Differential Function of EDRF in Systemic Arterial and Pulmonary Arterial System of Renal Hypertensive Rats

이병호,신화섭,허인회,Lee, Byung-Ho,Shin, Hwa-Sup,Huh, In-Hoe The Korean Society of Pharmacology 1993 대한약리학잡지 Vol.29 No.2

급성 신성 고혈압쥐 (2-kidney, 1-ligation type)의 전신성 동맥계와 폐 동맥계에 대한 내피 의존적 혈관반응성을 규명하기 위하여, 적출 혈관 및 마취상태의 흰쥐에 대한 acetylcholine (ACh)의 혈관이완작용 및 혈압강하 작용을 측정하였다. 혈장 renin 활성(PRA)은 신동맥 결찰전 $7.31{\pm}0.63\;ng/ml/hr$ A I에 비해 결찰 $6{\sim}8$일후에는 $19{\sim}22\;ng/ml/hr$ A I으로 유의성있게 증가하였으며, 이는 수축기혈압의 상승과 $(154{\pm}1.83{\rightarrow}190{\sim}215\;mmHg)$ 일정한 상관성을 유지하였다. 신성 고혈압쥐 및 정상 혈압쥐의 흉곽 대동맥은 내피세포 존재시 ACh에 의해 용량의존적으로 이완되었으며, 이때 신성고혈압쥐에서의 반응은 정상 혈압쥐에 비해 유의성있게 감소하였다(각각 34% 및 86%, p<0.01). 또한 ACh은 신성 고혈압쥐 및 정상 혈압쥐의 폐동맥에 대해서도 내피세포 존재시에 이완반응을 초래하였다. 그러나, 흉곽 대동맥에서와는 달리 두 군간에 유의성있는 차이가 없었다. 이들 반응은 내피세포 제거후 또는 EDRF 억제제 (L-NAME, MB, $10^{-5}$ M) 투여후 유의성있게 억제되었다. $ACh(0.1{\sim}10\;{\mu}g/kg,\;i.v.)$은 신성 고혈압쥐 및 정상 혈압쥐에서 전신성 동맥압의 강하를 초래하였는데, 신성 고혈압쥐에서 다소 감소하였으나 유의성있는 차이는 없었으며 ($SAPm;\;10\;{\mu}g/kg$에서 각각 39%, 46 %), 이들 작용은 L-NAME(30 mg/kg, i.v.) 전처치후 유의성있게 억제되었다. ACh에 의한 폐동맥압 강하는 신성 고혈압쥐 및 정상 혈압쥐 사이에 서로 비슷하게 나타났다. 그러나, 신성 고혈압 쥐 및 정상 혈압쥐에서 ACh에 의한 폐동맥압의 강하율은 전신성 동맥압의 강하율보다 유의성있게(p<0.01) 작았으며, 또한 L-NAME $(0.1{\sim}100\;mg/kg,\;i.v.)$에 의한 폐동맥압의 상승은 전신성 동맥압의 상승보다 유의성있게(p<0.01) 작았다. 이상의 실험 결과들은 급성 신성 고혈압쥐의 전신성 동맥계에서는 내피세포 손상이 초래되지만, 폐동맥계에서는 초래되지 않는다는것을 제시해준다. 또 신성고혈압쥐 및 정상 혈압쥐에서 EDRF 의 basal release 및 ACh 유발성 EDRF function은 전신성 동맥계에 비해 폐동맥계에서 적다는 것을 제시해준다. To investigate the endothelium dependent vascular reactivity of the systemic arterial and the pulmonary arterial system in acute renal hypertensive rats of 2-kidney, 1-ligation type (RHRs), acetylcholine (ACh)-induced vasodilation and depressor effects were evaluated in isolated arteries and in vivo, respectively, in the presence and absence of functional endothelium. ACh $(10^{-5}\;M)$ relaxed the intact thoracic aortas from RHRs and normotensive rats (NRs), but the effect was significantly smaller for those from RHRs (34 and 86%, respectively, p<0.01). ACh-induced vasodilation was completely abolished after removal of endothelial cell or pretreatment with EDRF inhibitors, L-NAME and MB, indicative of its dependence on intact endothelial or EDRF function. ACh also induced vasorelaxation of the intact pulmonary arteries from RHRs and NRs; however, unlike the effects on the thorcic aorta, no significant difference in amplitude was noted between two groups. ACh $(0.1{\sim}10\;{\mu}g/kg,\;i.v.)$ reduced mean systemic arterial pressure in anesthetized RHRs and in NRs to the similar magnitude (% change: 39 and 46% at $10\;{\mu}g/kg$, respectively) and these hypotensive effects were significantly decreased after pretreatment with L-NAME (30 mg/kg, i.v.). Deprssor effects of ACh on mean pulmonary arterial pressure were similar in RHRs and NRs with and without pretreatment of L-NAME. However, in both NRs and RHRs, the depressor effects of ACh on mean pulmonary arterial pressure were significantly reduced compared with those for mean systemic arterial pressure, and the increment of mean pulmonary arterial pressure noted after L-NAME $(0.1{\mu}100\;mg/kg,\;i.v.)$ was significantly smaller than that for mean systemic arterial pressure. These results indicate that in RHRs the endothelial cell function was impaired, at least in part, in systemic arterial system, but not in pulmonary arterial system, and both ACh-evoked and basal release of EDRF was less in the pulmonary arterial system than in systemic arterial system of both NRs and RHRs.

신성 고혈압쥐의 전신성 동맥계와 폐동맥계에 대한 EDRF 기능의 차이

이병호(Byung-Ho Lee),신화섭(Hwa-Sup Shin),허인회(In-Hoe Huh) 대한약리학회 1993 대한약리학잡지 Vol.29 No.2

급성 신성 고혈압쥐 (2-kidney, 1-ligation type)의 전신성 동맥계와 폐 동맥계에 대한 내피 의존적 혈관반응성을 규명하기 위하여, 적출 혈관 및 마취상태의 흰쥐에 대한 acetylcholine (ACh)의 혈관이완작용 및 혈압강하 작용을 측정하였다. 혈장 renin 활성(PRA)은 신동맥 결찰전 7.31 ± 0.63 ng/ml/hr A I에 비해 결찰 6 ~ 8일후에는 19 ~ 22 ng/ml/hr A I으로 유의성있게 증가하였으며, 이는 수축기혈압의 상승과 (154 ± 1.83{\rightarrow}190 ~ 215 mmHg) 일정한 상관성을 유지하였다. 신성 고혈압쥐 및 정상 혈압쥐의 흉곽 대동맥은 내피세포 존재시 ACh에 의해 용량의존적으로 이완되었으며, 이때 신성고혈압쥐에서의 반응은 정상 혈압쥐에 비해 유의성있게 감소하였다(각각 34% 및 86%, p<0.01). 또한 ACh은 신성 고혈압쥐 및 정상 혈압쥐의 폐동맥에 대해서도 내피세포 존재시에 이완반응을 초래하였다. 그러나, 흉곽 대동맥에서와는 달리 두 군간에 유의성있는 차이가 없었다. 이들 반응은 내피세포 제거후 또는 EDRF 억제제 (L-NAME, MB, 10^-5 M) 투여후 유의성있게 억제되었다. ACh(0.1 ~ 10μg/kg, i.v.)은 신성 고혈압쥐 및 정상 혈압쥐에서 전신성 동맥압의 강하를 초래하였는데, 신성 고혈압쥐에서 다소 감소하였으나 유의성있는 차이는 없었으며 (SAPm; 10μg/kg에서 각각 39%, 46 %), 이들 작용은 L-NAME(30 mg/kg, i.v.) 전처치후 유의성있게 억제되었다. ACh에 의한 폐동맥압 강하는 신성 고혈압쥐 및 정상 혈압쥐 사이에 서로 비슷하게 나타났다. 그러나, 신성 고혈압 쥐 및 정상 혈압쥐에서 ACh에 의한 폐동맥압의 강하율은 전신성 동맥압의 강하율보다 유의성있게(p<0.01) 작았으며, 또한 L-NAME (0.1 ~ 100 mg/kg, i.v.)에 의한 폐동맥압의 상승은 전신성 동맥압의 상승보다 유의성있게(p<0.01) 작았다. 이상의 실험 결과들은 급성 신성 고혈압쥐의 전신성 동맥계에서는 내피세포 손상이 초래되지만, 폐동맥계에서는 초래되지 않는다는것을 제시해준다. 또 신성고혈압쥐 및 정상 혈압쥐에서 EDRF 의 basal release 및 ACh 유발성 EDRF function은 전신성 동맥계에 비해 폐동맥계에서 적다는 것을 제시해준다. To investigate the endothelium dependent vascular reactivity of the systemic arterial and the pulmonary arterial system in acute renal hypertensive rats of 2-kidney, 1-ligation type (RHRs), acetylcholine (ACh)-induced vasodilation and depressor effects were evaluated in isolated arteries and in vivo, respectively, in the presence and absence of functional endothelium. ACh (10^-5 M) relaxed the intact thoracic aortas from RHRs and normotensive rats (NRs), but the effect was significantly smaller for those from RHRs (34 and 86%, respectively, p<0.01). ACh-induced vasodilation was completely abolished after removal of endothelial cell or pretreatment with EDRF inhibitors, L-NAME and MB, indicative of its dependence on intact endothelial or EDRF function. ACh also induced vasorelaxation of the intact pulmonary arteries from RHRs and NRs; however, unlike the effects on the thorcic aorta, no significant difference in amplitude was noted between two groups. ACh (0.1 ~ 10μg/kg, i.v.) reduced mean systemic arterial pressure in anesthetized RHRs and in NRs to the similar magnitude (% change: 39 and 46% at 10μg/kg, respectively) and these hypotensive effects were significantly decreased after pretreatment with L-NAME (30 mg/kg, i.v.). Deprssor effects of ACh on mean pulmonary arterial pressure were similar in RHRs and NRs with and without pretreatment of L-NAME. However, in both NRs and RHRs, the depressor effects of ACh on mean pulmonary arterial pressure were significantly reduced compared with those for mean systemic arterial pressure, and the increment of mean pulmonary arterial pressure noted after L-NAME (0.1μ100 mg/kg, i.v.) was significantly smaller than that for mean systemic arterial pressure. These results indicate that in RHRs the endothelial cell function was impaired, at least in part, in systemic arterial system, but not in pulmonary arterial system, and both ACh-evoked and basal release of EDRF was less in the pulmonary arterial system than in systemic arterial system of both NRs and RHRs.

Docosahexaenoic Acid가 Ibotenic Acid 혹은 Scopolamine으로 유발된 흰쥐의 기억력감소에 미치는 영향

강석연(Seog Youn Kang),김승희(Seung Hee Kim),정기경(Ki Kyung Jung),김태균(Tae Gyun Kim),한형미(Hyung-Mee Han),허인회(In Hoe Huh) 한국독성학회 1999 Toxicological Research Vol.15 No.2

The effect of docosahexaenoic acid (DHA) on the memory loss was investigated in two different animal models of dementia (active and passive avoidance models). In the active avoidance retention performance, DHA was administered to experimental animals for 24 days and ibotenic acid, a neurotoxin known to cause destruction of cholinergic nerve terminals, was injected into the nucleus basalis meynert on the 12th day. In the passive avoidance retention performance, DHA was administered to experimental animals for 24 days and either ibotenic acid or scopolamine was injected 24 hours (ibotenic acid) or 30 min (scopolamine) before the experiment. All animals were tested for the active and passive avoidance by the shuttle box and the reflex system, acetylcholinesterase (AChE) activity, AChE distribution by histochemical staining, amyloid protein and synaptophysin distribution by immunohistochemical staining and the degree of lipid peroxidation in the brain. DHA did not have any effect on the inhibition of the active and passive avoidance induced by ibotenic acid. On the other hand, scopolamine-induced inhibition of passive avoidance was partially reversed by DHA, indicating the implication of DHA in potentiation of cholinergic transmission. No differences were observed in AChE activity, AChE distribution, amyloid protein deposition synaptophysin distribution and the degree of lipid peroxidation between DHA-treated and vehicle (10% corn oil)-treated groups. These results demonstrated that administration of DHA for 24 days did not have any effect on the memory loss induced by ibotenic acid whereas scopolamine-induced memory loss was partially reversed by DHA. The precise role of cholinergic transmission potentiating effect of DHA in term of improving memory and/or learning ability remains to be elucidated.

N-Methyl-N-Nitrosourea 유도 자매염색분체교환생성과 DNA메칠화에 대한 Galangin의 억제효과

손수정(Soo Jung Sohn),김정한(Jung Han Kim),김영진(Young Jin Kim),허인회(In Hoe Huh),허문영(Moon Young Heo) 대한약학회 1995 약학회지 Vol.39 No.1

In order to evaluate the suppressive effects of galangin on the DNA damage induced by N-methyl-N-nitrosourea(MNU), in vitro sister chromatid exchange(SCE) test using Chinese Hamster ovary(CHO) cells was performed. Also the determinations of [3H] MNU-induced total DNA binding and methylated DNA were performed to find out the mechanism of action by galangin. MNU-induced SCEs were significantly decreased by simultaneous and pretreatment of galangin when S-9 mix was added only. In post-treatment, however, the MNU-induced SCEs were not decreased whether S-9 mix was added or not. [3H] MNU-induced total DNA binding was significantly inhibited by the treatment of galangin in calf thymus DNA and CHO cells. HPLC analysis of DNA hydrolysates shows that galangin caused a dose-dependant decrease in calf thymus DNA, but not significant decrease in CHO cells. These results suggest that the inhibition of galangin on the MNU-induced SCEs is due to the decrease of DNA binding and methylation with MNU. Therefore, galangin may be useful as a chemopreventive agent of alkylating agents.

생쥐 골수세포에서 아드리아마이신의 소핵생성에 미치는 N-마세틸시스테인의 억제효과

손수정(Su Jung Sohn),허인회(In Hoe Huh),최성규(Sung Gyu Choi),허문영(Moon Young Heo) 대한약학회 1993 약학회지 Vol.37 No.3

The anticlastogenic effect of N-acetylcysteine was tested in vivo in mouse bone-marrow micronucleus assay. The frequencies of micronuclei induced by adriamycin (5mg/kg i.p.) in bone marrow cells were decreased by the oral administration of N-acetylcysteine at 12 h before adriamycin injection. The observed suppressing effect was not a reflection of a delay in the formation of micronuclei by the cytotoxic effect of N-acetylcysteine. The anticlastogenic effects of SH compound including N-acetylcysteine, cysteine, cystine, S-carboxy methylcysteine and glutathione were also investigated by the multiple pretreatment. Each SH compound was administered orally every day for 5 days and adriamycin (5mg/kg i.p.) was injected at 24 h after the last dose of test compound. N-acetylcysteine and glutathione showed significantly the suppressive effect at dose of 10 and 25mg/kg for N-acetylcysteine and at the dose of 25mg/kg for glutathione. Our study suggests that N-acetylcysteine is capable of protecting the chromosomal damages in the normal cells during cancer chemotherapy by adriamycin, and may act as an anticlastogen against induction of micronuclei by superoxide generating agent such as adriamycin.

노인성치매에 대한 생화학적 연구(Ⅱ) : DHA와 DHEA가 흰쥐에서 Ibotenic acid로 유발된 능동적조건회피반응감소에 미치는 영향에 관한 연구 Effects of DHA and DHEA on active avoidance impaired rats induced by ibotenic acid

강석연,한형미,정기경,김태균,안향숙,허인회,김승희 식품의약품안전청 1997 식품의약품안전청 연보 Vol.1 No.-

Alzheimer's disease(AD) is ass☞ciated wit31 feature of extracellutar deposition of firoos protein aggregation in the form of amyloid plaque and a loss of choliBergic neurons. This study'as designed to evaluate the effects of docosahexaenoir acid(DHA ) and dehydroepiandrosteroneDHEA) in animal models of dementia which wa:T induced by neurotoxin(iboteni acid ) and of alcohot(16) ethanol). Ibotenic acid was injected into the nucleus basalis meynert region of the rat brain byfreotarically. The oral doses of DHA (675mg/kg) and DHEA (130rng/kg) were given respectively dur-lg 24 days daily, and ibotenic acid was injected at 33th day and of alcohol was given during 48 weeks.he effects of DHA and OHEA were tested the active avoidance and activity of acetylcholinesterasetchs), AChB distrib'ution, amyloid protein distribution, synaptophysin distribution and lipidfroxidatfDn in the brfin. There were Bo differences in active avoidance, amyloid distribution,rnaptofsj,sin dist,ibution and lipid pe,oxidation by DHA, DHEA in the rat b.sin. The rats we.e3ministered DHEA only showed decrease body weight significantly. Alcohol had no e(fect on activeroidance. These findinB proposed that DHA and DHEA Irvels may not be related to the memory im-tirment induced by ibotenic acid.