Erythropoietin enhances hydrogen peroxide-mediated dilatation of canine coronary collateral arterioles during myocardial ischemia in dogs in vivo.
We have previously demonstrated that endothelium-derived hydrogen peroxide (H(2)O(2)) plays an important role in the canine coronary microcirculation as an endothelium-derived hyperpolarizing factor in vivo. However, it remains to be examined whether endogenous H(2)O(2) is involved in the dilatation of coronary collaterals during myocardial ischemia in vivo and, if so, whether erythropoietin (EPO) enhances the responses. Canine subepicardial native collateral small arteries (CSA; ≥ 100 μm) and arterioles (CA; <100 μm) were observed using an intravital microscope. Experiments were performed after left anterior descending coronary artery ischemia (90 min) under the following eight conditions (n = 5 each): control, EPO, EPO+catalase, EPO+N-monomethyl-l-arginine (l-NMMA), EPO+l-NMMA+catalase, EPO+l-NMMA+iberiotoxin [Ca(2+)-activated K(+) (K(Ca)) channel blocker], EPO+l-NMMA+apamin+charybdotoxin (K(Ca) channel blocker), and EPO+wortmannin (phosphatidylinositol 3-kinase inhibitor). Myocardial ischemia caused significant vasodilatation in CA but not in CSA under control conditions, which was significantly decreased by catalase in CA. After EPO, the vasodilatation was significantly increased in both sizes of arteries and was significantly decreased by catalase. The enhancing effect of EPO was reduced by l-NMMA but not by catalase in CSA and was reduced by l-NMMA+catalase in CA, where the greater inhibitory effects were noted with l-NMMA+catalase, l-NMMA+iberiotoxin, L-NMMA+apamin+charybdotoxin, or wortmannin. EPO significantly ameliorated ischemia-induced impairment of myocardial Akt phosphorylation, which was abolished by l-NMMA+catalase or wortmannin. EPO also ameliorated oxidative stress and myocardial injury, as assessed by plasma 8-hydroxydeoxyguanosine and troponin-T, respectively. These results indicate that EPO enhances H(2)O(2)-mediated dilatation of coronary collateral arterioles during myocardial ischemia in dogs in vivo.
Yada
Toyotaka
T
Dept. of Medical Engineering and Systems Cardiology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan. yada@me.kawasaki-m.ac.jp
Shimokawa
Hiroaki
H
Hiramatsu
Osamu
O
Satoh
Minoru
M
Kashihara
Naoki
N
Takaki
Aya
A
Goto
Masami
M
Ogasawara
Yasuo
Y
Kajiya
Fumihiko
F
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002245:Carbon Dioxide / Q000097:blood; D003097:Collateral Circulation / Q000187:drug effects*; D003326:Coronary Circulation / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000097:blood; D004195:Disease Models, Animal; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004921:Erythropoietin / Q000494:pharmacology*; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D010100:Oxygen / Q000097:blood; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D026902:Potassium Channel Blockers / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020107:Troponin T / Q000097:blood; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000975:Antioxidants; D002245:Carbon Dioxide; D003849:Deoxyguanosine; D004791:Enzyme Inhibitors; D004921:Erythropoietin; D006861:Hydrogen Peroxide; D052250:Nitric Oxide Synthase Type III; D010100:Oxygen; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D026902:Potassium Channel Blockers; D047428:Protein Kinase Inhibitors; D020107:Troponin T; D014665:Vasodilator Agents