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J Thorac Cardiovasc Surg 2000;120:39-46
© 2000 The American Association for Thoracic Surgery

CARDIOTHORACIC TRANSPLANTATION

Improvement of rejection-induced diastolic abnormalities in rat cardiac allografts with inducible nitric oxide synthase inhibition

From the Department of Medicine, University of Michigan,^a Ann Arbor, Mich; Department of Surgery, University of Washington,^b Seattle, Wash; and the Departments of Surgery,^c Pediatrics,^d Medicine,^e and Pathology,^f Columbia University College of Physicians & Surgeons, New York, NY.

Supported in part by National Institutes of Health grant HL60900, American Heart Association Grant-in-Aid 92153, National Institutes of Health NRSA grant 1 F32 HL09356-1, and a Columbia University Department of Surgery Startup Funds Grant. Dr Pinsky is an Established Investigator of the American Heart Association.

Address for reprints: Henry M. Spotnitz, MD, Department of Surgery, Columbia College of Physicians & Surgeons, 622 West 168th St, PH 1422, New York, NY 10032 (E-mail: hms2{at}columbia.edu ).

Objective: Inhibition of inducible nitric oxide synthase (nitric oxide II) activity has been proposed as a method to attenuate capillary leak and edema during rejection of heterotopically transplanted rat hearts. Myocardial edema has previously been implicated in diastolic dysfunction during allograft rejection. Accordingly, we tested the hypothesis that inducible nitric oxide synthase inhibition with aminoguanidine would alleviate left ventricular stiffening and myocardial edema formation in 4-day heterotopic rat heart allografts.
Methods: Passive left ventricular filling was studied in American Cancer Institute Lewis rats receiving heterotopic heart transplants receiving either aminoguanidine, a selective nitric oxide synthase inhibitor (n = 6); dexamethasone (1 mg · kg^–1 · d^–1 administered subcutaneously) for 4 days after transplantation (n = 6); or intravenous saline solution (n = 6). American Cancer Institute–to–American Cancer Institute isografts (n = 6) were used as controls.
Results: Serum nitrite/nitrate levels in the aminoguanidine group (18 ± 3 mmol/L) and dexamethasone group (22 ± 4 mmol/L) were reduced versus the intravenous saline group (144 ± 36 mmol/L [SEM]) to levels seen in controls (25 ± 9 mmol/L). Left ventricular volume at 15 mm Hg for the aminoguanidine group was increased versus that for the intravenous saline solution group, similar to that for controls, and reduced versus dexamethasone-treated animals. Myocardial water content for the aminoguanidine-treated animals (78.3% ± 0.4%) was similar to those of intravenous saline–treated animals (78.0% ± 0.3%) but greater than those of controls (77.1% ± 0.2%) and dexamethasone-treated animals (76.7% ± 0.3%).
Conclusions: Nitric oxide II inhibition with aminoguanidine minimizes the reduction in left ventricular filling that is seen with allograft rejection through a mechanism that is not associated with attenuation of myocardial edema.

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