Ye-Bo Zhou

Enhanced Adipose Afferent Reflex Contributes to Sympathetic Activation in Diet-Induced Obesity Hypertension

We recently found that adipose afferent reflex (AAR) induced by chemical stimulation of white adipose tissue (WAT) increased sympathetic outflow and blood pressure in normal rats. The study was designed to test the hypothesis that AAR contributes to sympathetic activation in obesity hypertension. Male rats were fed with a control diet (12% kcal as fat) or high-fat diet (42% kcal as fat) for 12 weeks to induce obesity hypertension. Stimulation of WAT with capsaicin increased renal sympathetic nerve activity and mean arterial pressure. Both AAR and WAT afferent activity were enhanced in obesity hypertension (OH) compared with obesity nonhypertension (ON) and in ON compared with obesity-resistant or control diet rats. WAT sensory denervation induced by resiniferatoxin caused greater decreases in renal sympathetic nerve activity and mean arterial pressure in OH than ON and in ON than obesity-resistant or control. The depressor effect of resiniferatoxin lasted ≥3 weeks in OH. Leptin antagonist in WAT reduced renal sympathetic nerve activity and mean arterial pressure in OH. WAT injection of capsaicin increased plasma renin, angiotensin II, and norepinephrine levels in OH and caused more c-fos expression in paraventricular nucleus in OH than ON and in ON than obesity-resistant or control rats. Inhibiting paraventricular nucleus neurons with lidocaine attenuated renal sympathetic nerve activity in OH and ON, decreased mean arterial pressure in OH, and abolished the capsaicin-induced AAR in all groups. The results indicate that enhanced AAR contributes to sympathetic activation in OH, and paraventricular nucleus plays an important role in the enhanced AAR and sympathetic activation in OH.

Inflammatory cytokines in paraventricular nucleus modulate sympathetic activity and cardiac sympathetic afferent reflex in rats.

Aim:  This study was to determine the roles of inflammatory cytokines in paraventricular nucleus (PVN) in modulating sympathetic activity, blood pressure and cardiac sympathetic afferent reflex (CSAR).

Angiotensin-(1-7) in the rostral ventrolateral medulla modulates enhanced cardiac sympathetic afferent reflex and sympathetic activation in renovascular hypertensive rats.

Enhancement of the cardiac sympathetic afferent reflex (CSAR) contributes to sympathetic excitation in hypertension. The aim of the present study was to determine whether angiotensin (Ang)-(1–7) in the rostral ventrolateral medulla (RVLM) modulated the enhanced CSAR and sympathetic activation, and the signaling pathways that mediated these effects in the 2-kidney, 1-clip renovascular hypertension model. Cardiac sympathetic afferent reflex was evaluated using renal sympathetic nerve activity and mean arterial pressure responses to epicardial capsaicin application in anesthetized sinoaortic-denervated and cervical-vagotomized rats. RVLM microinjection of Ang-(1–7) induced greater increases in renal sympathetic nerve activity and mean arterial pressure, and greater enhancement in CSAR in 2-kidney, 1-clip rats than in sham-operated rats, which was blocked by Mas receptor antagonist A-779, adenylyl cyclase inhibitors SQ22536 and MDL-12,330A, and protein kinase A inhibitors rp-adenosine-3′,5′-cyclic monophosphorothionate and H-89. Mas receptor expression in RVLM was increased in 2-kidney, 1-clip rats. Treatment with A-779, SQ22536, MDL-12,330A, rp-adenosine-3′,5′-cyclic monophosphorothionate, or H-89 in RVLM inhibited CSAR and decreased renal sympathetic nerve activity and mean arterial pressure in 2-kidney, 1-clip rats, whereas cAMP analogue dibutyryl-cAMP had the opposite effects. Ang-(1–7) in RVLM increased, whereas A-779 decreased the cAMP level and the epicardial capsaicin application-induced increases in the cAMP level in RVLM. These results indicate that Ang-(1–7) in the RVLM enhances the CSAR and increases the sympathetic outflow and blood pressure via Mas receptor activation. The increased endogenous Ang-(1–7) and Mas receptor activity in RVLM contributes to the enhanced CSAR and sympathetic activation in renovascular hypertension, and the cAMP-protein kinase A pathway is involved in these Ang-(1–7)–mediated effects in the RVLM.

FNDC5 overexpression and irisin ameliorate glucose/lipid metabolic derangements and enhance lipolysis in obesity

Irisin is a cleaved and secreted fragment of fibronectin type III domain containing 5 (FNDC5), and contributes to the beneficial effects of exercise on metabolism. Here we report the therapeutical effects of FNDC5/irisin on metabolic derangements and insulin resistance in obesity, and show the lipolysis effect of irisin and its signal molecular mechanism. In obese mice, lentivirus mediated-FNDC5 overexpression enhanced energy expenditure, lipolysis and insulin sensitivity, and reduced hyperlipidemia, hyperglycemia, hyperinsulinism, blood pressure and norepinephrine levels; it increased hormone-sensitive lipase (HSL) expression and phosphorylation, and reduced perilipin level and adipocyte diameter in adipose tissues. Subcutaneous perfusion of irisin reduced hyperlipidemia and hyperglycemia, and improved insulin resistance. Either FNDC5 overexpression or irisin perfusion only induced a tendency toward a slight decrease in body weight in obese mice. In 3T3-L1 adipocytes, irisin enhanced basal lipolysis rather than isoproterenol-induced lipolysis, which were prevented by inhibition of adenylate cyclase or PKA; irisin increased the HSL and perilipin phosphorylation; it increased PKA activity, and cAMP and HSL mRNA levels, but reduced perilipin expression. These results indicate that FNDC5/irisin ameliorates glucose/lipid metabolic derangements and insulin resistance in obese mice, and enhances lipolysis via cAMP-PKA-HSL/perilipin pathway. FNDC5 or irisin can be taken as an effective therapeutic strategy for metabolic disorders.

Sympathetic activation by chemical stimulation of white adipose tissues in rats

Injection of leptin into white adipose tissue (WAT) increases sympathetic outflow. The present study was designed to determine the effects of capsaicin and other chemicals in WAT on the sympathetic outflow and blood pressure and the roles of WAT afferents and hypothalamic paraventricular nucleus (PVN) in the adipose afferent reflex (AAR). The AAR was induced by injection of capsaicin, bradykinin, adenosine, adenosine triphosphate (ATP), or leptin into inguinal WAT (iWAT) or retroperitoneal WAT (rWAT) in anesthetized rats. The iWAT injection of capsaicin increased the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) but not the heart rate. Bradykinin, adenosine, or leptin but not ATP in the iWAT caused similar effects to capsaicin on the RSNA and MAP. Intravenous, intramuscular, or intradermal injection of capsaicin had no significant effects on the RSNA and MAP. The effects of capsaicin in rWAT were similar to that in iWAT on the RSNA and MAP. Furthermore, injection of capsaicin into the iWAT increased the WAT afferent nerve activities, WAT efferent nerve activity, and brown adipose tissue efferent nerve activity. The iWAT denervation or chemical lesion of the PVN neurons with kainic acid abolished the AAR induced by the iWAT injection of capsaicin. These results indicate that the stimulation of iWAT afferents with capsaicin, bradykinin, adenosine, or leptin reflexly increases the RSNA and blood pressure. The iWAT afferents and the PVN are involved in the AAR induced by capsaicin in the iWAT.

Salusin-β in paraventricular nucleus increases blood pressure and sympathetic outflow via vasopressin in hypertensive rats

AIMS Salusin-β is a bioactive peptide with peripheral hypotensive, mitogenic and pro-atherosclerotic effects. The present study was designed to determine the roles of salusin-β in the paraventricular nucleus (PVN) and its relationship with arginine vasopressin (AVP) in hypertension and sympathetic activation. METHODS AND RESULTS Renovascular hypertension was induced by two-kidney, one-clip (2K1C) in male Sprague-Dawley rats. Acute experiments were carried out 4 weeks after 2K1C or sham-operation under urethane and alpha-chloralose anaesthesia. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) were recorded. Microinjection of salusin-β into the PVN increased the RSNA, MAP, and HR in a dose-related manner, whereas anti-salusin-β IgG in the PVN decreased the RSNA and MAP, and abolished the effects of salusin-β in 2K1C rats. However, either salusin-β or anti-salusin-β IgG in the PVN failed to cause any significant effects in sham-operated rats. The number of salusin-β-like immunopositive neurons in the PVN was significantly increased in 2K1C rats. Salusin-β in the PVN increased the plasma AVP and norepinephrine levels in 2K1C rats, but not in sham-operated rats. Iv injection of dTyr(CH2)5(Me)AVP (an AVP V1-receptor antagonist, AAVP) decreased RSNA and MAP, and abolished the effects of salusin-β in the PVN in 2K1C rats. Microinjection of AAVP into the rostral ventrolateral medulla (RVLM), but not into the PVN, abolished the effects of salusin-β on RSNA and HR. CONCLUSION Salusin-β in the PVN increases blood pressure, heart rate, and sympathetic outflow via both circulating AVP and AVP in the RVLM in hypertensive rats.

SOD1 gene transfer into paraventricular nucleus attenuates hypertension and sympathetic activity in spontaneously hypertensive rats

Excessive sympathetic activity contributes to the initiation and progression of hypertension. Reactive oxygen species in the paraventricular nucleus (PVN) is involved in sympathetic overdrive and hypertension. The present study was designed to investigate whether superoxide dismutase 1 (SOD1) overexpression in the PVN attenuated sympathetic activation and hypertension. Adenoviral vectors containing human SOD1 or null adenoviral vectors were microinjected into the PVN of Wistar rats and spontaneously hypertensive rats (SHR). Significant depressor effects were observed from weeks 1 to 4 after SOD1 gene transfer in SHR. Acute experiments were carried out at the end of the 3rd week. In the PVN, superoxide anion and angiotensin II levels were increased while SOD1 activity and protein expression were decreased in SHR, which were attenuated by SOD1 overexpression in the PVN. However, SOD1 overexpression had no significant effect on the SOD2 activity in the PVN. The blood pressure response to ganglionic blockade, cardiac sympathetic nerve activity, and cardiac sympathetic afferent reflex (CSAR) were enhanced, and the plasma norepinephrine level was increased in SHR, which were prevented by SOD1 gene transfer in the PVN. Furthermore, SOD1 overexpression decreased the ratio of left ventricular weight to body weight, cross-sectional areas of myocardial cells, media thickness, and the media/lumen ratio of small arteries in the heart in SHR. These results indicate that SOD1 overexpression in the PVN reduces arterial blood pressure, attenuates excessive sympathetic activity and CSAR, and improves myocardial and vascular remodeling in SHR.

Intermedin in Paraventricular Nucleus Attenuates Sympathetic Activity and Blood Pressure via Nitric Oxide in Hypertensive Rats

Intermedin (IMD) is a member of calcitonin/calcitonin gene–related peptide family, which shares the receptor system consisting of calcitonin receptor–like receptor (CRLR) and receptor activity–modifying proteins (RAMPs). This study investigated the effects of IMD in paraventricular nucleus (PVN) on renal sympathetic nerve activity and mean arterial pressure and its downstream mechanism in hypertension. Rats were subjected to 2-kidney 1-clip (2K1C) surgery to induce renovascular hypertension or sham operation. Acute experiments were performed 4 weeks later under anesthesia. IMD mRNA and protein were downregulated in 2K1C rats. Bilateral PVN microinjection of IMD caused greater decreases in renal sympathetic nerve activity and mean arterial pressure in 2K1C rats than in sham-operated rats, which were prevented by pretreatment with adrenomedullin receptor antagonist AM22-52 or nonselective nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester, and attenuated by selective neuronal NO synthase inhibitor N&ohgr;-propyl-l-arginine hydrochloride or endothelial NO synthase inhibitor N(5)-(1-iminoethyl)-l-ornithine dihydrochloride. AM22-52 increased renal sympathetic nerve activity and mean arterial pressure in 2K1C rats but not in sham-operated rats, whereas calcitonin/calcitonin gene–related peptide receptor antagonist calcitonin/calcitonin gene–related peptide 8-37 had no significant effect. CRLR and RAMP3 mRNA, as well as CRLR, RAMP2, and RAMP3 protein expressions, in the PVN were increased in 2K1C rats. Microinjection of IMD into the PVN increased the NO metabolites (NOx) level in the PVN in 2K1C rats, which was prevented by AM22-52. Chronic PVN infusion of IMD reduced, but AM22-52 increased, blood pressure in conscious 2K1C rats. These results indicate that IMD in the PVN inhibits sympathetic activity and attenuates hypertension in 2K1C rats, which are mediated by adrenomedullin receptors (CRLR/RAMP2 or CRLR/RAMP3) and its downstream NO.

Angiotensin-(1-7) in paraventricular nucleus modulates sympathetic activity and cardiac sympathetic afferent reflex in renovascular hypertensive rats.

Background Excessive sympathetic activity contributes to the pathogenesis and progression of hypertension. Enhanced cardiac sympathetic afferent reflex (CSAR) is involved in sympathetic activation. This study was designed to determine the roles of angiotensin (Ang)-(1–7) in paraventricular nucleus (PVN) in modulating sympathetic activity and CSAR and its signal pathway in renovascular hypertension. Methodology/Principal Findings Renovascular hypertension was induced with two-kidney, one-clip method. Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded in sinoaortic-denervated and cervical-vagotomized rats with anesthesia. CSAR was evaluated with the RSNA and MAP responses to epicardial application of capsaicin. PVN microinjection of Ang-(1–7) and cAMP analogue db-cAMP caused greater increases in RSNA and MAP, and enhancement in CSAR in hypertensive rats than in sham-operated rats, while Mas receptor antagonist A-779 produced opposite effects. There was no significant difference in the angiotensin-converting enzyme 2 (ACE2) activity and Ang-(1–7) level in the PVN between sham-operated rats and hypertensive rats, but the Mas receptor protein expression in the PVN was increased in hypertensive rats. The effects of Ang-(1–7) were abolished by A-779, adenylyl cyclase inhibitor SQ22536 or protein kinase A (PKA) inhibitor Rp-cAMP. SQ22536 or Rp-cAMP reduced RSNA and MAP in hypertensive rats, and attenuated the CSAR in both sham-operated and hypertensive rats. Conclusions Ang-(1–7) in the PVN increases RSNA and MAP and enhances the CSAR, which is mediated by Mas receptors. Endogenous Ang-(1–7) and Mas receptors contribute to the enhanced sympathetic outflow and CSAR in renovascular hypertension. A cAMP-PKA pathway is involved in the effects of Ang-(1–7) in the PVN.

Ionotropic glutamate receptors in paraventricular nucleus mediate adipose afferent reflex and regulate sympathetic outflow in rats

Chemical stimulation of white adipose tissue (WAT) induces adipose afferent reflex (AAR) and results in increases in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP). The enhanced AAR contributes to sympathetic activation and hypertension in obesity rats. This study was designed to investigate whether N‐methyl‐D‐aspartate receptors (NMDAR) and non‐NMDAR in paraventricular nucleus (PVN) modulate AAR and sympathetic outflow.