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

Objective: Inhibition of inducible nitric oxide synthase (nitric oxide II) activity has been proposed as a method to attenuate capillary leak and edem a during rejection of heterotopically transplanted rat hearts. Myocardial e dema has previously been implicated in diastolic dysfunction during allogra ft rejection. Accordingly, we tested the hypothesis that inducible nitric o xide synthase inhibition with aminoguanidine would alleviate left ventricul ar stiffening and myocardial edema formation in 4-day heterotopic rat heart allografts. Methods: Passive left ventricular filling was studied in American Cancer In stitute Lewis rats receiving heterotopic heart transplants receiving either aminoguanidine, a selective nitric oxide synthase inhibitor (n = 6); dexam ethasone (1 mg . kg(-1) . d(-1) administered subcutaneously) for 4 days aft er transplantation (n = 6); or intravenous saline solution (n = 6). America n 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 contro ls (25 +/- 9 mmol/L). Left ventricular volume at 15 mm Hg for the aminoguan idine group was increased versus that for the intravenous saline solution g roup, similar to that for controls, and reduced versus dexamethasone-treate d 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 d examethasone-treated animals (76.7% +/- 0.3%). Conclusions: Nitric oxide II inhibition with aminoguanidine minimizes the r eduction in left ventricular filling that is seen with allograft rejection through a mechanism that is not associated with attenuation of myocardial e dema.