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Exogenous NO triggers preconditioning via a cGMP- and mitoK_ATP-dependent mechanism

Departments of ¹Physiology, ²Cell Biology and Neuroscience, and ³Medicine, College of Medicine, University of South Alabama, Mobile, Alabama 36688

Submitted 9 October 2003 ; accepted in final form 18 March 2004

Exogenous nitric oxide (NO) triggers a preconditioning-like effect in heart via a pathway that is dependent on reactive oxygen species. This study examined the signaling pathway by which the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 2 µM) triggers its anti-infarct effect. Isolated rabbit hearts experienced 30 min of regional ischemia and 120 min of subsequent reperfusion. Infarct size was determined by triphenyltetrazolium chloride staining. Infarct size was reduced from 30.5 ± 3.0% of the risk zone in control hearts to 10.2 ± 2.0% in SNAP-treated hearts. Bracketing the SNAP infusion with either the guanylyl cyclase blocker 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (2 µM) or the mitochondrial ATP-sensitive K⁺ (mitoK_ATP) channel blocker 5-hydroxydecanoate (200 µM) completely blocked the infarct-sparing effect of SNAP (34.3 ± 3.8 and 32.2 ± 1.6% infarction, respectively). Pretreatment of hearts with 8-(4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphate (10 µM), which is a cell-permeable cGMP analog that activates protein kinase G, mimicked the preconditioning effect of SNAP by reducing infarct size to 7.5 ± 1.1% of the risk zone. This salutary effect was abolished by either the free radical scavenger N-(2-mercaptopropionyl)glycine (1 mM) or 5-hydroxydecanoate (100 µM; 28.9 ± 2.7 and 33.6 ± 5.0% infarction of the risk zone, respectively). To confirm these functional data and the effect of SNAP on the guanylyl cyclase-protein kinase G signaling pathway, cGMP levels were measured. SNAP increased the level from 0.18 ± 0.04 to 0.61 ± 0.14 pmol/mg of protein (P < 0.05). These data suggest that exogenous NO triggers the preconditioning effect by initiating a cascade of events including stimulation of guanylyl cyclase to make cGMP, activation of protein kinase G, opening of mitoK_ATP channels, and, finally, production of reactive oxygen species.

mitochondrial ATP-sensitive potassium channel; protein kinase G; S-nitroso-N-acetylpenicillamine; guanylyl cyclase

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