A REDOX-BASED MECHANISM FOR CARDIOPROTECTION INDUCED BY ISCHEMIC PRECONDITIONING IN PERFUSED RAT-HEART

Recent studies have suggested that mild redox alterations can regulate cell function. Therefore, we tested the hypothesis that alteration in the thiol redox state might be responsible for the cardioprotective e ffects conferred by ischemic preconditioning in the perfused rat heart . We find that preconditioning with four 5-minute periods of ischemia, each separated by 5 minutes of reflow, is associated with a significa nt loss of glutathione (3.98+/-0.32 mu mol/g dry wt, n=8) compared wit h no preconditioning (6.38+/-0.24 mu mol/g dry wt, n=14). We further f ind that the addition of N-acetylcysteine (NAG, a glutathione precurso r and antioxidant) during the preconditioning protocol not only blocks the loss of glutathione (5.60+/-0.31 mu mol/g dry wt, n=9) but also b locks the protective effects of preconditioning. It is observed that a fter 20 minutes of ischemia followed by 20 minutes of reflow, untreate d hearts recover 38+/-7% (n=5) of their initial preischemic contractil e function, whereas preconditioned hearts recover 91+/-11% (n=7). Hear ts preconditioned in the presence of NAC recover 24+/-3% (n=7) of thei r preischemic function. Similarly, the addition of NAC reverses the pr otective effect of preconditioning on creatine kinase release. On refl ow after 60 minutes of ischemia, creatine kinase release from control hearts was 271+/-20 IU . 20 min(-1). g dry wt(-1) (n=5), whereas preco nditioned hearts release only 170+/-26 IU . 20 min(-1). g dry wt(-1) ( n=6), and hearts preconditioned in the presence of NAC release 361+/-3 0 IU . 20 min(-1). g dry wt(-1) (n=5). We also find that hearts precon ditioned in the presence of NAC have less attenuation of the decline i n pH(i) than hearts preconditioned in the absence of drug. Thus, a red ox-sensitive mechanism may be involved in the protection afforded by i schemic preconditioning.