Abstract
BackgroundThe adipose afferent reflex (AAR), a sympatho-excitatory reflex, can promote the elevation of sympathetic nerve activity (SNA) and blood pressure (BP). Inflammation in the paraventricular nucleus (PVN) involves sympathetic abnormality in some cardiovascular diseases such as hypertension. This study was designed to explore the effects of tumor necrosis factor alpha (TNFα) in the PVN on the AAR and SNA in rats with obesity-related hypertension (OH) induced by a high-fat diet for 12 weeks.MethodsRenal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were continuously recorded in anesthetized rats, and their responses to capsaicin (CAP) stimulation of the right inguinal white adipose tissue were used to evaluate the AAR.ResultsCompared to the control rats, the systolic blood pressure (SBP), plasma norepinephrine (NE, indicating SNA) and TNFα levels, TNFα mRNA and protein levels, reactive oxygen species (ROS) content and NADPH oxidase activity in the PVN were significantly elevated in rats with OH. TNFα in the PVN markedly enhanced sympathoexcitation and AAR. Moreover, the enhancement of AAR caused by TNFα can be significantly strengthened by the pretreatment of diethyldithiocarbamate (DETC), a superoxide dismutase inhibitor, but attenuated by TNF-α receptor antagonist R-7050, superoxide scavenger PEG-SOD and NADPH oxidase inhibitor apocynin (Apo) in rats with OH. Acute microinjection of TNF-α into the PVN significantly increased the activity of NADPH oxidase and ROS levels in rats with OH, which were effectively blocked by R-7050. Furthermore, our results also showed that the increased levels of ROS, TNFα and NADPH oxidase subunits mRNA and protein in the PVN of rats with OH were significantly reversed by pentoxifylline (PTX, 30 mg/kg daily ip; in 10% ethanol) application, a cytokine blocker, for a period of 5 weeks. PTX administration also significantly decreased SBP, AAR and plasma NE levels in rats with OH.ConclusionsTNFα in the PVN modulates AAR and contributes to sympathoexcitation in OH possibly through NADPH oxidase-dependent ROS generation. TNFα blockade attenuates AAR and sympathoexcitation that unveils TNFα in the PVN may be a possible therapeutic target for the intervention of OH.
Highlights
The adipose afferent reflex (AAR), a sympatho-excitatory reflex, can promote the elevation of sympa‐ thetic nerve activity (SNA) and blood pressure (BP)
To investigate whether tumor necrosis factor α (TNFα) in the paraventricular nucleus (PVN) is involved in sympathetic activation and hypertension in obesity-related hypertension (OH), we firstly examined the mRNA and protein expressions of TNFα
We found that the pretreatment of R-7050, PEG-SOD or Apo in the PVN significantly inhibited the AAR enhancement caused by TNFα in rats with OH, but pretreatment of DETC further strengthened the AAR compared to the single TNFα injection (p < 0.05 for each, Fig. 4a–d)
Summary
The adipose afferent reflex (AAR), a sympatho-excitatory reflex, can promote the elevation of sympa‐ thetic nerve activity (SNA) and blood pressure (BP). This study was designed to explore the effects of tumor necrosis factor alpha (TNFα) in the PVN on the AAR and SNA in rats with obesity-related hypertension (OH) induced by a high-fat diet for 12 weeks. Recent studies on abnormality of sympathetic nerve activity (SNA) in obesity has targeted the hypothalamus and illustrated that hypothalamic paraventricular nuclei (PVN), an important central site for the integration of SNA and the regulation of cardiovascular function, can mediate obesity pathogenesis [9,10,11,12]. The increased abdominal visceral fat composed of white adipose tissue (WAT) is a very important contributing factor for the sympathetic overdrive and hypertension [13]. The adipose afferent reflex (AAR), a sympathoexcitatory reflex for increasing SNA and blood pressure (BP), can be induced by the stimulation of afferent nerve fibres of WAT with capsaicin (CAP) [13]. A related study from our laboratory demonstrated PVN mediated the enhanced AAR implicates the pathogenesis of obesityrelated hypertension (OH) [16]
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