Published Online
on October 21, 2002

A more recent version of this article appeared on October 29, 2002

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Submitted on June 12, 2002
Revised on August 8, 2002
Accepted on August 8, 2002

Effects of Selective Inhibitors of Nitric Oxide Synthase-2 Dimerization on Acute Cardiac Allograft Rejection

Matthias J. Szabolcs MD, Ji Sun PhD, Ningsheng Ma MD, Arline Albala MS, Robert R. Sciacca EngScD, Gary B. Philips PhD, John Parkinson PhD, Niloo Edwards MD, and Paul J. Cannon MD^*

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

^* To whom correspondence should be addressed. E-mail: pjc4{at}columbia.edu.

Background—Nitric oxide synthase-2 (NOS2) is expressed during acute cardiac allograft rejection in association with myocardial inflammation, contractile dysfunction, and death of cardiomyocytes by necrosis and apoptosis. Recently, allosteric inhibitors of NOS2 monomer dimerization that block NOS2 activity have been developed.

Methods and Results—To investigate effects of selective NOS2 blockade, 15 mg/kg of BBS-1 or BBS-2 was administered twice daily subcutaneously to rats starting the day of heterotopic heart transplantation. Cardiac allograft survival was increased significantly, from 6.8 days in controls to 13.3 and to 14.2 days in NOS2-inhibited allografts. At day 5 after heart transplantation, synthesis of NOx was reduced by 53%. There were significantly fewer T lymphocytes and macrophages in the inflammatory infiltrate, as well as less edema and cardiomyocyte damage, and the International Society of Heart and Lung Transplantation score fell from 5 to 4 and 3.5. NOS2 and nitrotyrosine immunostaining and the mean numbers of apoptotic cells and of apoptotic cardiomyocytes were significantly diminished in the treated allografts.

Conclusions—The data indicate that selective inhibition of NOS2 dimerization prolongs survival and reduces myocardial inflammation and cardiomyocyte damage in acute cardiac allograft rejection.

Key words: nitric oxide synthase • rejection • transplantation • apoptosis • inhibitors

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