1997 年度実績報告書

臓器への酸素供給を促進する内皮由来弛緩因子の新たな役割

研究課題

研究課題/領域番号	08457012
研究機関	香川医科大学
研究代表者	小坂博昭香川医科大学, 医学部, 教授 (60158897)
研究分担者	米山弘人香川医科大学, 医学部, 助手 (80294750) 精山明敏大阪大学, 医学部, 助手 (70206605)
キーワード	一酸化窒素(NO) / ヘモグロビン / 酸素放出 / 顕微分光 / 狭心症 / ニトログリセリン / 硝酸イソソルビド / 電子スピン共鳴
研究概要	臓器循環において、NOが血液から組織への酸素放出を促進させる可能性を検討した。ニトログリセリンや硝酸イソソルビドを投入したラットからの血液中には電子スピン共鳴でNOヘモグロビンを検出した。このようなNOヘモグロビンを含むラット血液の酸素解離曲線を検討したところ、ヘモグロビンと酸素との結合力が弱まっていることを初年度に初めて明らかにしている。今年度はin vivoで検討した。狭心症の特効薬であるニトロ系冠拡張薬の作用は、血管を拡張し心負荷を軽減することにあると思われてきた。新たに、一本の毛細血管でみた血液から組織への酸素放出が、その血管での血流増加によらずに、ニトロ系冠拡張薬によって有意に増加することを初めて明らかにした。枝分かれのない単一の肝類洞の2点で、酸素飽和度、赤血球速度、ヘモグロビン濃度を顕微分光装置で計測し、酸素放出速度を求めた。ニトログリセリンは酸素放出を急速に促進した。硝酸イソソルビドの酸素放出促進効果は持続的で長時間作動型の特徴と一致するものであった。この理由として2点間での酸素飽和度の差の有意な増加のみを観測した。オキシヘモグロビン流入量や肝の代謝の増加はなかった。これらの結果は、末梢組織で酸素を放出するときに、一個のNOが結合したHb四量体は、そのHb四量体の他のヘムに結合した酸素をより強く放出する可能性を示唆する。今回のデータは狭心症に対するニトロ系冠拡張薬の作用機構に対し核心的な資料のひとつとなるものと考える。

研究成果

(18件)

すべてその他

すべて文献書誌 (18件)

[文献書誌] H.Kosaka: "Elevation of oxygen release by nitroglycerin without increase in blood flow in hepatic microcirculation" Nature Medicine. 3(4). 456-459 (1997)
[文献書誌] K.Node: "Amelioration of ischemia-and reperfusion-induced myocardial injury by 17betaestradiol" Circulation. 96. 1953-1963 (1997)
[文献書誌] T-P.Huang: "Role of nitric oxide oxygen transport in hepatic sinusoids during endotoxemia" Hepatology. 26. 336-342 (1997)
[文献書誌] K.Node: "Effect of acute dynamic exercise on circulating plasma nitric oxide level and correlation to norepinephrine release in normal subjects." Am.J.Cardiol. 79. 526-528 (1997)
[文献書誌] Node-K: "Reversible reduction in plasma concentration of nitric oxide induced by cigarette smoking in young adults." Am.J.Cardiol. 79(11). 1538-1541 (1997)
[文献書誌] K.Node: "Bradykinin mediation of Ca2+ activated K+ channels regulates coronary blood flow in ischemic myocardium" Circulation. 95. 1560-1567 (1997)
[文献書誌] T.Mizuta: "Increased nitric oxide levels in exhaled air of rat lung allografts" J.Thorac.Cardiovasc.Surg. 113. 830-835 (1997)
[文献書誌] Node-K: "Reduced plasma concentrations of nitrogen oxide in individuals with essential hypertension" Hypertension. 30(3ptl). 405-408 (1997)
[文献書誌] Kosaka H: "Absence of mast cell involvement in leukocyte adhesion and emigration induced by inhibitio of nitric oxide synthase" Lab Inves. 77. 575-580 (1997)
[文献書誌] K.Node: "Roles of NO and Ca2+-activated K+channels in coronary vasodilation induced by 17betaestradiol in ischemic heart failure" FASEB J. 11. 793-799 (1997)
[文献書誌] T.Yamamoto: "Increase in experimental pulmonary metastasis in mice by L-arginine under inhibition of nitric oxide productionby NG-nitro-L-arginine methyl ester" Int.J.Cancer. 75. 140-144 (1998)
[文献書誌] J.Igarashi: "Inducible nitric oxide synthase augments injury elicited by oxidative stress in rat cardiac myocytes" Am.J.Physiol. 43. C245-C252 (1998)
[文献書誌] Hiroshi Murakami: "Blockade of nuronal nitric oxide synthase alters the baroreflex control of heart rate in the rabbit" Am.J.Physiol. 43. R181-186 (1998)
[文献書誌] I.Sugimoto: "The gain of the hepatorenal reflex in anesthetized dogs" J.Auton.Nerv.Syst. (in press).
[文献書誌] Y.Ogawa: "Stability of mutant superoxide dismutase-1 associated with familial amyotrophic lateral sclerosis determines the manner of copper release and induction of thioredoxin in erythrocytes" Biochem.Biopys.Res.Commun. 241. 251- (1997)
[文献書誌] Q.H.Chen: "Sinoaortic denervation enhances sodium retention and mild hypertention in Dahl saltsensitive rats" J.Auton.Nerv.Syst. (in press).
[文献書誌] H.Kosaka: "Increased oxygen dissociation by nitric oxide from RBC" Adv.Exp.Med.Biol. 19. 349-354 (1998)
[文献書誌] K.Okada: "Role of Endogenous Endothelin in the Development of Graft Arteriosclerosis in Rat Cardiac Allografts;Anti-Proliferative Effects of a Nonselective Endothelin Receptor Antagonist,Bosentan" Circulation. (in press).

1997 年度 実績報告書

臓器への酸素供給を促進する内皮由来弛緩因子の新たな役割

研究代表者

小坂 博昭 香川医科大学, 医学部, 教授 (60158897)

研究成果

[文献書誌] H.Kosaka: "Elevation of oxygen release by nitroglycerin without increase in blood flow in hepatic microcirculation" Nature Medicine. 3(4). 456-459 (1997)

[文献書誌] K.Node: "Amelioration of ischemia-and reperfusion-induced myocardial injury by 17betaestradiol" Circulation. 96. 1953-1963 (1997)

[文献書誌] T-P.Huang: "Role of nitric oxide oxygen transport in hepatic sinusoids during endotoxemia" Hepatology. 26. 336-342 (1997)

[文献書誌] K.Node: "Effect of acute dynamic exercise on circulating plasma nitric oxide level and correlation to norepinephrine release in normal subjects." Am.J.Cardiol. 79. 526-528 (1997)

[文献書誌] Node-K: "Reversible reduction in plasma concentration of nitric oxide induced by cigarette smoking in young adults." Am.J.Cardiol. 79(11). 1538-1541 (1997)

[文献書誌] K.Node: "Bradykinin mediation of Ca2+ activated K+ channels regulates coronary blood flow in ischemic myocardium" Circulation. 95. 1560-1567 (1997)

[文献書誌] T.Mizuta: "Increased nitric oxide levels in exhaled air of rat lung allografts" J.Thorac.Cardiovasc.Surg. 113. 830-835 (1997)

[文献書誌] Node-K: "Reduced plasma concentrations of nitrogen oxide in individuals with essential hypertension" Hypertension. 30(3ptl). 405-408 (1997)

[文献書誌] Kosaka H: "Absence of mast cell involvement in leukocyte adhesion and emigration induced by inhibitio of nitric oxide synthase" Lab Inves. 77. 575-580 (1997)

[文献書誌] K.Node: "Roles of NO and Ca2+-activated K+channels in coronary vasodilation induced by 17betaestradiol in ischemic heart failure" FASEB J. 11. 793-799 (1997)

[文献書誌] T.Yamamoto: "Increase in experimental pulmonary metastasis in mice by L-arginine under inhibition of nitric oxide productionby NG-nitro-L-arginine methyl ester" Int.J.Cancer. 75. 140-144 (1998)

[文献書誌] J.Igarashi: "Inducible nitric oxide synthase augments injury elicited by oxidative stress in rat cardiac myocytes" Am.J.Physiol. 43. C245-C252 (1998)

[文献書誌] Hiroshi Murakami: "Blockade of nuronal nitric oxide synthase alters the baroreflex control of heart rate in the rabbit" Am.J.Physiol. 43. R181-186 (1998)

[文献書誌] I.Sugimoto: "The gain of the hepatorenal reflex in anesthetized dogs" J.Auton.Nerv.Syst. (in press).

[文献書誌] Y.Ogawa: "Stability of mutant superoxide dismutase-1 associated with familial amyotrophic lateral sclerosis determines the manner of copper release and induction of thioredoxin in erythrocytes" Biochem.Biopys.Res.Commun. 241. 251- (1997)

[文献書誌] Q.H.Chen: "Sinoaortic denervation enhances sodium retention and mild hypertention in Dahl saltsensitive rats" J.Auton.Nerv.Syst. (in press).

[文献書誌] H.Kosaka: "Increased oxygen dissociation by nitric oxide from RBC" Adv.Exp.Med.Biol. 19. 349-354 (1998)

[文献書誌] K.Okada: "Role of Endogenous Endothelin in the Development of Graft Arteriosclerosis in Rat Cardiac Allografts;Anti-Proliferative Effects of a Nonselective Endothelin Receptor Antagonist,Bosentan" Circulation. (in press).

1997 年度実績報告書

小坂博昭香川医科大学, 医学部, 教授 (60158897)