INDUCTION OF MYOCARDIAL NITRIC-OXIDE SYNTHASE BY CARDIAC ALLOGRAFT-REJECTION

Cardiac transplantation, effective therapy for end-stage heart failure , is frequently complicated by allograft rejection, the mechanisms of which remain incompletely understood. Nitric oxide (NO), a vasodilator which is cytotoxic and negatively inotropic, can be produced in large amounts by an inducible NO synthase (iNOS) in response to cytokines. To investigate whether iNOS is induced during cardiac allograft reject ion, hearts from Lewis or Wistar-Furth rats were transplanted into Lew is recipients. At day 5, allogeneic grafts manifested reduced contract ility and histologic evidence of rejection (inflammatory infiltrate, e dema, necrosis of myocytes). The mRNA for iNOS and iNOS protein were d etected in ventricular homogenates and in isolated cardiac myocytes fr om rejecting allogeneic grafts but not in tissue and myocytes from syn geneic control grafts. Immunocytochemistry showed increased iNOS stain ing in infiltrating macrophages and in microvascular endothelial cells and cardiac muscle fibers and also in isolated purified cardiac myocy tes from the rejecting allografts. Using a myocardial cytosolic iNOS p reparation, nitrite formation from L-arginine and [H-3] citrulline for mation from [H-3]L-arginine were increased significantly in the reject ing allogeneic grafts (P < 0.01). Myocardial cyclic GRIP was also incr eased significantly (P < 0.05). The data indicate myocardial iNOS mRNA , protein and enzyme activity are induced in infiltrating macrophages and cardiac myocytes of the rejecting allogeneic grafts. Synthesis of NO by iNOS may contribute to myocyte necrosis and ventricular failure during cardiac allograft rejection.