Iida Y, Katusic Z S
Department of Anesthesiology, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
Stroke. 2000 Sep;31(9):2224-30. doi: 10.1161/01.str.31.9.2224.
The role of hydrogen peroxide in the regulation of cerebral arterial tone is not completely understood. Previous studies have demonstrated that hydrogen peroxide causes vasodilation of small cerebral arteries. The present study was designed to determine the mechanisms responsible for relaxations of large cerebral arteries to hydrogen peroxide.
Rings of canine middle cerebral arteries without endothelium were suspended for isometric force recording in modified Krebs-Ringer bicarbonate solution bubbled with 94% O(2)/6% CO(2) (37 degrees C, pH 7.4). Radioimmunoassay technique was used to determine the levels of cAMP and cGMP.
During contraction to UTP (3 x 10(-6) or 10(-5) mol/L), hydrogen peroxide (10(-6) to 10(-4) mol/L) caused concentration-dependent relaxations. Catalase (1200 U/mL) abolished the relaxations to hydrogen peroxide. Inhibition of cyclooxygenase by indomethacin (10(-5) mol/L) significantly reduced relaxations to hydrogen peroxide. In arteries contracted by KCl (20 mmol/L), the relaxations to hydrogen peroxide were significantly reduced. In the presence of a nonselective potassium channel inhibitor, BaCl(2) (10(-4) mol/L), a delayed rectifier potassium channel inhibitor, 4-aminopyridine (10(-3) mol/L), or a calcium-activated potassium channel inhibitor, charybdotoxin (3 x 10(-8) mol/L), the relaxations to hydrogen peroxide were also significantly reduced. An ATP-sensitive potassium channel inhibitor, glyburide (5 x 10(-6) mol/L), did not affect the relaxations to hydrogen peroxide. Hydrogen peroxide produced concentration-dependent increase in levels of cAMP. Indomethacin (10(-5) mol/L) inhibited the stimulatory effect of hydrogen peroxide on cAMP production. In contrast, hydrogen peroxide did not affect the levels of cGMP.
These results suggest that hydrogen peroxide may cause relaxations of large cerebral arteries in part by activation of arachidonic acid metabolism via cyclooxygenase pathway with subsequent increase in cAMP levels and activation of potassium channels.
过氧化氢在调节脑动脉张力中的作用尚未完全明确。以往研究表明，过氧化氢可引起脑小动脉血管舒张。本研究旨在确定脑大动脉对过氧化氢舒张反应的机制。
将犬大脑中动脉无内皮的血管环悬挂于用94%O₂/6%CO₂鼓泡的改良 Krebs-Ringer 碳酸氢盐溶液（37℃，pH 7.4）中，进行等长力记录。采用放射免疫分析技术测定环磷酸腺苷（cAMP）和环磷酸鸟苷（cGMP）水平。
在对三磷酸尿苷（UTP，3×10⁻⁶或10⁻⁵mol/L）收缩时，过氧化氢（10⁻⁶至10⁻⁴mol/L）引起浓度依赖性舒张。过氧化氢酶（1200 U/mL）可消除对过氧化氢的舒张反应。吲哚美辛（10⁻⁵mol/L）抑制环氧合酶可显著降低对过氧化氢的舒张反应。在由氯化钾（20 mmol/L）收缩的血管中，对过氧化氢的舒张反应显著降低。在存在非选择性钾通道抑制剂氯化钡（10⁻⁴mol/L）、延迟整流钾通道抑制剂4-氨基吡啶（10⁻³mol/L）或钙激活钾通道抑制剂蝎毒素（3×10⁻⁸mol/L）时，对过氧化氢的舒张反应也显著降低。ATP敏感性钾通道抑制剂格列本脲（5×10⁻⁶mol/L）不影响对过氧化氢的舒张反应。过氧化氢使cAMP水平呈浓度依赖性升高。吲哚美辛（10⁻⁵mol/L）抑制过氧化氢对cAMP生成的刺激作用。相反，过氧化氢不影响cGMP水平。
这些结果提示，过氧化氢可能部分通过环氧合酶途径激活花生四烯酸代谢，随后使cAMP水平升高并激活钾通道，从而引起脑大动脉舒张。
