EFFECT OF AMINOGUANIDINE AND CYCLOSPORINE ON LUNG ALLOGRAFT-REJECTION

Background. Aminoguanidine, a nitric oxide synthase inhibitor, has bee n shown to reduce the inflammatory allogeneic response. Here we used i t in combination with cyclosporine to evaluate its effect on a clinica lly relevant immunosuppressive protocol. Methods. Orthotopic left lung transplantation was performed in 120 rats, of which 24 were syngeneic Lewis to Lewis controls, and allogeneic transplantations were perform ed across major histoincompatibility barriers (ACI to Lewis). We studi ed synchronous histologic changes accompanying cytokines and nitric ox ide synthase messenger RNA by reverse transcriptase polymerase chain r eaction in the grafted lungs. Nitrate/nitrite, oxidized degradation pr oducts of nitric oxide, were measured in the whole blood, as were conc entrations of cyclosporine. Lung tissue was immunohistochemically stai ned for nitric oxide synthase protein. Rats receiving allografts were either untreated (24) or received low-dose cyclosporine (232 +/- 105 n g/mL blood by high-performance liquid chromatography), high-dose cyclo sporine (2,046 +/- 664 ng/mL), aminoguanidine alone (800 mg . kg(-1) . day(-1) intraperitoneally), or aminoguanidine plus low-dose cyclospor ine. Results. The results suggest that aminoguanidine combined with lo w doses of cyclosporine can reduce the allogeneic response across majo r histoincompatibilities in rodent lung transplantation. Its biologic effect may not exclusively depend on the inhibition of nitric oxide sy nthase and may, by other means, reduce proinflammatory cytokines. Conc lusions. Aminoguanidine may be an effective adjuvant to conventional i mmunosuppression.