Background: Recent research found that nitric oxide (NO) participated in the occurrence of cerebral ischemic damages, but there was still no unified conclusion about its exact effect. Objective: To discuss the effect of NO in cerebral ischemic reperfusion damage and compare the cerebral protective effects of two types of calcium channel antagonists. Design: A completely randomized controlled study. Setting and Materials: The study was completed in ICU laboratory in Beijing Children's Hospital Affiliated to Capital University of Medical Sciences. Sixty-six New Zealand rabbits with a weight of 2.0-2.4 kg were obtained from Experimental Animal Laboratory of Capital University of Medical Sciences. Methods: Bilateral common carotid arteries and vertebral arteries were occluded for 30 minutes to establish cerebral ischemic reperfusion models of rabbits. Thirty-six New Zealand rabbits were selected and divided into six groups: pseudo-surgery, 0.5-hour reperfusion, 1.5-hour reperfusion, 3-hour reperfusion, 6-hour reperfusion, and 24-hour reperfusion groups to detect NO and water contents in cerebral cortex homogenate. Another 30 New Zealand rabbits were selected and grouped into 5 groups: pseudo-surgery, placebo (0.9% normal saline), Nimodipine (initial dose of 5 μg/kg through intravenous injection within 20 minutes, maintaining at a injection speed of 0.5 μg/kg·min), Ketamine (initial dose of 20 mg/kg, through intravenous injection within 30 minutes, maintaining at a injection speed of 10 mg/kg·h), Nimodipine + Ketamine group. Continuous intravenous infusion started 30 minutes after reperfusion and the cerebral cortex was taken out until 6 hours after reperfusion. NO was detected by Griess method. Intracellular free Ca2+ ([Ca2+]i) in fresh cerebral slice were marked by Fluo-3 Ca2+ indicator. The relative fluorescence intensity of [Ca2+]i was detected under laser confocal microscope. Main Outcome Measures: Physiological parameter changes, cerebral cortex NO and water content changes following different time reperfusion, NO content, water content, and [Ca2+]i in the cerebral cortex of medication groups. Results: NO and water contents in the cerebral cortex gradually increased after reperfusion, and reached a relatively high level 6 hours later, which were (14.72 ± 1.66) μmol/g and (86.68 ± 1.90)% respectively (P < 0.05), and there was a correlation between NO and water content (r = 0.577, P < 0.01). NO contents significantly decreased in Nimodipine and Nimodipine + Ketamine groups, which were (5.08 ± 0.88) and (5.14 ± 1.12) μmol/g respectively (P < 0.01). Water contents significantly decreased in Nimodipine, Ketamin and Nimodipine + Ketamine groups, which were (76.13 ± 4.00)%, (81.04 ± 1.86)% and (78.16 ± 1.41)% respectively (P < 0.01) and more distinct decrease was found in Nimodipine group as compared with that in Ketamine group (P < 0.01). [Ca2+]i in placebo group distinctly increased as compared with that of pseudo-surgery group, which were 26.84 ± 1.39 and 4.99 ± 0.39 respectively (P < 0.01). [Ca2+]i decreased after the treatment of Nimodipine, Ketamine and Nimodipine + Ketamine, which were 7.74 ± 1.11, 13.30 ± 1.99, and 8.97 ± 2.01 respectively (P < 0.01), and more obvious decrease was in Nimodipine group as compared with that of in Ketamine group (P < 0.01). Conclusion: NO closely relates with the occurrence of cerebral ischemic reperfusion damage. Nimodipine and Ketamine have certain cerebral protective effects, but Ketamine has weaker effects than Nimodipine.