Exogenous nitric oxide can trigger a preconditioned state through a free radical mechanism, but endogenous nitric oxide is not a trigger of classical ischemic preconditioning.

Nitric oxide (NO) has been reported to play an important role in the late phase of ischemic preconditioning (PC) in the rabbit heart. However, the role of NO in the early phase of ischemic PC ("classical PC") is controversial. Accordingly, the present study was designed to determine whether NO contributes to the cardioprotective effect of classical PC in rabbits. Isolated hearts experienced 30 min of regional ischemia followed by 120 min of reperfusion. Infarct size was measured with triphenyltetrazolium chloride. In control hearts infarction was 30.2+/-3.3% of the risk zone. PC with 5 min of global ischemia and 10 min of reperfusion reduced infarct size to 10.2+/-2.4% (P<0.05). Perfusion with 2 microm S-nitroso-N-acetylpenicillamine (SNAP), a NO donor, in lieu of ischemia mimicked PC (4.4+/-1.9% infarction, P<0.01 v control). To determine whether this protection was dependent on either protein kinase C (PKC) as has previously been demonstrated for classical PC or free radicals known to be produced during exogenous NO administration, chelerythrine (5 microm), a PKC inhibitor, or N-(2-mercaptopropionyl)-glycine (300 microm), a free radical scavenger, was administered with or shortly after SNAP. Neither drug had any independent effect on infarct size, and each blocked SNAP's cardioprotection (31.0+/-5.1 and 25.7+/-5.2% infarction, resp.). N(omega)-nitro- L -arginine methyl ester (L -NAME, 100 microm), a NO synthase inhibitor, failed to block the cardioprotection from the above ischemic PC protocol (9.5+/-2.8% infarction, P<0.05 v control). L -NAME alone had no effect on infarct size (30.6+/-2.7%). These results suggest that the beneficial effect of exogenous NO production during SNAP pretreatment is mediated by a protein kinase C-dependent pathway via MPG-sensitive oxidants. However, we were unable to show any contribution of endogenous NO to classical PC's protection in isolated rabbit hearts. Copyright 2000 Academic Press.