A lipophilic nitric oxide donor and a lipophilic antioxidant compound protect rat heart against ischemia-reperfusion injury if given as hybrid molecule but not as a mixture.
Low concentrations of a hydrophilic nitric oxide donor (NOD) are reported to reduce myocardial reperfusion injury only when combined with a lipophilic antioxidant (AOX) to form a hybrid molecule (HYB). Here we tested whether liposoluble NOD requires to be combined with AOX to be protective. Isolated rat hearts underwent 30 minutes of ischemia and 120 minutes of reperfusion. To induce postconditioning, 1 μM solutions of the following liposoluble compounds were given during the first 20 minutes of reperfusion: NOD with weak (w-NOD) or strong NO-releasing potency (s-NOD); weak HYB built up with w-NOD and a per se ineffective AOX lead; strong HYB built up with s-NOD and the same AOX; mixtures of w-NOD plus AOX or s-NOD plus AOX. A significant reduction of infarct size with improved recovery of cardiac function was obtained only with weak HYB. We suggest that w-NOD requires the synergy with a per se ineffective AOX to protect. The synergy is possible only if the 2 moieties enter the cell simultaneously as a hybrid, but not as a mixture. It seems that strong HYB was ineffective because an excessive intracellular NO release produces a large amount of reactive species, as shown from the increased nitrotyrosine production.
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy. raffaella.rastaldo@unito.it
Raffaella
R
Rastaldo
Rastaldo
R
Raffaella
Sandra
S
Cappello
Cappello
C
Sandra
Antonella
A
Di Stilo
Di Stilo
DS
Antonella
Anna
A
Folino
Folino
F
Anna
Gianni
G
Losano
Losano
L
Gianni
Pasquale
P
Pagliaro
Pagliaro
P
Pasquale
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004357:Drug Synergism; D057775:Ischemic Postconditioning / Q000379:methods; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000975:Antioxidants; D002316:Cardiotonic Agents; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine