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In vivo role of heme oxygenase in ischemic coronary vasodilation

¹Physiology and ³Surgery, Medical College of Wisconsin, Watertown, Wisconsin 53226; ²Department of Physiology, Medical College of Georgia, Augusta, Georgia 30912; and ⁴Health Sciences Center, Louisiana State University, New Orleans, Louisiana 70112

Submitted 15 July 2003 ; accepted in final form 10 December 2003

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 N^G-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.

microcirculation; carbon monoxide; hypoperfusion; ischemia

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