control group 682 Korean Circulation J 2002;328:

4 Fig. 1. Changes in the body weight during ramipril treatment in all groups. OL-RMPindicates OLETF rats treated with ramipril, OL-CONOLETF rats not treated with ramipril, LT-RMPLETO rats treated with ramipril, LT-CONLETO rats not treated with ramipril. Values are meansd. p0.05 vs OL-CON, p0.05 vs LT-CON. 라미프릴투여후 6개월까지혈압의변화와경구당부하검사결과 - 심장의건중량당콜라겐양의비 (Collagen content/dry heart weight ratio) Fig. 2. The changes in systolic upper column and diastolic lower column blood pressure over the 6-month study period. OL-RMPindicates OLETF rats treated with ramipril, OL-CONOLETF rats not treated with ramipril, LT-RMPLETO rats treated with ramipril, LT-CON, LETO rats not treated with ramipril. Values are meansd. p0.05 vs each control group. OLETF쥐에서미세관상동맥의혈관벽비후와혈관주위섬유화에대한라미프릴의효과 683

5 Fig. 3. Wall thickness of coronary arterioles with internal diameters of 100 M A and small coronary arteries with internal diameters of M B, and perivascular fibrosis area fraction of coronary arterioles Cand small coronary arteries D. Each bar represents meansd. OL-RMPindicates OLETF rats treated with ramipril, OL-CON OLETF rats not treated with ramipril, LT-RMPLETO rats treated with ramipril, LT-CONLETO rats not treated with ramipril. p0.01 vs other groups. 고찰 684 Korean Circulation J 2002;328:

6 A B C D A B C D Fig. 4. Representative photographs of small coronary arteries stained with Masson s trichrome (upper panel) and picrosirius red (lower panel) from control OLETF rats (A), OLETF rats treated with ramipril (B), control LETO rats (C), and LETO rats treated with ramipril (D). Marked perivascular fibrosis and increase in arterial wall thickening was observed in control OLETF rats. Original maginification

7 본연구의제한점 - Korean Circulation J 2002;328:

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Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract