Cardioprotective role of endogenous hydrogen peroxide during ischemia-reperfusion injury in canine coronary microcirculation in vivo.

We have recently demonstrated that endogenous H2O2 plays an important role in coronary autoregulation in vivo. However, the role of H2O2 during coronary ischemia-reperfusion (I/R) injury remains to be examined. In this study, we examined whether endogenous H2O2 also plays a protective role in coronary I/R injury in dogs in vivo. Canine subepicardial small coronary arteries (>or=100 microm) and arterioles (<100 microm) were continuously observed by an intravital microscope during coronary I/R (90/60 min) under cyclooxygenase blockade (n=50). Coronary vascular responses to endothelium-dependent vasodilators (ACh) were examined before and after I/R under the following seven conditions: control, nitric oxide (NO) synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA), catalase (a decomposer of H2O2), 8-sulfophenyltheophylline (8-SPT, an adenosine receptor blocker), L-NMMA+catalase, L-NMMA+tetraethylammonium (TEA, an inhibitor of large-conductance Ca2+-sensitive potassium channels), and L-NMMA+catalase+8-SPT. Coronary I/R significantly impaired the coronary vasodilatation to ACh in both sized arteries (both P<0.01); L-NMMA reduced the small arterial vasodilatation (both P<0.01), whereas it increased (P<0.05) the ACh-induced coronary arteriolar vasodilatation associated with fluorescent H2O2 production after I/R. Catalase increased the small arterial vasodilatation (P<0.01) associated with fluorescent NO production and increased endothelial NOS expression, whereas it decreased the arteriolar response after I/R (P<0.01). L-NMMA+catalase, L-NMMA+TEA, or L-NMMA+catalase+8-SPT further decreased the coronary vasodilatation in both sized arteries (both, P<0.01). L-NMMA+catalase, L-NMMA+TEA, and L-NMMA+catalase+8-SPT significantly increased myocardial infarct area compared with the other four groups (control, L-NMMA, catalase, and 8-SPT; all, P<0.01). These results indicate that endogenous H2O2, in cooperation with NO, plays an important cardioprotective role in coronary I/R injury in vivo.

[1]  J. Mironneau,et al.  Potassium channel activation in vascular smooth muscle. , 1992, Advances in experimental medicine and biology.

[2]  Enrique Cadenas,et al.  Relative contributions of heart mitochondria glutathione peroxidase and catalase to H(2)O(2) detoxification in in vivo conditions. , 2002, Free radical biology & medicine.

[3]  P. Vanhoutte,et al.  Endothelium‐dependent hyperpolarization of canine coronary smooth muscle , 1988, British journal of pharmacology.

[4]  H. Maeda,et al.  Pivotal role of Cu,Zn-superoxide dismutase in endothelium-dependent hyperpolarization. , 2003, The Journal of clinical investigation.

[5]  H Shimokawa,et al.  Primary endothelial dysfunction: atherosclerosis. , 1999, Journal of molecular and cellular cardiology.

[6]  P. London.  Injury , 1969, Definitions.

[7]  T. Ehring,et al.  Cholinergic and α-adrenergic coronary constriction with increasing ischemia-reperfusion injury , 1995 .

[8]  J. Mehta,et al.  Impaired Canine Coronary Vasodilator Response to Acetylcholine and Bradykinin After Occlusion‐ Reperfusion , 1989, Circulation research.

[9]  C. Garland,et al.  K+ is an endothelium-derived hyperpolarizing factor in rat arteries , 1998, Nature.

[10]  R. London,et al.  Elevation in Cytosolic Free Calcium Concentration Early in Myocardial Ischemia in Perfused Rat Heart , 1987, Circulation research.

[11]  Q. Chai,et al.  Peroxynitrite Inhibits Ca2+-Activated K+ Channel Activity in Smooth Muscle of Human Coronary Arterioles , 2002, Circulation research.

[12]  H. Hayashi,et al.  Protective effects of hydrogen peroxide against ischemia/reperfusion injury in perfused rat hearts. , 2003, Circulation journal : official journal of the Japanese Circulation Society.

[13]  A. Takeshita,et al.  Possible Involvement of Rho-Kinase in the Pathogenesis of Hypertension in Humans , 2001, Hypertension.

[14]  Takashi Saito,et al.  Role for Hydrogen Peroxide in Flow-Induced Dilation of Human Coronary Arterioles , 2003, Circulation research.

[15]  N. Komai,et al.  NAD(P)H oxidase and uncoupled nitric oxide synthase are major sources of glomerular superoxide in rats with experimental diabetic nephropathy. , 2005, American journal of physiology. Renal physiology.

[16]  P. Vanhoutte,et al.  Oxygen-derived free radicals, endothelium, and responsiveness of vascular smooth muscle. , 1986, The American journal of physiology.

[17]  A. Hudetz,et al.  Increased expression of Ca2+-sensitive K+ channels in the cerebral microcirculation of genetically hypertensive rats: evidence for their protection against cerebral vasospasm. , 1998, Circulation research.

[18]  F Kajiya,et al.  In vivo observation of subendocardial microvessels of the beating porcine heart using a needle-probe videomicroscope with a CCD camera. , 1993, Circulation research.

[19]  F. Kajiya,et al.  Direct in vivo observation of subendocardial arteriolar response during reactive hyperemia. , 1995, Circulation research.

[20]  扇田 久和.  Amelioration of Ischemia-and Reperfusion-induced Myocardial Injury by the Selective Estrogen Receptor Modulator, Raloxifene, in the Canine Heart , 2003 .

[21]  F. Kajiya,et al.  In vivo visualization of subendocardial arteriolar response in renovascular hypertensive hearts. , 2003, American journal of physiology. Heart and circulatory physiology.

[22]  H Shimokawa,et al.  Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. , 2000, The Journal of clinical investigation.

[23]  P. Vanhoutte,et al.  Effects of hydrogen peroxide on the responsiveness of isolated canine bronchi: role of prostaglandin E2 and I2. , 1992, The American journal of physiology.

[24]  R. Busse,et al.  Display of the characteristics of endothelium‐derived hyperpolarizing factor by a cytochrome P450‐derived arachidonic acid metabolite in the coronary microcirculation , 1994, British journal of pharmacology.

[25]  C. Tiefenbacher,et al.  Restoration of endothelium-dependent vasodilation after reperfusion injury by tetrahydrobiopterin. , 1996, Circulation.

[26]  Yasuo Ogasawara,et al.  Hydrogen Peroxide, an Endogenous Endothelium-Derived Hyperpolarizing Factor, Plays an Important Role in Coronary Autoregulation In Vivo , 2003, Circulation.

[27]  T. Griffith,et al.  Inhibition of the gap junctional component of endothelium‐dependent relaxations in rabbit iliac artery by 18‐α glycyrrhetinic acid , 1998, British journal of pharmacology.

[28]  J. Falck,et al.  EDHF mediates flow-induced dilation in skeletal muscle arterioles of female eNOS-KO mice. , 2001, American journal of physiology. Heart and circulatory physiology.

[29]  P. Pratt,et al.  Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors. , 1996, Circulation research.

[30]  Y. Nakaya,et al.  Hydrogen peroxide-induced vascular relaxation in porcine coronary arteries is mediated by Ca2+-activated K+ channels , 2007, Heart and Vessels.

[31]  M. Fujishima,et al.  The importance of the hyperpolarizing mechanism increases as the vessel size decreases in endothelium-dependent relaxations in rat mesenteric circulation. , 1996, Journal of cardiovascular pharmacology.

[32]  T. Ehring,et al.  Cholinergic and alpha-adrenergic coronary vasomotion [corrected] with increasing ischemia-reperfusion injury. , 1995, The American journal of physiology.

[33]  R. Bache,et al.  Increased extravascular forces limit endothelium-dependent and -independent coronary vasodilation in congestive heart failure. , 2001, Cardiovascular research.

[34]  A. Weston,et al.  Acetylcholine releases endothelium‐derived hyperpolarizing factor and EDRF from rat blood vessels , 1988, British journal of pharmacology.

[35]  D. S. Weiss,et al.  Inhibition of adenosine-induced coronary vasodilation by block of large-conductance Ca(2+)-activated K+ channels. , 1994, The American journal of physiology.

[36]  Y. Shinozaki,et al.  New nonradioactive microspheres and more sensitive X-ray fluorescence to measure regional blood flow. , 1992, The American journal of physiology.

[37]  Hiroaki Shimokawa,et al.  Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in human mesenteric arteries. , 2002, Biochemical and biophysical research communications.

[38]  F. Kajiya,et al.  Beneficial effect of hydroxyfasudil, a specific Rho-kinase inhibitor, on ischemia/reperfusion injury in canine coronary microcirculation in vivo. , 2005, Journal of the American College of Cardiology.

[39]  G. Freeman,et al.  TNF-α and H2O2 induce IL-18 and IL-18Rβ expression in cardiomyocytes via NF-κB activation , 2003 .