BIOCHEMICAL PATHWAYS OF CELL-DAMAGE DURING THE OXYGEN PARADOX OF THE RAT-HEART

1. The standard O2-paradox has been studied in the Langendorff-perfuse d rat heart. 2. Perfusion of glucose-free saline under anoxia did not cause release of creatine kinase (CK) although, it is suggested, there was a progressive rise in Ca2+!i. 3. Ca2+-depletion after anoxia cau sed CK release. 4. Prolonged anoxic perfusion (55 min) produced a mark edly reduced release of CK on Ca2+-depletion because, it is suggested, of the reduction in substrates for the release mechanism. 5. No prote ction against the O2-paradox was found with oxygen radical scavengers and inhibitors. 6. Lowering Ca2+!o during reoxygenation to 0.1 mM did not reduce CK release. 7. Neither 1 mM amiloride (Na+/H+ antiporter i nhibitor) nor 2 x 10(-6)M 1-(5-isoquinolinesulphonyl) piperazine (prot ein kinase C inhibitor) reduced CK release, unlike their effects in th e Ca2+-paradox. 8. An hypothesis for events in the O2-paradox in prese nted: anoxia causes a loss of Ca2+-homeostasis and a rise in Ca2+!i t hereby activating a transmembrane NAD(P) oxido-reductase/diaphorase (s tage 1); the return of O2 synergistically activates this molecular com plex and causes CK release (stage 2).