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Ỉ
⚽
ᶞ
Ꮫ ࡢ ✀ 㢮
༤ኈ㸦་Ꮫ㸧
Ꮫ グ ␒ ྕ
⏥➨㸲㸳㸷ྕ
Ꮫ ᤵ ᖺ ᭶ ᪥
ᖹᡂ㸯㸴ᖺ 㸱᭶㸯㸴᪥
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Ꮫつ๎➨㸲᮲➨㸯㡯ヱᙜ
Ꮫ ㄽ ᩥ 㢟 ┠
The effect of central injection of
angiotensin-converting enzyme inhibitor and the
AT
1-receptor antagonist on the induction by LPS of
fever and brain interleukin-1ș response in rats
㸦LPS ᢞࡼࡿࣛࢵࢺࡢⓎ⇕⬻࡛ࡢࣥࢱ࣮ࣟ
࢟ࣥ 1ș⏘⏕ཬࡰࡍࣥࢪ࢜ࢸࣥࢩࣥኚ㓝⣲㜼ᐖ
AT
1ཷᐜయᣕᢠ⸆ࡢ⬻ᐊෆᢞࡢຠᯝ㸧
Ꮫㄽᩥᑂᰝጤဨ
ᰝ 㔜 ᨻ ༓ ⛅
ᰝ Ἑ ྜ ᗣ ᫂ Ώ 㑔 㐩 ⏕
Ꮫ ㄽ ᩥ ࡢ ෆ ᐜ ࡢ せ ᪨
᭱㏆ࠊ⚾㐩ࡣ LPS ࡢ㟼⬦ෆᢞࡼࡿࣛࢵࢺࡢⓎ⇕ࡸ⫢⮚࡛ࡢࣥࢱ࣮ࣟ࢟ࣥ 1ș(IL-1ș)ࡢ⏘ ⏕ࡀࠊࣥࢪ࢜ࢸࣥࢩࣥኚ㓝⣲(ACE)㜼ᐖ⸆ 1 ᆺཷᐜయᣕᢠ⸆ࡼࡾᢚไࡉࢀࡿᐇࢆⓎぢࡋࡓࠋ ࡇࡢ⤖ᯝࡣᮎᲈ࡛ࡢࣥࢪ࢜ࢸࣥࢩࣥϩ(ANGϩ)ࡑࡢ 1 ᆺཷᐜయ(AT1ࣞࢭࣉࢱ࣮)ࡀ LPS ࡼࡿᮎ ᲈ࡛ࡢⓎ⇕ᛶࢧࢺ࢝ࣥࡢ⏘⏕㛵ࡋ࡚࠸ࡿࢆ♧၀ࡋ࡚࠸ࡿࠋ୍᪉ࠊ⬻ෆࡶ ANG ⣔ࡀᏑᅾ ࡋࠊᮎᲈࡢ ANGϩࡶ⾑ᅽ࣭Ỉศㄪ⠇㛵ࡋ࡚࠸ࡿࡀุࡗ࡚࠸ࡿࠋࡲࡓࠊ⬻ᐊෆ LPS ࢆ ᢞࡍࡿⓎ⇕ࡸ IL-1ș⏘⏕ቑຍࡀ⏕ࡌࡿࠋࡋࡋࠊ⬻ෆࡢ ANGϩࡀ IL-1șࡢ⏘⏕㛵ࡍࡿ ࠺ࡣᮍࡔ᫂ࡽ࡛ࡣ࡞࠸ࠋᮏ◊✲࡛ࡣࠊࡇࡢྍ⬟ᛶࢆ㏣ồࡍࡿ┠ⓗ࡛ࠊLPS ࡢ⬻ᐊෆᢞࡼࡿⓎ⇕⬻ෆ࡛ࡢ IL-1șࡢ⏘⏕ཬࡰࡍ ACE 㜼ᐖ⸆ AT1ཷᐜయᣕᢠ⸆ࡢຠᯝࢆ᳨ウࡋࡓࠋࡲࡓࠊⓎ⇕
ࡢࡢẁ㝵 ANGϩࡀస⏝ࡋ࡚࠸ࡿࡢࡘ࠸࡚ࡶ᳨ウࡋࡓࠋ ᪉ ἲ
10 㐌㱋ࡢ㞝 Wistar ࣛࢵࢺࢆ⏝ࡋࡓࠋᐇ㦂ࡢ 2 㐌㛫๓(8 㐌㱋)ࢫࢸࣥࣞࢫ〇ࡢ࢝ࢽ࣮ࣗࣞ
(0.8mm,O.D.)ࢆഃ⬻ᐊ᳜࠼㎸ࡳࠊࡑࡢ 1 㐌㛫ᚋయ ࢆ ᐃࡍࡿⅭࡢ transmitter (Data Science ♫)ࢆ⭡⭍ෆ᳜࠼㎸ࢇࡔࠋࣛࢵࢺࢆ Saline ⩌ࠊLPS(0.2ȣg)⩌ࠊLPS(2ȣg)⩌ࠊLisinopril(ACE 㜼ᐖ ;50ȣg)+LPS(2ȣg)⩌ࠊLosartan(AT1ཷᐜయᣕᢠ⸆;50ȣg)+LPS(2ȣg)⩌ࡢ 5 ⩌ศࡅࡓࠋ12:00
ࡽ 13:00 ࡢ㛫ࡑࢀࡒࢀࡢ⸆ရࢆ⬻ᐊෆࡺࡗࡃࡾᢞࡋࠊࡑࡢᚋࠊయ ᐃ࠶ࡿ࠸ࡣ⤌⧊ෆࡢ IL-1 ș⃰ᗘࡢ ᐃࢆ⾜ࡗࡓࠋIL-1ș⃰ᗘࡢ ᐃࡢⅭ⸆ရࡢ⬻ᐊෆᢞ 2 㛫ࡲࡓࡣ 4 㛫ᚋ⬻ࢆ㏿ࡸ ฟࡋࡓࠋ⬻ࢆどᗋୗ㒊࣭ᾏ㤿࣭ᑠ⬻ษࡾศࡅࠊᾮయ❅⣲࡛⤖ࡋ-85Υ࡛ಖᏑࡋࡓࠋIL-1ș⃰ ᗘࡣ ELISA ࢟ࢵࢺࢆ⏝࠸ࠊ⺮ⓑ 100ȣg ᙜࡓࡾࡢ㔞࡛⾲ࡋࡓࠋࡲࡓࠊIL-1ș(20ng ⩌)ࠊIL-1ș(200ng)
⩌ࠊLisinopril(50ȣg)+IL-1ș(200ng)⩌ࠊLosartan(50ȣg)+IL-1ș(200ng)⩌ࡶྠᵝయ ᐃࢆ⾜ࡗ
ࡓࠋᑦࠊLosartan+IL-1ș⩌ IL-1ș⩌ࡘ࠸࡚ࡣⓎ⇕ࡢ᭱⤊࣓ࢹ࢚࣮ࢱ࣮࡛࠶ࡿ PGE2ࡢ⬻ෆྛ
㒊ࡢ⃰ᗘ(⺮ⓑ 100ȣg ᙜࡓࡾ)ࢆ ELISA ࢟ࢵࢺ࡛ ᐃࡋࡓࠋ ⤖ ᯝ
ࣛࢵࢺࡢ⬻ᐊෆ LPS ࢆᢞࡍࡿࠊᑐ↷ࡢ Saline ᢞ⩌ẚ㍑ࡋ࡚⏝㔞౫Ꮡᛶయ ࡀୖ᪼ࡋ ࡓࠋLisinopril ࠶ࡿ࠸ࡣ Losartan ࡢే⏝ࡼࡾࡇࡢᛂࡣ᭷ពᢚไࡉࢀࡓࠋ⬻ෆྛ㒊ࡢ IL-1ș⃰ ᗘࡢୖ᪼ᛂࡣࠊ㛫 LPS ࡢᢞ㔞౫Ꮡࡋ࡚Ⓨ⌧ࡋࡓࠋ≉࡚ࡢ⬻㒊࡛ IL-1șቑຍᛂࡀ ㉳ࡇࡗࡓࡢࡣࠊLPS ࡢ 2ȣg ࢆ⬻ᐊෆᢞࡋࡓ 4 㛫ᚋ࡛࠶ࡗࡓࠋࡋࡓࡀࡗ࡚ Lisinopril ࠶ࡿ࠸ࡣ Losartanࡢ LPS ࡢే⏝ࡣ 2ȣg ࡢ LPS ᢞ 4 㛫ᚋ᳨࡛ウࡋࡓࠋࡑࡢ⤖ᯝࠊどᗋୗ㒊ᾏ㤿࡛ࡣ LPS༢⊂ᢞẚ㍑ࡋ᭷ព IL-1ș⃰ᗘࡣᢚไࡉࢀࡓࠋᑠ⬻࡛ࡣᢚไഴྥࡣ♧ࡋࡓࡶࡢࡢࠊ᭷ពᕪ ࡣ⮳ࡽ࡞ࡗࡓࠋ୍᪉ࠊ⬻ᐊෆ IL-1șࢆᢞࡍࡿᑐ↷ࡢ Saline ᢞ⩌ẚ㍑ࡋ࡚⏝㔞౫Ꮡᛶ య ࡀୖ᪼ࡋࡓࠋLisinopril ࠶ࡿ࠸ࡣ Losartan ࡢే⏝ࡼࡗ࡚ࡶࡇࡢᛂࡣᢚไࡉࢀࡎࠊࡴࡋࢁ
losartanే⏝⩌࡛ᢞ 90 ศᚋࡢయ ࡣ᭷ពୖ᪼ࡋࡓࠋIL-1șᢞ 90 ศᚋࡢ⬻ෆࡢ PGE2⃰ᗘࢆ
ᐃࡋࡓࡀࠊLosartan+ IL-1ș⩌ IL-1ș⩌ࢆẚ㍑ࡋ࡚ࡶ᭷ពᕪࡣㄆࡵࡽࢀ࡞ࡗࡓࠋ ⪃ ᐹ ㏆ᖺࠊ⚾㐩ࡣ ANGϩࡑࡢ 1 ᆺཷᐜయࡀ LPS ࡢ㟼⬦ෆᢞࡼࡿⓎ⇕⫢⮚࡛ࡢⓎ⇕ᛶࢧࢺ࢝ ࣥ⏘⏕㛵ࡍࡿᐇࢆⓎぢࡋࡓࠋᅇࡢ⤖ᯝࡣࠊ⬻ෆࡢ ANGϩࡑࡢ 1 ᆺཷᐜయࡀ LPS ࡢ⬻ᐊ ෆᢞࡼࡿⓎ⇕⬻ෆࡢ IL-1ș⏘⏕㈉⊩ࡋ࡚࠸ࡿࡇࢆ♧၀ࡋ࡚࠸ࡿࠋࡲࡓࠊIL-1șࡼࡿⓎ⇕ ࡀࠊACE 㜼ᐖ⸆ AT1ཷᐜయᣕᢠ⸆ࡼࡾᢚไࡉࢀ࡞ࡗࡓᐇࡽࠊANGϩࡢⓎ⇕ᛂࡢస⏝ Ⅼࡣ LPS ᢞࡽ IL-1șࡀㄏᑟࡉࢀࡿࡲ࡛ࡢ㛫࡛࠶ࡾࠊࡑࢀ௨ୗ࡛ࡣ࡞࠸ࡀ᫂ࡽ࡞ࡗࡓࠋᐇ
㝿ࠊAT1ཷᐜయᣕᢠ⸆ࡣ IL-1șࡼࡿ PGE2⏘⏕ຠᯝࡀ࡞ࡗࡓࠋ⚾㐩ࡣࡇࢀࡽࡢ⤖ᯝࡽࠊ⬻ෆ
ࡢ ANGϩࡣ 1 ᆺཷᐜయࢆࡋ࡚⬻ෆࡢⓎ⇕ᛶࢧࢺ࢝ࣥࡢ⏘⏕㛵ࡍࡿࡶࡢ᥎ᐹࡍࡿࠋᚋ ࡣࠊANGϩࡀࡢ⣽⬊࠾࠸࡚ࢧࢺ࢝ࣥ⏘⏕ࢆஹ㐍ࡉࡏࡿࡢࠊ࠶ࡿ࠸ࡣࡑࡢᶵᗎࡘ࠸࡚ࠊ⤌ ⧊Ꮫⓗ࣭ศᏊ⏕≀ⓗ᳨ウࢆ⾜࠺ᚲせࡀ࠶ࡿࡶࡢ⪃࠼ࡿࠋ ⤖ ㄽ ⬻ෆࡢ ANGϩࡑࡢ 1 ᆺཷᐜయࡣࠊLPS ࡢ⬻ᐊෆᢞࡼࡿⓎ⇕⬻ෆ࡛ࡢ IL-1șࡢ⏘⏕㛵 ࡋ࡚࠸ࡿࡶࡢ᥎ᐹࡉࢀࡿࠋ
ㄽ ᩥ ᑂ ᰝ ࡢ ⤖ ᯝ ࡢ せ ᪨
ᮏ◊✲ࡣࠊLPS ࡢ⬻ᐊෆᢞࡼࡿࣛࢵࢺࡢⓎ⇕⬻ෆ࡛ࡢ IL-1șࡢ⏘⏕ཬࡰࡍ ACE 㜼ᐖ⸆ (Lisinopril)࠶ࡿ࠸ࡣ AT1ཷᐜయᣕᢠ⸆(Losartan)ࡢຠᯝࢆ᳨ウࡋࡓࡶࡢ࡛࠶ࡿࠋࡑࡢ⤖ᯝࠊLPS ࡼ ࡿ IL-1ș⏘⏕ࡢஹ㐍Ⓨ⇕ࡣࠊLisinopril ࠶ࡿ࠸ࡣ Losartan ࡢే⏝ࡼࡾᢚไࡉࢀࡿࡀࢃࡗࡓࠋ ୍᪉ࠊIL-1șࡢ⬻ᐊෆᢞࡼࡿⓎ⇕ࡣ Lisinopril ࡼࡾኚࡋ࡞ࡗࡓࡀࠊLosartan ే⏝ࡼࡾⓎ⇕ࡀࡴࡋࢁ⤒㐣ࡢ୍㒊࡛ஹ㐍ࡋࡓࠋ⬻ෆ PGE2⃰ᗘࡘ࠸࡚ࡣ Losartan+IL-1ș⩌ IL-1ș⩌ࡢ㛫
ᐇࡀ᫂ࡽ࡞ࡗࡓࠋᮏ◊✲ࡣࠊỈศ࣭ᚠ⎔ㄪ⠇㔜せ࡞ᙺࢆᯝࡓࡍ⬻ෆࡢ ANGϩࡢⓎ⇕ᛶࢧ ࢺ࢝ࣥ⏘⏕ࡢ㛵ࢆゎ᫂ࡋࡓࡶࡢ࡛࠶ࡾࠊⓎ⇕࣭ෆศἪ࣭ᚠ⎔ࡢ◊✲㡿ᇦ࠾࠸࡚᫂ࡽᏛ⾡ Ỉ‽ࢆ㧗ࡵࡓࡶࡢㄆࡵࡿࠋ
