Objective To investigate whether pro-inflammatory cytokines (PICs) in the paraventricular nucleus (PVN) regulate the enhanced sympathetic activities in spontaneously hypertensive rats (SHR), and whether N-methyl-D-aspartate receptor (NMDAR) in PVN mediate the effects of PICs on sympathetic activities.Methods SHR and normotensive wistar-Kyoto(WKY)rats were used in this experiment. TNF receptor and IL-1β receptor (IL-1RI) protein levels were measured by Western blot. PICs, including TNF-α and IL-1β levels were measured by ELISA. Rats were placed in a stereotaxic instrument to complete the microinjection of drugs. The coordinates for the PVN were determined according to the Paxinos and Watson rat atlas. The raw RSNA and integrated RSNA were simultaneously recorded on a PowerLab data acquisition system. The right carotid artery was cannulated for recording of mean arterial pressure (MAP). Results TNF-α receptor p55TNFR, p75TNFR and IL-1β receptor IL-1RI protein expression and TNF-α and IL-1β levels in PVN were all increased in SHR compared with WKY rats (P< 0.05). Bilateral microinjection of etanercept or IL-1ra into PVN to block the effects of TNF-α or IL-1β decreased the sympathetic activities in SHR rats significantly (P< 0.05). Bilateral microinjection of NMDAR blockers, both DL-2amino-5-phosphonovaleri acid (APV) and MK-801 (Dizocilpine) into PVN decreased the RSNA and MAP in both SHR and WKY rats. APV or MK 801 caused greater decreases in RSNA and MAP in SHR than WKY rats. In addition, pretreatment with APV or MK 801 attenuated the increased RSNA and MAP caused by microinjection of TNF-α or IL-1β into PVN to a lower level in SHR than in WKY rats (P< 0.05). Conclusions TNF and IL-1β receptor protein as well as TNF-α and IL-1β cytokines levels in PVN are all increased in SHR rats. NMDAR in PVN mediates enhanced sympathetic activities and elevated blood pressure caused by TNF-α and IL-1β in SHR.