백서에서 Puromycin Aminonucleoside유발 국소성 분절성 사구체 경화증에서 미세혈관 변화 및 혈관확장제의 효과

Abstract

[한글]

국소성 분절성 사구체경화증은 일부의 사구체에서 분절상의 경화를 보이는 사구체신염으로, 다량의 단백뇨를 보이며 치료에 잘 반응하지 않아 결국 신기능 소실이 초래되는 질환이다. 그 발생원인과 병리기전은 아직 확실하게 증명되어 있지는 않으나 최근에 들어

동맥경화증과 유사한 기전 내지는 미세혈관의 변화가 중요한 요인으로 대두되고 있다. 이에 본 연구에서는 사구체 경화증의 진행인자로서 신장 미세혈관의 반응항진(hyperreactivity) 또는 미세연축(microspasm)및 구조적 변화가 중요한 인자로 작용할 것으로 가정하고, 백서에서 puromycin aminonu-cleoside(PAN) 및 protamine sulfate를 투여하여 사람에서와 비슷한 분절성 사구체 경화증을 유발시도 하였으며, 질병발생 억제를 목적으로 혈관확장제인 verapamil 또는 enalapril을 투여하였으며 지질대사 개선제인 lovastatin을 투여한 비교군을 두어 각 약재간의 투여효과를 비교관찰하였다. 또한 Microfil 관류를 통한 혈관의 입체적 관찰을 시도하여 미세헐관의 변화가본 질환의 발생 및 진행에 어떠한 역할

을 하는지 살펴보아 다음과 같은 결론을 얻었다.

1. PAN과 protamine sulfate의 반복투여로 단백뇨 및 고지혈증을 동반한 신증후군이 유발되었으며, 형태학적으로는 국소성 분절성 경화증 소견을 보였다.

2. Verapamil, enalapril 및 lovastatin의 투여로 단백뇨, 혈중 요소질소 및 크레아티닌치의 변동에는 의의있는 영향을 미치지는 못하였다. 혈중 알부민치는 verapamil 투여군에서 단순신증후군 유발군이나 enalapril 및 lovastatin 투여군에 비하여 유의하게 높았

다.

3. 사구체의 분절성경화성 변화는 단순 신증후군 유발군이나 verapamil, enalapril 및 lovastatin 등의 병용투여군에서 모두 시간경과에 따라 진행되었으나, 단순 신증후군 유발군에 비하여 약물투여군에서 그 진행속도의 둔화를 볼 수 있었다. 사구체 경화의 감소효과는 verapamil 투여군이 타군에 비하여 의의있게 높았다.

4. 신동맥 Microfil 관류 소견상 단순 신증후군 유발군보다 약물의 병용투여군에서, 엽간 및 소엽간 동맥과 사구체 수입세동맥의 염주상분절 및 협착발생의 감소를 보였으며, 사구체 모세혈관망 결손의 정도도 감소하였다.

결론적으로 사구체 분절성 경화성 변화가 enalapril 및 lovastatin의 투여로 완화되고 verapamil의 투여로 더욱 완화됨을 볼 때, 국소성 분절성 사구체 경화의 발생 및 진행기

전에는 고지혈증 및 혈압상승 등에 부가하여 신장미세혈관의 연축에 의한 혈류 역동학적 변화도 중요하게 관여하는 것으로 사료된다.

Effects of verapamil, enalapril, and lovastatin on the microvascular changes of

puromycin-Induced focal segmental glomerulosclerosls In rats

Ki-Soo Pai

Department of Medical Science The Graduate School, Yonsei University

(Directed by Professor In Joon Choi)

Puromycin with protamine sulfate induces proteinuria and glomerular changes in

rats similar to those found in human focal segmental glomerulosclerosis. This study

was undertaken in order both to see whether the respective use of verapamil,

enalapril and lovastatin can prevent or ameliorate and to evaluate the mechanisms

involved.

Unilateral nephrectomised Munich-Wistar rats were divided in 5 groups and to

induce nephrotic syndrome, 4 out of 5 groups were administered with puromycin

aminonucleoside(10 mg/kg, subcutaneously) and protamine sulfate(25 mg/kg,

intraperitoneally) for the first 4 days of every 14 experimental periods, and then

concomitantly with verapamil(10 mg/kg/day, intraperitoneally), enalapril

(2mg/kg/day, intraperitoneally) and lovastatin(4 mg/kg/day, subcutaneously),

respectively to each group except one for comparison.

Percentages of glomerular scleroses were observed on day 28 and 56 of experiment

in varying degrees according to the groups; such as 0% and 0% in simple nephrectomy

group, 6.0±3.3% and 50.3±12.0% in untreated simple nephrotic group, 3.6±1.5% and

22.4±7.7% in verapamil treated group, 6.7±6.1% and 35.61±14.4% in enalapril

treated group, and 4.3±7.3% and 44.3±9.3% in lovastatin treated group. Verapamil

effect was superior to other drugs in this study(p<0.05). Microfil(silicon rubber)

was perfused to the rats just prior to sacrifice, which revealed numerous areas of

microvascular constriction, narrowing and luminal irregularity without fixed

structural abnormality of vessel itself on serial section examinations. The

microvascular changes, presumably microvascular hyperreactivity or microspasms

could be prevented in some degree in the verapamil, enalapril and lovastatin

treated groups compared to those in the untreated simple nephrotic group.

The similarity of this experimental focal segmental glomerulosclerosis in rats to

that of human suggests that microvascular spasm may be one of the significant

factors engaging the pathogenesis of this disease in human also. So the conclusion

is that it may be possible to prevent the development or to delay the progress of

this disease process succesfully by using appropriate drugs such as calcium-channel

blockers, angiotensin converting enzyme inhibitors, and antilipemic agents.

[영문]

Puromycin with protamine sulfate induces proteinuria and glomerular changes in rats similar to those found in human focal segmental glomerulosclerosis. This study was undertaken in order both to see whether the respective use of verapamil, enalapril and lovastatin can prevent or ameliorate and to evaluate the mechanisms involved.

Unilateral nephrectomised Munich-Wistar rats were divided in 5 groups and to induce nephrotic syndrome, 4 out of 5 groups were administered with puromycin aminonucleoside(10 mg/kg, subcutaneously) and protamine sulfate(25 mg/kg, intraperitoneally) for the first 4 days of every 14 experimental periods, and then concomitantly with verapamil(10 mg/kg/day, intraperitoneally), enalapril (2mg/kg/day, intraperitoneally) and lovastatin(4 mg/kg/day, subcutaneously), respectively to each group except one for comparison.

Percentages of glomerular scleroses were observed on day 28 and 56 of experiment in varying degrees according to the groups; such as 0% and 0% in simple nephrectomy group, 6.0±3.3% and 50.3±12.0% in untreated simple nephrotic group, 3.6±1.5% and

22.4±7.7% in verapamil treated group, 6.7±6.1% and 35.61±14.4% in enalapril treated group, and 4.3±7.3% and 44.3±9.3% in lovastatin treated group. Verapamil effect was superior to other drugs in this study(p<0.05). Microfil(silicon rubber) was perfused to the rats just prior to sacrifice, which revealed numerous areas of microvascular constriction, narrowing and luminal irregularity without fixed structural abnormality of vessel itself on serial section examinations. The microvascular changes, presumably microvascular hyperreactivity or microspasms

could be prevented in some degree in the verapamil, enalapril and lovastatin treated groups compared to those in the untreated simple nephrotic group.

The similarity of this experimental focal segmental glomerulosclerosis in rats to that of human suggests that microvascular spasm may be one of the significant factors engaging the pathogenesis of this disease in human also. So the conclusion is that it may be possible to prevent the development or to delay the progress of this disease process succesfully by using appropriate drugs such as calcium-channel blockers, angiotensin converting enzyme inhibitors, and antilipemic agents.