Conceptualization, J.-H.B., J.-X.W., Q.C., Y.-H.L., Z.-L.M. and G.-Q.Z.; Formal analysis, J.-H.B., J.-X.W., X.-L.W. and G.-Q.Z.; Funding acquisition, J.-H.B. and G.-Q.Z.; Investigation, J.-H.B., J.-X.W., X.-L.W., Y.J., M.J., J.-L.C. and W.-Y.H.; Methodology, J.-H.B., J.-X.W. and G.-Q.Z.; Project administration, G.-Q.Z.; Resources, G.-Q.Z.; Supervision, Z.-L.M. and G.-Q.Z.; Validation, G.-Q.Z.; Writing—original draft, J.-H.B., J.-X.W. and G.-Q.Z.; Writing—review & editing, Q.C., Y.-H.L., Z.-L.M. and G.-Q.Z. All authors have read and agreed to the published version of the manuscript.

Figure 1. Effects of lipopolysaccharide (LPS) on RSNA, MAP and HR in rats. Rat was subjected to intraperitoneal injection of LPS (3 mg/Kg body weight). (A,B) LPS-induced changes in renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) in the first hour after the LPS injection; (C–E) LPS-induced changes in plasma norepinephrine level, heart rate variability analyses, MAP and HR 24 h after the LPS injection; (F) LPS-induced changes in plasma TNF-α and IL-1β levels 24 h after the LPS injection * p < 0.05. n = 6.

Figure 1. Effects of lipopolysaccharide (LPS) on RSNA, MAP and HR in rats. Rat was subjected to intraperitoneal injection of LPS (3 mg/Kg body weight). (A,B) LPS-induced changes in renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) in the first hour after the LPS injection; (C–E) LPS-induced changes in plasma norepinephrine level, heart rate variability analyses, MAP and HR 24 h after the LPS injection; (F) LPS-induced changes in plasma TNF-α and IL-1β levels 24 h after the LPS injection * p < 0.05. n = 6.

Figure 2. Roles of the DEX microinjection to the paraventricular nucleus (PVN) on LPS-induced RSNA, MAP and HR changes. The PVN microinjection was carried out 24 h after the intraperitoneal injection of LPS. (A) Representative images showing the roles of DEX (0.4 nmol) on LPS-induced RSNA, MAP and HR changes; (B) dose-effects of DEX (0, 0.004, 0.04 and 0.4 nmol) (* p < 0.05 vs. 0 nmol); (C) time-effects of DEX († p < 0.05 vs. PBS); (D) effects of PVN microinjection of DEX (0.4 nmol) on LPS-induced RSNA, MAP and HR changes; (E) effects of DEX (0.4 nmol) on LPS-induced changes in norepinephrine level; (F) effects of DEX (0.4 nmol) on LPS-induced changes in plasma TNF-α and IL-1β levels (* p < 0.05. n = 6).

Figure 2. Roles of the DEX microinjection to the paraventricular nucleus (PVN) on LPS-induced RSNA, MAP and HR changes. The PVN microinjection was carried out 24 h after the intraperitoneal injection of LPS. (A) Representative images showing the roles of DEX (0.4 nmol) on LPS-induced RSNA, MAP and HR changes; (B) dose-effects of DEX (0, 0.004, 0.04 and 0.4 nmol) (* p < 0.05 vs. 0 nmol); (C) time-effects of DEX († p < 0.05 vs. PBS); (D) effects of PVN microinjection of DEX (0.4 nmol) on LPS-induced RSNA, MAP and HR changes; (E) effects of DEX (0.4 nmol) on LPS-induced changes in norepinephrine level; (F) effects of DEX (0.4 nmol) on LPS-induced changes in plasma TNF-α and IL-1β levels (* p < 0.05. n = 6).

Figure 3. Roles of α2 receptors (α2R) in the effects of DEX in LPS-treated rats. PVN microinjection was carried out 24 h after the intraperitoneal injection of LPS. (A) α2R mRNA expressions in the PVN in NS- and LPS-treated rats; (B) time-effect of LPS on α2A receptor protein expression in the PVN; (C) PVN microinjection of α2 receptors antagonist yohimbine (10 nmol) on RSNA, MAP and HR in LPS-treated rats; (D) effects of pretreatment with yohimbine (10 nmol) on the roles of α2R agonist DEX (0.4 nmol) or clonidine (20 nmol) in the PVN in LPS-treated rats. The pretreatment was made 10 min before administration of DEX or clonidine. * p < 0.05. n = 6.

Figure 3. Roles of α2 receptors (α2R) in the effects of DEX in LPS-treated rats. PVN microinjection was carried out 24 h after the intraperitoneal injection of LPS. (A) α2R mRNA expressions in the PVN in NS- and LPS-treated rats; (B) time-effect of LPS on α2A receptor protein expression in the PVN; (C) PVN microinjection of α2 receptors antagonist yohimbine (10 nmol) on RSNA, MAP and HR in LPS-treated rats; (D) effects of pretreatment with yohimbine (10 nmol) on the roles of α2R agonist DEX (0.4 nmol) or clonidine (20 nmol) in the PVN in LPS-treated rats. The pretreatment was made 10 min before administration of DEX or clonidine. * p < 0.05. n = 6.

Figure 4. ROS mediates the effects of DEX in LPS-treated rats. PVN microinjection was carried out 24 h after the intraperitoneal injection of LPS. (A) Superoxide production in the PVN in saline- and LPS-treated rats; (B) DHE fluorescence staining in the PVN in saline- and LPS-treated rats; (C) NADPH oxidase activity in saline- and LPS-treated rats; (D) effects of superoxide scavenger tempol (20 nmol), NADPH oxidase inhibitor apocynin (1 nmol) and superoxide dismutase inhibitor DETC (10 nmol) in the PVN in LPS-treated rats; (E) effects of pretreatment with tempol, apocynin or DETC on the roles of DEX in the PVN in the LPS-treated rats. * p < 0.05. n = 6.

Figure 4. ROS mediates the effects of DEX in LPS-treated rats. PVN microinjection was carried out 24 h after the intraperitoneal injection of LPS. (A) Superoxide production in the PVN in saline- and LPS-treated rats; (B) DHE fluorescence staining in the PVN in saline- and LPS-treated rats; (C) NADPH oxidase activity in saline- and LPS-treated rats; (D) effects of superoxide scavenger tempol (20 nmol), NADPH oxidase inhibitor apocynin (1 nmol) and superoxide dismutase inhibitor DETC (10 nmol) in the PVN in LPS-treated rats; (E) effects of pretreatment with tempol, apocynin or DETC on the roles of DEX in the PVN in the LPS-treated rats. * p < 0.05. n = 6.

Figure 5. The cAMP-PKA pathway contributes to the effects of DEX in LPS-treated rats. PVN microinjection was carried out 24 h after the intraperitoneal injection of LPS. (A) effects of DEX on cAMP level, adenylate cyclase (AC) and protein kinase A (PKA) activity in Saline- and LPS-treated rats; (B) effects of PVN microinjection of db-cAMP (a cell permeable cAMP analog, 1 nmol), SQ22536 (an adenylyl cyclase inhibitor, 2 nmol) or Rp-cAMP (a PKA inhibitor, 1 nmol) in LPS-treated rats; (C) pretreatment with db-cAMP on the roles of DEX in LPS-treated rats; (D) effects of pretreatment with db-cAMP, SQ22536 or Rp-cAMP on the roles of DEX in LPS-treated rats. The pretreatment was carried out 10 min before administration of DEX. * p < 0.05. n = 6.

Figure 5. The cAMP-PKA pathway contributes to the effects of DEX in LPS-treated rats. PVN microinjection was carried out 24 h after the intraperitoneal injection of LPS. (A) effects of DEX on cAMP level, adenylate cyclase (AC) and protein kinase A (PKA) activity in Saline- and LPS-treated rats; (B) effects of PVN microinjection of db-cAMP (a cell permeable cAMP analog, 1 nmol), SQ22536 (an adenylyl cyclase inhibitor, 2 nmol) or Rp-cAMP (a PKA inhibitor, 1 nmol) in LPS-treated rats; (C) pretreatment with db-cAMP on the roles of DEX in LPS-treated rats; (D) effects of pretreatment with db-cAMP, SQ22536 or Rp-cAMP on the roles of DEX in LPS-treated rats. The pretreatment was carried out 10 min before administration of DEX. * p < 0.05. n = 6.

Figure 6. GABA in the effects of DEX in the LPS-treated rats. PVN microinjection was carried out 24 h after the intraperitoneal injection of LPS. (A) Effects of PVN microinjection of vigabatrin (a GABA transaminase enzyme inhibitor, 10 nmol), gabazine (a GABAA receptor antagonist, 0.1 nmol) or (a GABAB receptor antagonist, CGP35348 10 nmol) on RSNA, MAP and HR; (B) effects of pretreatment with vigabatrin, gabazine or CGP35348 on the roles of DEX in reducing RSNA, MAP and HR in LPS-treated rats; (C) effects of pretreatment with vigabatrin, gabazine or CGP35348 on the roles of DEX in superoxide production and NADPH oxidase activity in LPS-treated rats (pretreatment was carried out 10 min before administration of DEX); (D) immunofluorescent staining for α2A receptors (red), GABAA receptors (green) in the PVN. Nuclei were stained with DAPI (blue). Abbreviation: 3V, the third ventricle. * p < 0.05. n = 6.

Figure 6. GABA in the effects of DEX in the LPS-treated rats. PVN microinjection was carried out 24 h after the intraperitoneal injection of LPS. (A) Effects of PVN microinjection of vigabatrin (a GABA transaminase enzyme inhibitor, 10 nmol), gabazine (a GABAA receptor antagonist, 0.1 nmol) or (a GABAB receptor antagonist, CGP35348 10 nmol) on RSNA, MAP and HR; (B) effects of pretreatment with vigabatrin, gabazine or CGP35348 on the roles of DEX in reducing RSNA, MAP and HR in LPS-treated rats; (C) effects of pretreatment with vigabatrin, gabazine or CGP35348 on the roles of DEX in superoxide production and NADPH oxidase activity in LPS-treated rats (pretreatment was carried out 10 min before administration of DEX); (D) immunofluorescent staining for α2A receptors (red), GABAA receptors (green) in the PVN. Nuclei were stained with DAPI (blue). Abbreviation: 3V, the third ventricle. * p < 0.05. n = 6.

Figure 7. Roles of the PVN in the effects of intravenous infusion (iv) of DEX on the LPS-induced sympathetic activation. Intravenous infusion of DEX for 4 h was carried out 24 h after intraperitoneal injection (ip) of LPS. Bilateral PVN microinjection was performed 5 min before the infusion of DEX. (A) Effects of DEX (2 or 8 ng/Kg/min, iv) on the LPS-induced RSNA, MAP and HR changes (* p < 0.05 vs. Saline+Saline) († p < 0.05 vs. LPS+Saline) (‡ p < 0.05 vs. LPS+DEX) (2 ng/Kg/min); (B,C) effects of DEX (2 or 8 ng/Kg/min, iv) on the LPS-induced heart rate variability changes and plasma norepinephrine level changes; (D) effects of PVN microinjection of yohimbine (10 nmol) or DETC (10 nmol) on the roles of DEX (8 ng/Kg/min, iv) in inhibiting LPS-induced RSNA, MAP and HR changes; (E,F) effects of intravenous infusion (iv) of DEX on the roles of the LPS-induced changes in oxidative stress and inflammation in the PVN; (G,H) effects of microinjection of yohimbine (10 nmol) or DETC (10 nmol) in the PVN on the roles of DEX in inhibiting LPS-induced changes in oxidative stress and inflammation in the PVN (* p < 0.05. n = 6).

Figure 7. Roles of the PVN in the effects of intravenous infusion (iv) of DEX on the LPS-induced sympathetic activation. Intravenous infusion of DEX for 4 h was carried out 24 h after intraperitoneal injection (ip) of LPS. Bilateral PVN microinjection was performed 5 min before the infusion of DEX. (A) Effects of DEX (2 or 8 ng/Kg/min, iv) on the LPS-induced RSNA, MAP and HR changes (* p < 0.05 vs. Saline+Saline) († p < 0.05 vs. LPS+Saline) (‡ p < 0.05 vs. LPS+DEX) (2 ng/Kg/min); (B,C) effects of DEX (2 or 8 ng/Kg/min, iv) on the LPS-induced heart rate variability changes and plasma norepinephrine level changes; (D) effects of PVN microinjection of yohimbine (10 nmol) or DETC (10 nmol) on the roles of DEX (8 ng/Kg/min, iv) in inhibiting LPS-induced RSNA, MAP and HR changes; (E,F) effects of intravenous infusion (iv) of DEX on the roles of the LPS-induced changes in oxidative stress and inflammation in the PVN; (G,H) effects of microinjection of yohimbine (10 nmol) or DETC (10 nmol) in the PVN on the roles of DEX in inhibiting LPS-induced changes in oxidative stress and inflammation in the PVN (* p < 0.05. n = 6).

Figure 8. Roles of the PVN in the effects of intravenous infusion (iv) of DEX on the LPS-induced oxidative stress and inflammation. Intravenous infusion of DEX for 4 h was carried out 24 h after intraperitoneal injection (ip) of LPS. Bilateral PVN microinjection was performed 5 min before the infusion of DEX. (A,B) Effects of DEX (2 or 8 ng/Kg/min) on the LPS-induced changes in plasma superoxide production, NADPH oxidase activity, TNF-α and IL-1β level; (C,D), effects of PVN microinjection of yohimbine (10 nmol) or DETC (10 nmol) on the roles of DEX in inhibiting LPS-induced changes in plasma superoxide production, NADPH oxidase activity, TNF-α and IL-1β levels; (E,F) HE staining showed the effects of PVN microinjection of yohimbine (10 nmol) or DETC (10 nmol) on the roles of DEX in attenuating LPS-induced changes in lung and kidney injury. * p < 0.05. n = 6.

Figure 8. Roles of the PVN in the effects of intravenous infusion (iv) of DEX on the LPS-induced oxidative stress and inflammation. Intravenous infusion of DEX for 4 h was carried out 24 h after intraperitoneal injection (ip) of LPS. Bilateral PVN microinjection was performed 5 min before the infusion of DEX. (A,B) Effects of DEX (2 or 8 ng/Kg/min) on the LPS-induced changes in plasma superoxide production, NADPH oxidase activity, TNF-α and IL-1β level; (C,D), effects of PVN microinjection of yohimbine (10 nmol) or DETC (10 nmol) on the roles of DEX in inhibiting LPS-induced changes in plasma superoxide production, NADPH oxidase activity, TNF-α and IL-1β levels; (E,F) HE staining showed the effects of PVN microinjection of yohimbine (10 nmol) or DETC (10 nmol) on the roles of DEX in attenuating LPS-induced changes in lung and kidney injury. * p < 0.05. n = 6.

Figure 9. Schematic diagram showing the roles of DEX in the PVN in regulating sympathetic activity. Abbreviations: AC, adenylate cyclase; DEX, dexmedetomidine; GABAAR, type A γ-aminobutyric acid receptor; IL-1β, interleukin-1β; NE, norepinephrine; NOX, NADPH oxidase; PKA, protein kinase A; PVN, paraventricular nucleus; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α; α1R, α1 adrenergic receptor; α2R, α2 adrenergic receptor.

Figure 9. Schematic diagram showing the roles of DEX in the PVN in regulating sympathetic activity. Abbreviations: AC, adenylate cyclase; DEX, dexmedetomidine; GABAAR, type A γ-aminobutyric acid receptor; IL-1β, interleukin-1β; NE, norepinephrine; NOX, NADPH oxidase; PKA, protein kinase A; PVN, paraventricular nucleus; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α; α1R, α1 adrenergic receptor; α2R, α2 adrenergic receptor.