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(Circulation. 2004;109:1668-1673.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Metabolic and Functional Protection by Selective Inhibition of Nitric Oxide Synthase 2 During Ischemia-Reperfusion in Isolated Perfused Hearts

Ravichandran Ramasamy, PhD; Yuying C. Hwang, PhD; Yulin Liu, MD; Ni Huiping Son, MD; Ningsheng Ma, MD; John Parkinson, PhD; Robert Sciacca, EngScD; Arline Albala, MS; Niloo Edwards, MD; Matthias J. Szabolcs, MD; Paul J. Cannon, MD

From the Departments of Medicine (Y.L., N.H.S., R.S., A.A., P.J.C.), Pathology (M.J.S.), and Surgery (R.R., Y.C.H., N.M., N.E.), Columbia University, College of Physicians and Surgeons, New York, NY, and Berlex Biosciences Inc (J.P.), Richmond, Calif.

Correspondence to Paul J. Cannon, Department of Medicine, Division of Cardiology, Columbia University, College of Physicians and Surgeons, 622 W 168th St, PH10 408 STEM, New York, NY 10032. E-mail pjc4{at}columbia.edu

Received June 19, 2003; de novo received October 14, 2003; revision received October 14, 2003; accepted December 22, 2003.

Background— Drugs that selectively block nitric oxide synthase (NOS) 2 enzyme activity by inhibiting dimerization of NOS2 monomers have recently been developed.

Methods and Results— To investigate whether selective inhibition of NOS2 is cardioprotective, rats were pretreated for 2 days with BBS2, an inhibitor of NOS2 dimerization, at 15 mg/kg SC. Isolated buffer-perfused hearts from treated (n=9) and control (n=7) hearts were subjected to 20 minutes of ischemia followed by 60 minutes of reperfusion. NOS2 protein was upregulated in all hearts at the end of ischemia and of reperfusion; NOS2 enzyme activity was 60% lower in hearts from the treated animals. In the treated hearts, the increase in end-diastolic pressure was significantly attenuated at the end of ischemia, and the return of developed pressure at reperfusion was greater (P<0.05). Creatine kinase release at reperfusion was lower in treated hearts than in controls (P=0.02). At the end of ischemia and of reperfusion, myocardial ATP levels were significantly higher in the treated hearts than in controls (P<0.05). In the treated hearts under ischemic conditions, lactate content was higher and the lactate/pyruvate ratio was lower than in controls (P<0.05); GAPDH activity was higher; and G-3-P and aldose reductase activity were lower. At reperfusion, in the treated hearts, there was less histological damage and less apoptosis of cardiac muscle cells.

Conclusions— Pretreatment with BBS2, a selective inhibitor of NOS2, improves contractile performance, preserves myocardial ATP, and reduces damage and death of cardiac myocytes during ischemia and reperfusion of isolated buffer-perfused rat hearts.

Key Words: nitric oxide synthase • ischemia • reperfusion

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