The effect of carvedilol on enhanced ADP-ribosylation and red blood cell membrane damage caused by free radicals.
OBJECTIVE
Previous studies have reported that the beta and alpha adrenoceptor blocker carvedilol has unique protective effects on free radical-induced myocardial injury. The aim of this study was to examine how carvedilol regulates reactive-oxygen-species-mediated signaling and decreases red blood cell membrane damage in heart perfusion and in a rheological model.


METHODS
The ischemia-reperfusion-induced oxidative cell damage, and changes in the intracellular signaling mediated by reactive oxygen species and peroxynitrite were studied on rat hearts in a Langendorff perfusion system (n=15). The effect of carvedilol on red blood cell suspension viscosity (hematocrit: 60%) incubated with free radical generator (phenazine methosulphate) was also investigated (n=10). The measurements were performed on a capillary viscosimeter.


RESULTS
In both studies a protective effect of carvedilol was found, as the decrease of red blood cell suspension viscosity and K(+) concentration in the supernatant indicated. Carvedilol significantly decreased the ischemia-reperfusion-induced free radical production and the NAD(+) catabolism and reversed the poly- and mono(ADP-ribosyl)ation. Carvedilol also decreased the lipid peroxidation and membrane damages as determined by free malondialdehyde production and the release of intracellular enzymes. The self ADP-ribosylation of isolated poly(ADP-ribose) polymerase was also significantly inhibited by carvedilol.


CONCLUSIONS
Our results show that carvedilol can modulate the reactive-oxygen-species-induced signaling through poly- and mono(ADP-ribosyl)ation reactions, the NAD(+) catabolism in postischemic perfused hearts and has a marked scavenger effect on free radical generator-induced red blood cell membrane damage. All these findings may play an important role in the beneficial effects of carvedilol treatment in different cardiovascular diseases.
Habon
T
T
First Department of Medicine, Division of Cardiology, University of Pecs Medical School, Ifjusag u. 13, H-7634, Pecs, Hungary. thabon@clinics.pote.hu
Szabados
E
E
Kesmarky
G
G
Halmosi
R
R
Past
T
T
Sumegi
B
B
Toth
K
K
D036002:ADP Ribose Transferases; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D018674:Adrenergic Antagonists / Q000494:pharmacology*; D000818:Animals; D001809:Blood Viscosity / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D004910:Erythrocyte Membrane / Q000378:metabolism; D018056:Hemorheology; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D010477:Perfusion; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D018674:Adrenergic Antagonists; D002227:Carbazoles; D011412:Propanolamines; D017382:Reactive Oxygen Species; D000077261:Carvedilol; D009243:NAD; D000246:Adenosine Diphosphate Ribose; D036002:ADP Ribose Transferases; D011065:Poly(ADP-ribose) Polymerases