Yada Toyotaka, Shimokawa Hiroaki, Hiramatsu Osamu, Goto Masami, Ogasawara Yasuo, Kajiya Fumihiko
Annu Int Conf IEEE Eng Med Biol Soc. 2013;2013:3861-4. doi: 10.1109/EMBC.2013.6610387.
We have previously demonstrated that endothelium-derived hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor (EDHF) in canine coronary microcirculation in vivo. However, the role of H2O2/EDHF during angiotensin type 1 receptor blockers (ARB) administration in metabolic coronary dilatation in vivo remains to be examined. We examined whether H2O2 during ARB administration is involved in pacing-induced metabolic coronary vasodilatation in dogs in vivo and if so, whether such beneficial effects of ARB administration acutely improve coronary vasodilatation in diabetes mellitus (DM).
Canine subepicardial coronary small arteries (CSA,≥ 100 μm) and arterioles (CA, <100 μm) in left anterior descending artery area were continuously observed by an intravital microscope under cyclooxygenase blockade(ibuprofen, 12.5 mg/kg, intravenous infusion, iv). Experiments were performed during paired right ventricular pacing under the following 4 conditions (n=5 each); (i) control, (ii) DM(alloxan 40 mg/ kg, iv, 1 week prior to study), (iii) DM+ARB(olmesartan, 10 μg/kg/min, 10 min, intracoronary infusion,ic)+L-NMMA (NOS inhibitor, 2 !mol/min, ic) and (iv)DM+ARB+catalase (H2O2 discomposer, 1000 U/ml, 5 min, ic).
Cardiac tachypacing (60 to 120 bpm) caused coronary vasodilatation in both-sized arteries under control conditions. DM significantly decreased the vasodilatation compared with control in CSA and there was a residual vasodilatation for the loss of NO in CA, whereas DM+ARB+L-NMMA improved the vasodilatation compared with DM alone in CA and was significantly decreased by DM+ARB+catalase in CA.
These results indicate that H2O2 during ARB administration is involved in pacing-induced metabolic coronary vasodilatation in DM in vivo and that there are substantial compensatory interactions between NO and H2O2.
我们之前已经证明，内皮源性过氧化氢（H2O2）是犬体内冠状动脉微循环中的一种内皮源性超极化因子（EDHF）。然而，在血管紧张素1型受体阻滞剂（ARB）给药过程中，H2O2/EDHF在体内代谢性冠状动脉扩张中的作用仍有待研究。我们研究了ARB给药过程中的H2O2是否参与犬体内起搏诱导的代谢性冠状动脉血管舒张，如果是，ARB给药的这种有益作用是否能急性改善糖尿病（DM）中的冠状动脉血管舒张。
在环氧化酶阻断（布洛芬，12.5mg/kg，静脉输注，iv）下，通过活体显微镜连续观察左前降支区域的犬心外膜下冠状动脉小动脉（CSA，≥100μm）和小动脉（CA，<100μm）。在以下4种条件下（每组n = 5）进行右心室配对起搏实验：（i）对照，（ii）DM（四氧嘧啶40mg/kg，iv，研究前1周），（iii）DM + ARB（奥美沙坦，10μg/kg/min，10min，冠状动脉内输注，ic）+ L - NMMA（一氧化氮合酶抑制剂，2μmol/min，ic）和（iv）DM + ARB +过氧化氢酶（H2O2分解剂，1000U/ml，5min，ic）。
在对照条件下，心脏快速起搏（60至120次/分钟）导致两种大小动脉的冠状动脉血管舒张。与对照相比，DM显著降低了CSA中的血管舒张，并且CA中一氧化氮丧失后仍有残余血管舒张，而与单独的DM相比，DM + ARB + L - NMMA改善了CA中的血管舒张，并且DM + ARB +过氧化氢酶在CA中显著降低了这种血管舒张。
这些结果表明，ARB给药过程中的H2O2参与了DM犬体内起搏诱导的代谢性冠状动脉血管舒张，并且一氧化氮和H2O2之间存在大量的代偿性相互作用。
