In vivo role of heme oxygenase in ischemic coronary vasodilation.
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 approximately 40 mmHg; flow velocity decreased by approximately 50%; dL/dt reduced by approximately 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 micromol.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.
Nishikawa
Yasuhiro
Y
Department of Physiology, Medical College of Wisconsin, Watertown, WI 53226, USA.
Stepp
David W
DW
Merkus
Daphne
D
Jones
Deron
D
Chilian
William M
WM
D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism; D003326:Coronary Circulation / Q000502:physiology*; D006152:Cyclic GMP / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D007213:Indomethacin / Q000494:pharmacology; D008833:Microcirculation / Q000502:physiology; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology; D015221:Potassium Channels / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D015221:Potassium Channels; D019323:omega-N-Methylarginine; D011189:Potassium Chloride; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2; D006152:Cyclic GMP; D007213:Indomethacin