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Ann Thorac Surg 1997;64:1647
© 1997 The Society of Thoracic Surgeons
DR SUSUMU TANAKA (Saitama, Japan): This is an excellent and ingenious presentation, Dr Tseng. We have studied the effect of a nitric oxide synthase inhibitor on reperfusion injury of the brain after hypothermic cardiac arrest. Twelve pigs were used for this study. The NOS inhibitor L-NAME was administered intravenously just before the start of reperfusion, followed by a 60-minute continuous venous infusion. The NO concentration was determined by the electrode method. Saline solution was administered in a control group. The NO level was significantly increased in the control group, but not in the L-NAME group. Recovery of somatosensory evoked potentials was noticed in all animals in the L-NAME group but not in control pigs. These results indicate that L-NAME may protect the brain against reperfusion injury after hypothermic cardiac arrest.
So I would like to ask two questions. What is the best time to administer the NOS inhibitor? Second, what is the best NOS inhibitor in humans?
DR TSENG: Thank you for your comments. We administered 7-nitroindazole in this experiment before arrest, after arrest, and every 2 hours. We are also investigating the effects of nNOS inhibitors and necrosis. For those experiments, we posttreated the animals and have seen some reduction in neurologic injury. Based on our findings, either pretreatment or posttreatment is effective.
With respect to humans, we feel that specific inhibition of nNOS is important. Our preliminary pilot experiments with LNNA, which also inhibits endothelial NOS, showed an increase in apoptosis. Other experimental nNOS inhibitors are being developed that may be more clinically feasible than 7-nitroindazole.
DR JOHN E. MAYER, JR (Boston, MA): I think this is an important issue about the different isoforms of NOS, and we probably have been on the other side of this with some experiments that show that, at least acutely, L-arginine infusions may improve the recovery of both the heart as well as cerebral blood flow after ischemia under hypothermic conditions.
I wonder if you could tell us a little more about this agent and what the 7-nitroindazole effects are on the other forms of NOS, particularly inducible and endothelial forms.
DR TSENG: In vitro data indicate that 7-nitroindazole has approximately the same selectivity for neuronal and endothelial NOS but a lower selectivity for the inducible isoform. However, in vivo, the administration of 7-nitroindazole was found to have no effect on mean arterial pressure, which was confirmed in our experiments. 7-Nitroindazole in vivo acts as a relatively selective neuronal inhibitor with little endothelial effects.
DR JAKOB VINTEN-JOHANSEN (Atlanta, GA): That was a very nice study. Have you done a study in which you have given L-arginine as a precursor or an NO donor to possibly augment the injury to test the opposite side of the question?
Second, in your opinion, do you think that NO is working through peroxynitrite, and did you get any information or measurements on peroxynitrite production?
DR TSENG: Those are very interesting questions. However, we did not use L-arginine in our model nor have we measured peroxynitrite.
DR GEORGIOS KANELLOPOULOS (St. Louis, MO): Thank you for your interesting work and nice presentation. I would like to ask you what the reason was behind your choice to kill the animals in your study at 8 hours after the onset of reperfusion. I ask this question because, in studies of global brain ischemia-reperfusion in the normothermic rat, neuronal apoptosis appears to be most prominent at 24 through 72 hours after the onset of the reperfusion. Therefore one might have expected that the number of apoptotic neurons in the brain would peak at 24 to 72 hours after a period of deep HCA, too.
DR TSENG: Thank you for your comments. We have performed pilot experiments in which we sacrificed the animals 8, 20, and 72 hours after arrest to examine neurologic injury over time in our model. We have found that maximal apoptosis occurred at 8 hours, diminished by 20 hours, and essentially disappeared by 72 hours. This early evidence of apoptosis is unusual but may be related to the use of hypothermia, which appeared to delay the severity of necrosis to 72 hours.
Related Article
Ann. Thorac. Surg. 1997 64: 1639-1647.
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