title: Attenuation of myocardial ischemia/reperfusion injury by superinduction of inducible nitric oxide synthase.
abstract: BACKGROUND
  Nitric oxide (NO) has been implicated as a mediator in myocardial ischemia/reperfusion (I/R) injury, but its functional properties have been conflicting. We investigated whether NO has a protective role against I/R injury.
  
  
  RESULTS
  Using endothelial NO synthase knockout (eNOS KO) mice, inducible NOS KO mice, the NO donor S-nitroso-N-acetylpenicillamine (SNAP), and the NOS inhibitor N-iminoethyl-L-ornithine (L-NIO), we performed studies of isolated perfused hearts subjected to 30 minutes of global ischemia followed by reperfusion. After 60 minutes of reperfusion, nitrite levels in the coronary effluent in the SNAP and eNOS KO groups were significantly elevated compared with other groups. Immunoblot and immunohistochemistry showed that iNOS was markedly induced in the eNOS KO hearts. Under spontaneous beating conditions during reperfusion, increased NO activity was correlated with a prevention of the hyperdynamic contractile response and enhanced myocardial protection, as evidenced by a reduction in myocardial injury and infarct size. During prolonged reperfusion, SNAP-treated hearts were able to preserve contractile functions for 180 minutes, whereas L-NIO-treated hearts showed a sustained deterioration in contractility.
  
  
  CONCLUSIONS
  NO protects against I/R injury by preventing the hyperdynamic response of isolated perfused hearts during early reperfusion. In the eNOS KO hearts, a paradoxical increase in NO production was seen, accompanied by a superinduction of iNOS, possibly due to an adaptive mechanism.
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA. skanno@andrew.cmu.edu
authors.forename: S
authors.initials: S
authors.lastname: Kanno
authors.forename: P C
authors.initials: PC
authors.lastname: Lee
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: C
authors.initials: C
authors.lastname: Ho
authors.forename: B P
authors.initials: BP
authors.lastname: Griffith
authors.forename: L L
authors.initials: LL
authors.lastname: Shears
authors.forename: T R
authors.initials: TR
authors.lastname: Billiar
mesh_terms: D000818:Animals; D003402:Creatine Kinase / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000201:enzymology*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009952:Ornithine / Q000031:analogs & derivatives / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D020030:Nitric Oxide Donors; C110881:S-nitro-N-acetylpenicillamine; D009569:Nitric Oxide; C065027:N(G)-iminoethylornithine; D009952:Ornithine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D003402:Creatine Kinase; D010396:Penicillamine