INFLAMMATORY CELL-DERIVED NO MODULATES CARDIAC ALLOGRAFT CONTRACTILE AND ELECTROPHYSIOLOGICAL FUNCTION

We previously demonstrated that inhibition of inducible nitric oxide ( NO) synthase (iNOS) ameliorated acute cardiac allograft. rejection. Th is study used a rat cardiac transplant model to characterize contracti le and electrophysiological dysfunction during early acute rejection, further examine the role of NO and iNOS in this process, and determine which cells expressed iNOS during early rejection. During early acute rejection, before significant myocyte necrosis, allograft papillary m uscles had reduced tension development and rates of tension developmen t and decline during B-adrenergic, adenylate cyclase, and calcium stim ulation compared with isografts and normals [e.g., tension of 36 (allo graft) vs. 73 (isograft) mN/mm(2) during calcium stimulation, P < 0.00 1]. Allografts had resting membrane potential depolarization and reduc ed action potential amplitude and upstroke velocity. iNOS mRNA was exp ressed in infiltrating inflammatory cells but not in allograft myocyte s, endothelial cells, or isografts. Corticosteroids attenuated allogra ft contractile and electrophysiological dysfunction and inhibited iNOS enzyme activity. Direct iNOS inhibition with aminoguanidine inhibited NO production and prevented allograft contractile and electrophysiolo gical dysfunction (e.g., tension of 64 mN/mm(2) during calcium stimula tion, P < 0.001). We conclude that Ii early allograft rejection caused contractile and electrophysiological dysfunction that was largely med iated by iNOS expression in infiltrating inflammatory cells, 2) cortic osteroid-mediated amelioration of allograft contractile and electrophy siological dysfunction may reflect inhibition of iNOS, and 3) iNOS inh ibition may offer an alternative in management of immune-mediated myoc ardial dysfunction.