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Acute allograft rejection in patients after cardiac transplantation is associated with intense infiltration of inflammatory cells. It has been shown in animal studies that this inflammatory process is accompanied by an induction of nitric oxide synthase (NOS) enzyme within the grafted organ. We sought to test the hypothesis that acute rejection in cardiac transplanted patients is associated with an increased production of nitric oxide. The radical nitric oxide is unstable in blood and oxidized to nitrite and nitrate; nitrate is secreted by the kidneys. Therefore, nitric oxide production was indirectly assessed by measuring urinary nitrate excretion. During a period of 1 yr, 86 consecutive patients after cardiac transplantation underwent one or more right heart biopsies (total 194) in order to assess for acute graft rejection. At the time of biopsies, urine was collected under sterile conditions. Urinary nitrate excretion was expressed as the ratio of nitrate to creatinine concentration in the urine (μmol/mmol). Urinary nitrate excretion was 99.7±9.2 (mean±SEM) for patients without evidence of rejection, and tended to increase for patients with moderate/severe rejection (128±15.1). In a subgroup of patients who underwent several biopsies and showed different degrees of rejection (7 patients, 48 biopsies), urinary nitrate excretion significantly increased by about 99% during episodes of acute rejection. It is concluded that urinary nitrate excretion appears to be elevated in a subgroup of cardiac transplanted patients during episodes of acute rejection. Results are consistent with the hypothesis that acute graft rejection stimulates the production/release of nitric oxide. Because of a large inter- and intraindividual variation in urinary nitrate excretion, this parameter appears not to be suitable for diagnosis of acute rejection in cardiac transplanted patients.