(Circulation. 2000;101:2742.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Attenuation of Myocardial Ischemia/Reperfusion Injury by Superinduction of Inducible Nitric Oxide Synthase
From the Department of Biological Sciences, Carnegie Mellon University (S.K., Y.Z., C.H.), and the Department of Surgery, University of Pittsburgh (P.C.L., B.P.G., L.L.S., T.R.B.), Pittsburgh, Pa. Drs Kanno and Lee contributed equally to this work.
Correspondence to Shinichi Kanno, Department of Biological Sciences, Carnegie Mellon University, 4400 Fifth Ave, Pittsburgh, PA 15213. E-mail skanno{at}andrew.cmu.edu
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.
Methods and 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.
Key Words: nitric oxide • nitric oxide synthase • ischemia • reperfusion • hemodynamics
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