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활성산소종으로 손상되는 토끼 복부 대동맥 내피에서 Captopril과 Enalapril의 항산화효과

Title
활성산소종으로 손상되는 토끼 복부 대동맥 내피에서 Captopril과 Enalapril의 항산화효과
Other Titles
Antioxidant Effect of Captopril and Enalapril on Reactive Oxygen Species-Induced Endothelial Dysfunction in the Rabbit Abdominal Aorta
Author
김지훈
Alternative Author(s)
Kim, Ji-Hoon
Advisor(s)
김혁
Issue Date
2012-02
Publisher
한양대학교
Degree
Doctor
Abstract
배경: 활성산소종 (reactive oxygen species
ROS)은 다양한 심혈관계질환과 관계가 있는 것으로 알려져 있다. 특히 혈관 내피세포는 활성산소종에 의한 손상에 매우 취약하다. 여러 연구들에서 angiotensin-converting enzyme (ACE) inhibitor 들이 이러한 손상에 대하여 보호 효과가 있는 것으로 나타나고 있다. 하지만 이러한 효과들이 약제의 sulfhydryl group에 의해 이루어지는 지에 대해서는 논란이 있다. 이 연구에서는 흔히 쓰이는 sulfhydryl-containing ACE inhibitor인captopril과non-sulfhydryl-containing ACE inhibitor인enalapril의 항산화효과에 대해서, 토끼 복부 대동맥의 산화질소 매개 혈관 내피 의존성 이완 (nitric oxide-mediated vascular endothelial relaxation)을 통해 알아보았다. 대상 및 방법: 박리된 토끼 복부 대동맥 환상절편을 Krebs-Henseleit 용액이 들어있는 수조에 넣고, 여러 농도 (10-5, 3 × 10-5, 10-4과 3 × 10-4 M) 의captopril 혹은 enalapril을 전처치 한 뒤 용액을 전기분해 (DC 15 mA, 35초)하여 ROS를 발생시켰다. 약물 전처치와 전기분해 전후로 norepinephrine (10-6 M)으로 혈관수축을 유도한 뒤, acetylcholine (3 × 10-8, 10-7, 3 × 10-7과 10-6 M) 을 연속적으로 투여하며 혈관의 이완 정도를 측정하여 혈관 내피의 기능유지 여부를 판단하였다. 항산화 작용과 superoxide anion (O2•
-)과hydrogenperoxide (H2O2) 제거효과와의 관련성을 알아보고자 Cu/Zn superoxide dismutase (SOD) 억제제인 diethyldithiocarbamate (DETCA
0.5 mM)와catalase 억제제인3-amino-1,2,4-triazole (3AT
50 mM)을 전처치 후 그 반응을 관찰하였다. 결과: Captopril과enalapril은 모두 ROS 노출에도 농도에 비례하여 혈관 내피 의존성 이완을 유지시켰다 (P < 0.0001). DETCA에 의한 SOD 억제는 captopril과enalapril의 항산화효과를 약화시켰지만 (P < 0.0001), 3AT에 의한 catalase억제는 이들 반응에 아무런 영향을 미치지 않았다. 결론: Sulfhydryl group의 유무와 상관없이, captopril과enalapril은 모두 박리된 토끼 복부 대동맥에서 농도에 비례하여 항산화효과를 가진다. 이들 항산화효과의 기전에는 superoxide anion 제거 작용이 일부 관여한다.|Background: Reactive oxygen species (ROS) are known to be related to many cardiovascular diseases. Vascular endothelium is very liable to injury by ROS. Many studies demonstrated that angiotensin-converting enzyme (ACE) inhibitors have beneficial effects against ROS. We investigated the antioxidant effect of captopril and enalapril (sulfhydryl-containing and non-sulfhydryl-containing ACE inhibitors, respectively) in nitric oxide mediated vascular endothelium-dependent relaxations. Materials and Methods: Isolated rabbit abdominal aorta ring segments were exposed to ROS by electrolysis (DC 15 mA, 35 seconds) of the organ bath medium (Krebs-Henseleit solution) after pretreatment with various concentrations (10-5, 3 × 10-5, 10-4, and 3 × 10-4 M) of captopril and enalapril. Before and after electrolysis, endothelial function was measured by preconstricting the vessels with norepinephrine (10-6 M) followed by the cumulative addition of acetylcholine (3 × 10-8, 10-7, 3 × 10-7, and 10-6 M). The relevance of superoxide anion and hydrogen peroxide scavenging effect of captopril and enalapril was investigated by additional pretreatment with diethyldithiocarbamate (DETCA
0.5 mM), an inhibitor of Cu/Zn superoxide dismutase (SOD), and 3-amino-1,2,4-triazole (3AT
50 mM), an inhibitor of catalase. Results: Both captopril and enalapril preserved vascular endothelium-dependent relaxation after exposure to ROS in a dose-dependent manner (P < 0.0001). Cu/Zn SOD inhibition by DETCA pretreatment attenuated the antioxidant effect (P < 0.0001), but catalase inhibition by 3AT pretreatment did not influence the antioxidant effect of captopril and enalapril. Conclusions: Both sulfhydryl-containing ACE inhibitor captopril and non-sulfhydryl-containing ACE inhibitor enalapril protect endothelium against free radical injury in a dose-dependent manner in the isolated rabbit abdominal aorta. This protective effect is related to superoxide anion scavenging.
Background: Reactive oxygen species (ROS) are known to be related to many cardiovascular diseases. Vascular endothelium is very liable to injury by ROS. Many studies demonstrated that angiotensin-converting enzyme (ACE) inhibitors have beneficial effects against ROS. We investigated the antioxidant effect of captopril and enalapril (sulfhydryl-containing and non-sulfhydryl-containing ACE inhibitors, respectively) in nitric oxide mediated vascular endothelium-dependent relaxations. Materials and Methods: Isolated rabbit abdominal aorta ring segments were exposed to ROS by electrolysis (DC 15 mA, 35 seconds) of the organ bath medium (Krebs-Henseleit solution) after pretreatment with various concentrations (10-5, 3 × 10-5, 10-4, and 3 × 10-4 M) of captopril and enalapril. Before and after electrolysis, endothelial function was measured by preconstricting the vessels with norepinephrine (10-6 M) followed by the cumulative addition of acetylcholine (3 × 10-8, 10-7, 3 × 10-7, and 10-6 M). The relevance of superoxide anion and hydrogen peroxide scavenging effect of captopril and enalapril was investigated by additional pretreatment with diethyldithiocarbamate (DETCA
URI
https://repository.hanyang.ac.kr/handle/20.500.11754/136885http://hanyang.dcollection.net/common/orgView/200000419612
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GRADUATE SCHOOL[S](대학원) > MEDICINE(의학과) > Theses (Ph.D.)
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