The long-acting dihydropyridine calcium channel blocker, azelnidipine, is suggested to inhibit sympathetic nerve activity. We previously demonstrated that oxidative stress in the rostral ventrolateral medulla (RVLM) activates sympathetic nerve activity. The aim of the present study was to determine whether oral administration of azelnidipine inhibits sympathetic nerve activity and if so to determine whether the effect is mediated by antioxidant effect in the RVLM. Azelnidipine, hydralazine, or vehicle was orally administered for 28 days to stroke-prone spontaneously hypertensive rats. Reductions in systolic blood pressure were similar in azelnidipine and hydralazine groups. Heart rate was significantly higher in the hydralazine group than in the control, but not altered in the azelnidipine group. Urinary norepinephrine excretion as an indicator of sympathetic nerve activity was significantly lower in the azelnidipine group, whereas it was significantly higher in the hydralazine group than in the control. Levels of thiobarbituric acid-reactive substances and nicotinamide adenine dinucleotide phosphate oxidase activity were significantly lower in the azelnidipine group than in control. Superoxide dismutase activity was significantly increased in the azelnidipine group more than in the control. These results suggest that azelnidipine decreases an indicator of sympathetic nerve activity by antioxidant effect mediated through inhibition of nicotinamide adenine dinucleotide phosphate oxidase activity and activation of superoxide dismutase in the RVLM of stroke-prone spontaneously hypertensive rats.