TY - JOUR
T1 - Hypoxic conditioning suppresses nitric oxide production upon myocardial reperfusion
AU - Ryou, Myoung Gwi
AU - Sun, Jie
AU - Oguayo, Kevin N.
AU - Manukhina, Eugenia B.
AU - Downey, H. Fred
AU - Mallet, Robert T.
N1 - Funding Information:
This study was supported by grants HL-064785, HL-071684, and AT-003598 from the U.S. National Institutes of Health.
PY - 2008/6
Y1 - 2008/6
N2 - Physiologically modulated concentrations of nitric oxide (NO) are generally beneficial, but excessive NO can injure myocardium by producing cytotoxic peroxynitrite. Recently we reported that intermittent, normobaric hypoxia conditioning (IHC) produced robust cardioprotection against infarction and lethal arrhythmias in a canine model of coronary occlusion-reperfusion. This study tested the hypothesis that IHC suppresses myocardial nitric oxide synthase (NOS) activity and thereby dampens explosive, excessive NO formation upon reperfusion of occluded coronary arteries. Mongrel dogs were conditioned by a 20 d program of IHC (FIO 2 9.5-10%; 5-10 min hypoxia/cycle, 5-8 cycles/d with intervening 4 min normoxia). One day later, ventricular myocardium was sampled for NOS activity assays, and immunoblot detection of the endothelial NOS isoform (eNOS). In separate experiments, myocardial nitrite (NO 2 -) release, an index of NO formation, was measured at baseline and during reperfusion following 1 h occlusion of the left anterior descending coronary artery (LAD). Values in IHC dogs were compared with respective values in non-conditioned, control dogs. IHC lowered left and right ventricular NOS activities by 60%, from 100-115 to 40-45 mU/g protein (P < 0.01), and decreased eNOS content by 30% (P < 0.05). IHC dampened cumulative NO 2 - release during the first 5 min reperfusion from 32 ± 7to14 ± 2 imol/g (P < 0.05), but did not alter hyperemic LAD flow (15 ± 2 vs. 13 ± 2 ml/g). Thus, IHC suppressed myocardial NOS activity, eNOS content, and excessive NO formation upon reperfusion without compromising reactive hyperemia. Attenuation of the NOS/NO system may contribute to IHC-induced protection of myocardium from ischemia-reperfusion injury.
AB - Physiologically modulated concentrations of nitric oxide (NO) are generally beneficial, but excessive NO can injure myocardium by producing cytotoxic peroxynitrite. Recently we reported that intermittent, normobaric hypoxia conditioning (IHC) produced robust cardioprotection against infarction and lethal arrhythmias in a canine model of coronary occlusion-reperfusion. This study tested the hypothesis that IHC suppresses myocardial nitric oxide synthase (NOS) activity and thereby dampens explosive, excessive NO formation upon reperfusion of occluded coronary arteries. Mongrel dogs were conditioned by a 20 d program of IHC (FIO 2 9.5-10%; 5-10 min hypoxia/cycle, 5-8 cycles/d with intervening 4 min normoxia). One day later, ventricular myocardium was sampled for NOS activity assays, and immunoblot detection of the endothelial NOS isoform (eNOS). In separate experiments, myocardial nitrite (NO 2 -) release, an index of NO formation, was measured at baseline and during reperfusion following 1 h occlusion of the left anterior descending coronary artery (LAD). Values in IHC dogs were compared with respective values in non-conditioned, control dogs. IHC lowered left and right ventricular NOS activities by 60%, from 100-115 to 40-45 mU/g protein (P < 0.01), and decreased eNOS content by 30% (P < 0.05). IHC dampened cumulative NO 2 - release during the first 5 min reperfusion from 32 ± 7to14 ± 2 imol/g (P < 0.05), but did not alter hyperemic LAD flow (15 ± 2 vs. 13 ± 2 ml/g). Thus, IHC suppressed myocardial NOS activity, eNOS content, and excessive NO formation upon reperfusion without compromising reactive hyperemia. Attenuation of the NOS/NO system may contribute to IHC-induced protection of myocardium from ischemia-reperfusion injury.
KW - Cardioprotection
KW - Dogs
KW - Intermittent hypoxia
KW - Myocardial ischemia
KW - Nitric oxide synthase
UR - http://www.scopus.com/inward/record.url?scp=46449139649&partnerID=8YFLogxK
U2 - 10.3181/0710-RM-282
DO - 10.3181/0710-RM-282
M3 - Article
C2 - 18408142
AN - SCOPUS:46449139649
SN - 1535-3702
VL - 233
SP - 766
EP - 774
JO - Experimental Biology and Medicine
JF - Experimental Biology and Medicine
IS - 6
ER -