TY - JOUR
T1 - In vivo role of heme oxygenase in ischemic coronary vasodilation
AU - Nishikawa, Yasuhiro
AU - Stepp, David W
AU - Merkus, Daphne
AU - Jones, Deron
AU - Chilian, William M.
PY - 2004/6
Y1 - 2004/6
N2 - The heart constitutively expresses heme oxygenase (HO)-2, which catabolizes heme-containing proteins to produce biliverdin and carbon monoxide (CO). The heart also contains many possible substrates for HO-2 such as heme groups of myoglobin and cytochrome P-450s, which potentially could be metabolized into CO. As a result of observations that CO activates guanylyl cyclase and induces vascular relaxation and that HO appears to confer protection from ischemic injury, we hypothesized that the HO-CO pathway is involved in ischemic vasodilation in the coronary microcirculation. Responses of epicardial coronary arterioles to ischemia (perfusion pressure ∼40 mmHg; flow velocity decreased by ∼50%; dL/dt reduced by ∼60%) were measured using stroboscopic fluorescence microangiography in 34 open-chest anesthetized dogs. Ischemia caused vasodilation of coronary arterioles by 36 ± 6%. Administration of NG-monomethyl-L-arginine (L-NMMA, 3 μmol·kg-1·min-1 intracoronary), indomethacin (10 mg/kg iv), and K+ (60 mM, epicardial suffusion) to prevent the actions of nitric oxide, prostaglandins, and hyperpolarizing factors, respectively, partially inhibited dilation during ischemia (36 ± 6 vs. 15 ± 4%; P < 0.05). The residual vasodilation during ischemia after antagonist administration was inhibited by tin mesoporphyrin IX (SnMP, 10 mg/kg iv), which is an inhibitor of HO (15 ± 4 vs. 7 ± 2%; P < 0.05 vs. before SnMP). The guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (10-5 M, epicardial suffusion) also inhibited vasodilation during ischemia in the presence of L-NMMA with indomethacin and KCl. Moreover, administration of heme-L-arginate, which is a substrate for HO, produced dilation after ischemia but not after control conditions. We conclude that during myocardial ischemia, HO-2 activation can produce cGMP-mediated vasodilation presumably via the production of CO. This vasodilatory pathway appears to play a backup role and is activated only when other mechanisms of vasodilation during ischemia are exhausted.
AB - The heart constitutively expresses heme oxygenase (HO)-2, which catabolizes heme-containing proteins to produce biliverdin and carbon monoxide (CO). The heart also contains many possible substrates for HO-2 such as heme groups of myoglobin and cytochrome P-450s, which potentially could be metabolized into CO. As a result of observations that CO activates guanylyl cyclase and induces vascular relaxation and that HO appears to confer protection from ischemic injury, we hypothesized that the HO-CO pathway is involved in ischemic vasodilation in the coronary microcirculation. Responses of epicardial coronary arterioles to ischemia (perfusion pressure ∼40 mmHg; flow velocity decreased by ∼50%; dL/dt reduced by ∼60%) were measured using stroboscopic fluorescence microangiography in 34 open-chest anesthetized dogs. Ischemia caused vasodilation of coronary arterioles by 36 ± 6%. Administration of NG-monomethyl-L-arginine (L-NMMA, 3 μmol·kg-1·min-1 intracoronary), indomethacin (10 mg/kg iv), and K+ (60 mM, epicardial suffusion) to prevent the actions of nitric oxide, prostaglandins, and hyperpolarizing factors, respectively, partially inhibited dilation during ischemia (36 ± 6 vs. 15 ± 4%; P < 0.05). The residual vasodilation during ischemia after antagonist administration was inhibited by tin mesoporphyrin IX (SnMP, 10 mg/kg iv), which is an inhibitor of HO (15 ± 4 vs. 7 ± 2%; P < 0.05 vs. before SnMP). The guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (10-5 M, epicardial suffusion) also inhibited vasodilation during ischemia in the presence of L-NMMA with indomethacin and KCl. Moreover, administration of heme-L-arginate, which is a substrate for HO, produced dilation after ischemia but not after control conditions. We conclude that during myocardial ischemia, HO-2 activation can produce cGMP-mediated vasodilation presumably via the production of CO. This vasodilatory pathway appears to play a backup role and is activated only when other mechanisms of vasodilation during ischemia are exhausted.
KW - Carbon monoxide
KW - Hypoperfusion
KW - Ischemia
KW - Microcirculation
UR - http://www.scopus.com/inward/record.url?scp=2542497841&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=2542497841&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00671.2003
DO - 10.1152/ajpheart.00671.2003
M3 - Article
C2 - 15148058
AN - SCOPUS:2542497841
SN - 0363-6135
VL - 286
SP - H2296-H2304
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 6 55-6
ER -