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 lipohilic 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-min ischemia and 120-min reperfusion. To induce postconditioning, 1 M solutions of the following liposoluble compounds were given during the first 20-min of reperfusion: NOD with weak (w-NOD) or strong NO releasing potency (s-NOD); weak hybrid (w-HYB) built up with w-NOD and a per se ineffective antioxidant (AOX) lead; strong HYB (s-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 w-HYB. We suggest that w-NOD requires the synergy with a per se ineffective AOX to protect. The synergy is possible only if the two moieties enter the cell simultaneously as a hybrid, but not as a mixture. It appears that s-HYB was ineffective because an excessive intracellular NO release produces a large amount of reactive species, as shown from the increased nitrotyrosine production.