1998 Fiscal Year Annual Research Report

NO消去剤の抗ショック治療への応用

Research Project

Project/Area Number	09557127
Research Institution	Kumamoto University
Principal Investigator	前田浩熊本大学, 医学部, 教授 (90004613)
Co-Investigator(Kenkyū-buntansha)	澤智裕熊本大学, 医学部, 助手 (30284756) 赤池孝章熊本大学, 医学部, 助教授 (20231798)
Keywords	NO / エンドトキシンショック / NO消去剤 / ニトロソα_1-プロテアーゼインヒビター / 抗ショック剤
Research Abstract	我々はこれまでの研究により、エンドトキシンショックにおいて過剰に産生されるNOが、遷延性の低血圧に直接関与していること、さらにエンドトキシンショックモデルにNO消去剤(PTIO)を投与すると、抗ショック作用が認められることを明らかにしてきた。しかしながら一方で、NO合成阻害剤投与は、むしろ肝機能異常を増悪させることも報告されていろる。これらの矛盾する知見は、エンドトキシンショックにおいて、NOが防御的作用と障害作用の相反する活性を有していることによるものと思われる。そこで本年度は、NOの供給剤であるニトロソ化α_1-PIプロテアーゼインヒビター(ニトロソα_1-PI)を作製しエンドトキシンショックなどにおける多臓器不全に対する治療への応用の可能性について検討した。このため、ヒトの血漿中に多量に含まれ、血中の主要のプロテアーゼインヒビターとして知られるα_1-PIを、分離精製した後、α_1-PIを10等量(モル比)のisoamylnitriteで処理しニトロソα_1-PIを得た。このニトロソα_1-PIは、α_1-PIのSH基にNOを一個結合させたものであり、水溶液中でも非常に安定にNOを長時間保持していた。さらに、得られたニトロソα_1-PIは、少なくともラット肝の虚血再還流障害モデルにおいて、著明な臓器保護作用を示した。この様な予備的知見をふまえ、今後さらに、各種エンドトキシンショックモデルにおけるNO消去剤PTIOとニトロソα_1-PIの薬理効果を検討する予定である。

Research Products
(15 results)

All Other

All Publications (15 results)

[Publications] T.Akaike,et al.: "Free radicals in viral pathogenesis:Molecular mechanisms involving superoxide and NO" Proc.Soc.Exp.Biol.Med.217. 64-73 (1998)
[Publications] M.Yoshida,et al.: "Effect of the NO scavenger carboxy-PTIO on enthothelium-dependent vasorelaxation of various blood vessels from rabbits" Life Sciences. 62. 203-211 (1998)
[Publications] H.Maeda,et al.: "Human matrix metalloprotease activation by insults of bacterial infection involving ptoteases and free radicals" Biol.Chem.379. 193-200 (1998)
[Publications] J.Wu,et al.: "Modulation of enhanced vascular permeability in tumors by a bradykinin antagonist,a cyclooxygenase inhibitor,and a nitric oxide scavenger" Cancer Res.58. 159-165 (1998)
[Publications] K.Maruo,et al.: "Involvement of bradykinin generation in intravascular dissemination of Vibrio vulnificus and provention of invasion by a bradykinin antagonist" Infect.Immun.66. 866-869 (1998)
[Publications] H.Maeda,et al.: "Nitric oxide and oxygen radicals in infection,inflammation and cancer" Biochemistry(Moscow). 63. 854-865 (1998)
[Publications] K.Sato,et al.: "Therapeutic effect of erythromycin on influenza virus-induced lung injuly in mice" Am.J.Respir.Crit.Care Med. 157. 853-857 (1998)
[Publications] T.Sawa,et al.: "Lipid peroxyl radicals from oxidized oils and heme-iron:Implication of a high-fat diet in colon carcinogenesis" Cancer Epidemiol.Biomarkers&Prevention. 7. 1007-1012 (1998)
[Publications] M.Yoshida,et al.: "The possible effect of nitric oxide on relaxation and noradrenaline release in the isolated rabbit urethra" Eur.J.Pharmacol.357. 213-219 (1998)
[Publications] N.Nakatsubo,et al.: "Improved nitric oxide detection using 2,3-diaminonaphthalene and its application to the evaluation of novel nitric oxide synthase inhibitors" Biol.Pharm.Bull.21. 1247-1250 (1998)
[Publications] K.Doi,et al.: "Induction of heme oxygenase-1 by nitric oxide and ischemia in experimental solid tumors and implications for tumor growth" Br.J.Cancer. (in press). (1999)
[Publications] S.Fujii,et al.: "Role of nitric oxide in pathogenesis of herpes simplex virus encephalitis in rats" Virology. (in press). (1999)
[Publications] H.Maeda,et al.: "Free radical generation from heterocyclic amines by cytochrome b5 reductase in the presence of NADH" Cancer Letters. (in press). (1999)
[Publications] H.Maeda,et al.: "Kallikrein-kinin in infection and cancer" Immunopharmacology. (in press). (1999)
[Publications] T.Akaike,et al.: "Nitric Oxide and Infection(ed.F.C.Fang)" Plenum Publishing Co.,New York(in press), (1999)

1998 Fiscal Year Annual Research Report

NO消去剤の抗ショック治療への応用

Principal Investigator

前田 浩 熊本大学, 医学部, 教授 (90004613)

Research Products

[Publications] T.Akaike,et al.: "Free radicals in viral pathogenesis:Molecular mechanisms involving superoxide and NO" Proc.Soc.Exp.Biol.Med.217. 64-73 (1998)

[Publications] M.Yoshida,et al.: "Effect of the NO scavenger carboxy-PTIO on enthothelium-dependent vasorelaxation of various blood vessels from rabbits" Life Sciences. 62. 203-211 (1998)

[Publications] H.Maeda,et al.: "Human matrix metalloprotease activation by insults of bacterial infection involving ptoteases and free radicals" Biol.Chem.379. 193-200 (1998)

[Publications] J.Wu,et al.: "Modulation of enhanced vascular permeability in tumors by a bradykinin antagonist,a cyclooxygenase inhibitor,and a nitric oxide scavenger" Cancer Res.58. 159-165 (1998)

[Publications] K.Maruo,et al.: "Involvement of bradykinin generation in intravascular dissemination of Vibrio vulnificus and provention of invasion by a bradykinin antagonist" Infect.Immun.66. 866-869 (1998)

[Publications] H.Maeda,et al.: "Nitric oxide and oxygen radicals in infection,inflammation and cancer" Biochemistry(Moscow). 63. 854-865 (1998)

[Publications] K.Sato,et al.: "Therapeutic effect of erythromycin on influenza virus-induced lung injuly in mice" Am.J.Respir.Crit.Care Med. 157. 853-857 (1998)

[Publications] T.Sawa,et al.: "Lipid peroxyl radicals from oxidized oils and heme-iron:Implication of a high-fat diet in colon carcinogenesis" Cancer Epidemiol.Biomarkers&Prevention. 7. 1007-1012 (1998)

[Publications] M.Yoshida,et al.: "The possible effect of nitric oxide on relaxation and noradrenaline release in the isolated rabbit urethra" Eur.J.Pharmacol.357. 213-219 (1998)

[Publications] N.Nakatsubo,et al.: "Improved nitric oxide detection using 2,3-diaminonaphthalene and its application to the evaluation of novel nitric oxide synthase inhibitors" Biol.Pharm.Bull.21. 1247-1250 (1998)

[Publications] K.Doi,et al.: "Induction of heme oxygenase-1 by nitric oxide and ischemia in experimental solid tumors and implications for tumor growth" Br.J.Cancer. (in press). (1999)

[Publications] S.Fujii,et al.: "Role of nitric oxide in pathogenesis of herpes simplex virus encephalitis in rats" Virology. (in press). (1999)

[Publications] H.Maeda,et al.: "Free radical generation from heterocyclic amines by cytochrome b5 reductase in the presence of NADH" Cancer Letters. (in press). (1999)

[Publications] H.Maeda,et al.: "Kallikrein-kinin in infection and cancer" Immunopharmacology. (in press). (1999)

[Publications] T.Akaike,et al.: "Nitric Oxide and Infection(ed.F.C.Fang)" Plenum Publishing Co.,New York(in press), (1999)

前田浩熊本大学, 医学部, 教授 (90004613)