alpha-melanocyte stimulating hormone (alpha-MSH) is an important regulator of food intake, metabolic rate, and inflammation. Recently, alpha-MSH was shown to influence sympathetic activity and blood pressure regulation. In the present study, we investigated the cardiovascular effects of alpha-MSH in the nucleus tractus solitarii (NTS) of spontaneously hypertensive rats (SHR). Because nitric oxide (NO) is well-known to involve in central cardiovascular regulation, we elucidated the role of NO in the cardiovascular responses induced by alpha-MSH. In urethane-anesthetized SHR, unilateral microinjection of alpha-MSH (0.3-300 pmol) into the NTS produced dose-responsive depressor and bradycardic effects. The cardiovascular effects of alpha-MSH were abrogated by the antagonist of melanocortin receptor (MC3/4-R), SHU9119. Pretreatment with precursor of nitric oxide, L-arginine, enhanced the duration of alpha-MSH-mediated hypotensive effects, whereas prior application of L-NAME, a universal inhibitor of nitric oxide synthase (NOS), significantly attenuated the effects of alpha-MSH. Prior injection with inhibitor of inducible NOS, aminoguanidine, but not inhibitor of neuronal NOS, 7-nitroindazole, attenuated the hypotensive effect of alpha-MSH. In summary, these results indicated alpha-MSH induced depressor and bradycardic effects in the NTS of SHR. Besides, the hypotensive mechanism of alpha-MSH was mediated via MC4-R and involved with iNOS activation in the NTS of SHR.