Xing-Ya Gao

Paraventricular nucleus is involved in the central pathway of cardiac sympathetic afferent reflex in rats

Our previous studies have shown that angiotensin II and reactive oxygen species in the paraventricular nucleus (PVN) modulate the cardiac sympathetic afferent reflex (CSAR). The present study was designed to demonstrate more conclusively that the PVN is an important component of the central neurocircuitry of the CSAR. In anaesthetized Sprague–Dawley rats with sinoaortic denervation and cervical vagotomy, renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were continuously recorded. The CSAR was evaluated by the response of the RSNA to epicardial application of bradykinin or capsaicin. Bilateral microinjection of the anaesthetic, lignocaine, into the PVN abolished the CSAR without significant effects on the baseline RSNA and MAP, while l‐glutamate, which excites the neurons in the PVN, enhanced the CSAR and increased the baseline RSNA and MAP. Bilateral electrolytic lesions of the PVN irreversibly abolished the CSAR without significant effects on the baseline RSNA and MAP. Bilateral selective lesions of the neurons in the PVN with kainic acid induced rapid and great increases in both RSNA and MAP which returned to nearly normal levels in 60 min. At the 90th minute after kainic acid, epicardial application of bradykinin or capsaicin failed to induce the CSAR. These results indicate that inhibition or lesion of the PVN abolishes the CSAR, but excitation of the neurons in the PVN enhances the CSAR, suggesting that the PVN is an important component of the central neurocircuitry of the CSAR.

Angiotensin AT1 receptors in paraventricular nucleus contribute to sympathetic activation and enhanced cardiac sympathetic afferent reflex in renovascular hypertensive rats

Sympathetic activity is enhanced in hypertension, which contributes to the pathogenesis of hypertension and progression of organ damage. The cardiac sympathetic afferent reflex (CSAR) is enhanced in renovascular hypertension and involved in the sympathetic activation. The present study was designed to investigate whether angiotensin II (Ang II) and Ang II type 1 (AT1) receptors in paraventricular nucleus (PVN) contribute to the enhanced CSAR and sympathetic outflow in experimental renovascular hypertensive rats. Hypertension was induced by the two‐kidney one‐clip (2K1C) method. The normotensive rats underwent sham operation (Sham). Acute experimentation was carried out at the end of the 4th week. Under urethane and α‐chloralose anaesthesia, the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded in rats with sino‐aortic denervation and cervical vagotomy. The AT1 receptor expression was determined with Western blot. The CSAR was evaluated by the response of RSNA and MAP to epicardial application of 1.0 nmol of capsaicin. The AT1 receptor expression in the PVN was increased, and Ang II in the PVN augmented the enhanced CSAR and RSNA in 2K1C rats. The effects of Ang II were abolished by pretreatment with the AT1 receptor antagonist, losartan, in 2K1C rats. Losartan in the PVN normalized the enhanced CSAR and decreased the RSNA and MAP in 2K1C rats. These results indicate that the increased activity of AT1 receptors in the PVN contributes to the enhanced CSAR and excessive sympathetic activation in renovascular hypertensive rats.

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) and angiotension II in the rostral ventrolateral medulla modulate the cardiac sympathetic afferent reflex and sympathetic activity in rats

The rostral ventrolateral medulla (RVLM) plays a pivotal role in regulating sympathetic vasomotor activity. The cardiac sympathetic afferent reflex (CSAR) contributes to the enhanced sympathetic outflow in chronic heart failure and hypertension. The aim of the present study was to determine whether angiotensin (Ang) II and Ang-(1–7) in the RVLM modulate the CSAR and sympathetic activity. Bilateral sinoaortic denervation and vagotomy were carried out in anesthetized rats. The CSAR was evaluated as the renal sympathetic nerve activity (RSNA) response to epicardial application of capsaicin. The effects of bilateral microinjection of Ang II, Ang-(1–7), the AT1 receptor antagonist losartan or the Mas receptor antagonist d-alanine-Ang-(1–7) (A-779) into the RVLM were determined. Either Ang II or Ang-(1–7) enhanced the CSAR as well as increased RSNA and mean arterial pressure (MAP) in a dose-dependent manner. Pretreatment with losartan but not the A-779 abolished the effects of Ang II, while A-779 but not the losartan eliminated the effects of Ang-(1–7). The RVLM microinjection of losartan alone had no direct effect on the CSAR, RSNA, and MAP, but A-779 alone attenuated the CSAR and decreased RSNA and MAP. These results indicate that Ang-(1–7) is as effective as Ang II in sensitizing the CSAR and increasing sympathetic outflow. In contrast to Ang II, the effects of Ang-(1–7) are not mediated by AT1 receptors but by Mas receptors. Mas receptors, but not the AT1 receptors, in the RVLM are involved in the tonic control of the CSAR.

Superoxide anions in the paraventricular nucleus mediate the enhanced cardiac sympathetic afferent reflex and sympathetic activity in renovascular hypertensive rats

An enhanced cardiac sympathetic afferent reflex (CSAR) is involved in the sympathetic activation in renovascular hypertension. The present study was designed to determine the role of superoxide anions in the paraventricular nucleus (PVN) in mediating the enhanced CSAR and sympathetic activity in renovascular hypertension in the two-kidney, one-clip (2K1C) model. Sinoaortic denervation and vagotomy were carried out, and renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded under anesthesia. The CSAR was evaluated by the response of RSNA to the epicardial application of capsaicin. Superoxide anion levels and NAD(P)H oxidase activity in the PVN increased in 2K1C rats and were much higher in 2K1C rats than in sham-operated (sham) rats after the epicardial application of capsaicin or PVN microinjection of ANG II. In both 2K1C and sham rats, PVN microinjection of the superoxide anion scavenger tempol or the NAD(P)H oxidase inhibitor apocynin abolished the CSAR, whereas the SOD inhibitor diethyldithiocarbamic acid (DETC) potentiated the CSAR. Tempol and apocynin decreased but DETC increased baseline RSNA and MAP. ANG II in the PVN caused larger responses of the CSAR, baseline RSNA, and baseline MAP in 2K1C rats than in sham rats. The effects of ANG II were abolished by pretreatment with tempol or apocynin in both 2K1C and sham rats and augmented by DETC in the PVN in 2K1C rats. These results indicate that superoxide anions in the PVN mediate the CSAR and the effects of ANG II in the PVN. Increased superoxide anions in the PVN contribute to the enhanced CSAR and sympathetic activity in renovascular hypertension.

Enhanced cardiac sympathetic afferent reflex involved in sympathetic overactivity in renovascular hypertensive rats

Sympathetic outflow is increased in hypertension. The aim of the present study was to investigate whether the cardiac sympathetic afferent reflex (CSAR) is enhanced in two‐kidney one‐clip (2K1C) renovascular hypertensive rats, and whether the enhanced CSAR contributes, in part, to the increased sympathetic outflow. Furthermore, the role of central angiotensin II type 1 (AT1) receptors in mediating the CSAR was determined. Under urethane and α‐chloralose anaesthesia, the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded in sinoaortic denervated and cervical vagotomized rats. The CSAR was evaluated by the response of RSNA and MAP to epicardial application of 1.0 nmol of capsaicin. Compared with sham‐operated rats, the CSAR, baseline RSNA and plasma noradrenaline level were significantly enhanced in 2K1C rats. Intrapericardial administration of resiniferatoxin, which abolishes the CSAR because of the desensitization of transient receptor potential vanilloid 1‐containing cardiac afferent fibres, decreased the RSNA and MAP. The enhanced CSAR in 2K1C rats was normalized by intracerebroventricular administration of the AT1 receptor antagonist losartan. Intracerebroventricular administration of angiotensin II further potentiated the enhanced CSAR in 2K1C rats, a response which was abolished by pretreatment with losartan. These results indicate that the CSAR is enhanced in 2K1C rats and the enhanced CSAR contributes, in part, to the sympathetic activation and hypertension. Central AT1 receptors are involved in the enhanced CSAR in 2K1C rats.

Reactive oxygen species in the paraventricular nucleus mediate the cardiac sympathetic afferent reflex in chronic heart failure rats

The aim of this study was to determine whether reactive oxygen species (ROS) in the paraventricular nucleus (PVN) mediate both the cardiac sympathetic afferent reflex (CSAR) and angiotensin II‐induced CSAR enhancement in chronic heart failure (CHF) rats. CSAR was evaluated from the responses of renal sympathetic nerve activity (RSNA) to epicardial application of bradykinin. In both CHF and sham‐operated rats, PVN microinjection of the superoxide anion scavengers tempol or tiron almost abolished the CSAR, but the superoxide dismutase inhibitor DETC potentiated the CSAR. PVN pretreatment with tempol or tiron abolished, whereas DETC augmented, the angiotensin II‐induced CSAR enhancement. In CHF rats, superoxide anion and malondialdehyde (MDA) levels in the PVN were increased, but were normalized by the AT1 receptor antagonist losartan. PVN microinjection of tempol decreased superoxide anion and MDA levels, but epicardial application of bradykinin or PVN microinjection of angiotensin II increased superoxide anion and MDA to higher levels in CHF rats than in sham‐operated rats. These results indicate that ROS in the PVN mediates the CSAR and the effect of angiotensin II in the PVN on the CSAR in both CHF and sham‐operated rats. Increased ROS in the PVN are involved in the enhanced CSAR in CHF.

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.