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1 Department of Physiology, University of South Alabama, College of Medicine, Mobile, AL, USA
2 Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, AL, USA
3 Department of Physiology, University of South Alabama, College of Medicine, Mobile, AL, USA; Department of Medicine, University of South Alabama, Mobile, AL, USA
* To whom correspondence should be addressed. E-mail: jdowney{at}usouthal.edu.
Exogenous nitric oxide (NO) triggers a preconditioning-like effect in the heart by a pathway dependent on reactive oxygen species. This study examined the signaling pathway by which S-nitroso-N-acetylpenicillamine (SNAP) (2µM), a NO donor, triggers its anti-infarct effect. Isolated rabbit hearts experienced 30 min of regional ischemia followed by 120 min of 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 (ODQ) (2µM) or the mitochondrial KATP channel blocker 5-hydroxydecanoate (5-HD) (200µM) 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 (8-pCPT-cGMP) (10µM), a cell-permeable cGMP analog that activates protein kinase G, mimicked SNAP's preconditioning effect by reducing infarct size to 7.5±1.1% of the risk zone. This salutary effect was abolished by either N-(2-mercaptopropionyl) glycine (MPG) (1mM), a free radical scavenger, or 5-HD (100µM) (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-PKG signaling pathway, cGMP levels were measured. SNAP increased the level from 0.18±0.04 to 0.61±0.14 pmol/mg 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 mitochondrial KATP channels and finally production of reactive oxygen species.
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