Nitric oxide mediates neurologic injury after hypothermic circulatory arrest

Background. Prolonged hypothermic circulatory arrest (HCA) causes neurologi c injury. However, the mechanism of this injury is unknown. We hypothesized that HCA causes nitric oxide production to result in neuronal necrosis. Th is study was undertaken to determine whether the neuronal nitric oxide synt hase inhibitor 17477AR reduces necrosis after HCA. Methods. Thirty-two dogs underwent 2 hours of HCA at 18 degrees C. Nitric o xide synthase catalytic assay and intracerebral microdialysis for nitric ox ide production were performed in acute nonsurvival experiments (n = 16). Si xteen animals survived for 72 hours after HCA: Group 1 (n = 9) was treated with 17477AR (Astra Arcus), and group 2 (n = 7) received vehicle only. Anim als were scored from 0 (normal) to 500 (coma) for neurologic function and f rom 0 (normal) to 100 (severe) for neuronal necrosis. Results. Administration of 17477AR reduced nitric oxide production in the s triatum by 94% (HCA alone), 3.65 +/- 2.42 mu mol/L; HCA and 17477AR, 0.20 /- 0.14 mu mol/L citrulline). Dogs treated with 17477AR after HCA had super ior neurologic function (62.22 +/- 29.82 for group 1 versus 141.86 +/- 61.5 3 for group 2, p = 0.019) and significantly reduced neuronal necrosis (9.33 +/- 4.67 for group 1 versus 38.14 +/- 2.23 for group 2, p < 0.00001) compa red with untreated HCA dogs. Conclusions. Our results provide evidence that neuronal nitric oxide syntha se mediates neuronal necrosis after HCA and plays a significant role in HCA -induced neurotoxicity. Pharmacologic strategies to inhibit neuronal nitric oxide synthase after the ischemic period of HCA may be clinically benefici al. (C) 1999 by The Society of Thoracic Surgeons.