In vivo role of heme oxygenase in ischemic coronary vasodilation

In vivo role of heine oxygenase in ischemic coronary vasodilation. Am J Physiol Heart Circ Physiol 286: H2296--H2304, 2004; 10.1152/ajpheart.00671.2003.--The heart constitutively expresses heine oxygenase (HO)-2, which catabolizes heine-containing proteins to produce biliverdin and carbon monoxide (CO). The heart also contains many possible substrates for HO-2 such as heine 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 openchest anesthetized dogs. Ischemia caused vasodilation of coronary arterioles by 36 [+ or -] 6%. Administration of [N.sup.G]-monomethyl-L-arginine (L-NMMA, 3 [micro]molx[kg.sup.-1]x[min.sup.-1] intracoronary), indomethacin (10 mg/kg iv), and [K.sup.+] (60 mM, epicardial suffusion) to prevent the actions of nitric oxide, prostaglandins, and hyperpolarizing factors, respectively, partially inhibited dilation during ischemia (36 [+ or -] 6 vs. 15 [+ or -] 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 [+ or -] 4 vs. 7[+ or -] 2%; P < 0.05 vs. before SnMP). The guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one ([10.sup.-5] M, epicardial suffusion) also inhibited vasodilation during ischemia in the presence of L-NMMA with indomethacin and KC1. 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