In vivo role of heme oxygenase in ischemic coronary vasodilation

Abstract

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 ϳ40 mmHg; flow velocity decreased by ϳ50%; dL/dt reduced by ϳ60%) were measured using stroboscopic fluorescence microangiography in 34 openchest anesthetized dogs. Ischemia caused vasodilation of coronary arterioles by 36, indomethacin (10 mg/kg iv), and K ϩ (60 mM, epicardial suffusion) to prevent the actions of nitric oxide, prostaglandins, and hyperpolarizing factors, respectively, partially inhibited dilation during ischemia (36 Ϯ 6 vs. 15 Ϯ 4%; P Ͻ 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 Ϯ 4 vs. 7 Ϯ 2%; P Ͻ 0.05 vs. before SnMP). The guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (10 Ϫ5 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 THE HEART REQUIRES CONTINUOUS oxygen delivery and blood flow to support the high levels of aerobic metabolism of working cardiac muscle. Interruption in coronary blood flow causes an imbalance between oxygen delivery and consumption. This imbalance results in the release of vasodilators that increase perfusion (15, 32) but to date, the identity of these vasodilators remains unclear.Carbon monoxide (CO) is an endogenously generated gas that is produced from catabolism of heme by heme oxygenase (HO). CO stimulates soluble guanylyl cyclase (GC), increases cGMP in vascular tissue, and elicits vasodilation (9, 13). HO enzyme activity has been described in numerous tissues including heart (1, 33) and vascular endothelium (35, 36). Moreover, a growing consensus is that HO activity may be cardioprotective (10, 17). Recent studies suggest that CO participates in vascular regulation during normal (23, 49) and abnormal physiological conditions including endotoxin shock (48), chronic hypoxia (6), portal hypertension (16), and subarachnoid hemorrha...

Preemptive heme oxygenase-1 gene delivery reveals reduced mortality and preservation of left ventricular function 1 yr after acute myocardial infarction

“…On the other hand, HO-1 could potentially maintain or improve cardiac performance by reducing coronary vascular tone. HO-derived CO activates soluble guanylate cyclase analogous to nitric oxide and has been reported to contribute to ischemia-induced vasodilation in dogs (38). Furthermore, bilirubin improved postischemic LV functional recovery in isolated rat hearts subjected to global ischemia (21).…”

Pharmacological and Clinical Aspects of Heme Oxygenase

“…The HO-CO pathway is involved in ischemic vasodilation in the coronary microcirculation (Nishikawa et al, 2004). The occurrence of severe right ventricular enlargement after chronic hypoxia was shown in HO-1-deficient compared with wild-type mice (Yet et al, 1999) and the cardiac-specific expression of HO-1 protected against ischemia and reperfusion .…”

“…It has been reported that HO-2 activation occurs in ischemic hearts in dogs and that inhibition of the HO HEME OXYGENASE AND PHARMACOLOGICAL/DRUG DEVELOPMENT system inhibits vasodilation during ischemia in the presence of NO and COX inhibitors (Nishikawa et al, 2004). CORM-3 prevents ischemic damage (Guo et al, 2004).…”

Carbon monoxide in biological systems: an experimental and clinical study

“…In sheep during hypoxemia, a decrease in PVR was shown after inhalation of CO (Nachar et al, 2001). Investigation of the coronary microcirculation in dog hearts in vivo showed that during ischemia HO activation caused dilatation, but only when other systems such as NO, prostaglandins and K + channels where impaired (Nishikawa, Stepp, Merkus, Jones, & Chilian, 2004).…”

“…Perhaps when CO is administrated, less NO is produced resulting in unaltered vascular tone. Accordingly, one finding in vivo showed an effect of CO only when the NO system was inhibited (Nishikawa et al, 2004).…”