The role of heme oxygenase-related carbon monoxide and ventricular fibrillation in ischemic/reperfused hearts.
Reperfusion-induced ventricular fibrillation (VF) and heme oxygenase (HO)-related carbon monoxide (CO) production in isolated ischemic/reperfused rat hearts were studied by gas chromatography. Hearts were subjected to 30 min ischemia followed by 2 h reperfusion, and the expression of HO-1 mRNA (about 4-fold) was observed in ischemic/reperfused-nonfibrillated hearts. In fibrillated hearts, the reduction (about 75%) in HO-1 mRNA expression was detected. These changes in HO-1 mRNA expression were reflected in tissue CO production. Thus, in the absence of VF, CO production was increased about 3.5-fold, while in the presence of VF, CO production was under the detectable level in comparison with the control group. Our results suggest that the stimulation of HO-1 mRNA expression may lead to the prevention of reperfusion VF via an increase in endogenous CO production. To prove this, hearts were treated with 1 microM of N-tert-butyl-alpha-phenylnitrone (PBN) as an inducer of HO-1. PBN treatment resulted in about 20 times increase in HO-1 mRNA expression, and even a higher production rate in endogenous CO. HO protein level and enzyme activity followed the same pattern, as it was observed in HO-1 mRNA expression, in fibrillated and nonfibrillated myocardium. Five mM/l of zinc-protoporphyrin IX (ZnPPIX) significantly blocked HO enzyme activity and increased the incidence of VF, therefore the application of ZnPPIX led to a significant reduction in HO-1 mRNA and protein expression. Our data provide direct evidence of an inverse relationship between the development of reperfusion-induced VF and endogenous CO production. Thus, interventions that are able to increase tissue CO content may prevent the development of reperfusion-induced VF.
Department of Pharmacology, School of Medicine, University of Debrecen, Debrecen, Hungary.
Istvan
I
Bak
Gabor
G
Papp
Tibor
T
Turoczi
Edit
E
Varga
Levente
L
Szendrei
Miklos
M
Vecsernyes
Ferenc
F
Joo
Arpad
A
Tosaki
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002248:Carbon Monoxide / Q000494:pharmacology*; D002849:Chromatography, Gas; D005609:Free Radicals; D006321:Heart / Q000187:drug effects*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism*; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000378:metabolism*
D005609:Free Radicals; D012333:RNA, Messenger; D012313:RNA; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing)