Local ionotropic glutamate receptors are required to trigger and sustain ramping of sympathetic nerve activity by hypothalamic paraventricular nucleus TNFα.

Tumor necrosis factor-α (TNFα) in the hypothalamic paraventricular nucleus (PVN) contributes to increased sympathetic nerve activity (SNA) in cardiovascular disease models, but mechanisms are incompletely understood. As previously reported, bilateral PVN TNFα (0.6 pmol, 50 nL) induced acute ramping of splanchnic SNA (SSNA) that averaged +64 ± 7% after 60 min and +109 ± 17% after 120 min (P < 0.0001, n = 10). Given that TNFα can rapidly strengthen glutamatergic transmission, we hypothesized that progressive activation of ionotropic glutamate receptors is critically involved. When compared with that of vehicle (n = 5), prior blockade of PVN AMPA or NMDA receptors in anesthetized (urethane/α-chloralose) adult male Sprague-Dawley rats dose-dependently (ED50: 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), 2.48 nmol; D-(-)-2-amino-5-phosphonopentanoic acid (APV), 12.33 nmol), but incompletely (Emax: NBQX, 64%; APV, 41%), attenuated TNFα-induced SSNA ramping (n = 5/dose). By contrast, combined receptor blockade prevented ramping (1.3 ± 2.1%, P < 0.0001, n = 5). Whereas separate blockade of PVN AMPA or NMDA receptors (n = 5/group) had little effect on continued SSNA ramping when performed 60 min after TNFα injection, combined blockade (n = 5) or PVN inhibition with the GABA-A receptor agonist muscimol (n = 5) effectively stalled, without reversing, the SSNA ramp. Notably, PVN TNFα increased local TNFα immunofluorescence after 120, but not 60 min. Findings indicate that AMPA and NMDA receptors each contribute to SSNA ramping to PVN TNFα, and that their collective availability and ongoing activity are required to initiate and sustain the ramping response. We conclude that acute sympathetic activation by PVN TNFα involves progressive local glutamatergic excitation that recruits downstream neurons capable of maintaining heightened SSNA, but incapable of sustaining SSNA ramping.NEW & NOTEWORTHY The proinflammatory cytokine TNFα contributes to heightened SNA in cardiovascular disease models, but mechanisms remain obscure. Here, we demonstrate that TNFα injection into the hypothalamic PVN triggers SNA ramping by mechanisms dependent on local ionotropic glutamate receptor availability, but largely independent of TNFα autoinduction. Continued SNA ramping depends on ionotropic glutamate receptor and neuronal activity in PVN, indicating that strengthening and/or increased efficacy of glutamatergic transmission is necessary for acute sympathoexcitation by PVN TNFα.

Novel choline analog 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol produces sympathoinhibition, hypotension, and antihypertensive effects.

The search for new drugs remains an important focus for the safe and effective treatment of cardiovascular diseases. Previous evidence has shown that choline analogs can offer therapeutic benefit for cardiovascular complications. The current study investigates the effects of 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol (LQFM032) on cardiovascular function and cholinergic-nitric oxide signaling. Synthesized LQFM032 (0.3, 0.6, or 1.2 mg/kg) was administered by intravenous and intracerebroventricular routes to evaluate the potential alteration of mean arterial pressure, heart rate, and renal sympathetic nerve activity of normotensive and hypertensive rats. Vascular function was further evaluated in isolated vessels, while pharmacological antagonists and computational studies of nitric oxide synthase and muscarinic receptors were performed to assess possible mechanisms of LQFM032 activity. The intravenous and intracerebroventricular administration of LQFM032 elicited a temporal reduction in mean arterial pressure, heart rate, and renal sympathetic nerve activity of rats. The cumulative addition of LQFM032 to isolated endothelium-intact aortic rings reduced vascular tension and elicited a concentration-dependent relaxation. Intravenous pretreatment with L-NAME (nitric oxide synthase inhibitor), atropine (nonselective muscarinic receptor antagonist), pirenzepine, and 4-DAMP (muscarinic M1 and M3 subtype receptor antagonist, respectively) attenuated the cardiovascular effects of LQFM032. These changes may be due to a direct regulation of muscarinic signaling as docking data shows an interaction of choline analog with M1 and M3 but not nitric oxide synthase. Together, these findings demonstrate sympathoinhibitory, hypotensive, and antihypertensive effects of LQFM032 and suggest the involvement of muscarinic receptors.

Median preoptic nucleus excitatory neurotransmitters in the maintenance of hypertensive state.

The crucial role of the median preoptic nucleus (MnPO) in the maintenance of hydroelectrolytic balance and autonomic regulation have been highlighted. Recently, the participation of the MnPO in the control of sympathetic nerve activity was demonstrated in essential hypertension model. However, peculiarities on the neurochemical changes underlying the differential role of MnPO during hypertension remain to be clarified. Therefore, this study aimed to investigate the main excitatory pathways that modulate MnPO neurons in hypertensive rats. Spontaneously hypertensive rats (SHR) and rats submitted previously to the Goldblatt protocol (two kidneys; one clip; 2K1C) were used. Rats of both groups (250 to 350 g, n = 6) were anesthetized with urethane (1.2 g/kg,i.v.) and instrumented to record mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA). Nanoinjection (100 nl) of saline (NaCl, 150 mM), losartan (AT1 receptor antagonist; 10 mM) and kynurenic acid (glutamate receptor antagonist; 50 mM) into the MnPO were performed. In 2K1C rats, glutamatergic blockade promoted decreases in MAP and RSNA (-19.1 ± 0.9 mmHg, -21.6 ± 2.8%, p < 0.05) when compared to saline (-0.4 ± 0.6 mmHg, 0.2 ± 0.7%, p < 0.05). Angiotensinergic inhibition also reduced these parameters (-11.5 ± 1.2 mmHg, -10.5 ± 1.0%, p < 0.05) in 2K1C. In SHR, Kynurenic acid nanoinjections produced hypotension and sympathoinhibition (-21.0 ± 2.5 mmHg, -24.7 ± 2.4%, p < 0.05), as well losartan nanoinjections (-9.7 ± 1.2 mmHg; p < 0.05) and RSNA (-12.0 ± 2.4%, p < 0.05). These findings support the conclusion that a tonic excitatory neurotransmission exerted by angiotensin II, and mostly by glutamate in the MnPO could participate in the modulation of blood pressure and RSNA independent on whether hypertension is primarily neurogenic or is secondary to stenosis in renal artery.

Preclinical Assessment of Cardiovascular Alterations Induced by Birch Polypore Mushroom, Piptoporus betulinus (Agaricomycetes).

Piptoporus betulinus has been used in folk medicine for millennia. However, no data currently exist regarding its potential cardiovascular activity. In this work, the crude ethanolic extract and fractions (hexane, ethyl acetate, and water) with increased polarity from the partitioning process, as well as stigmasterol (the major metabolite isolated from P. betulinus), were administered orally at different doses to normotensive male Wistar rats an hour before recording mean arterial pressure, heart rate, renal blood flow, renal vascular conductance, arterial blood flow, and arterial vascular conductance. The acute oral administration of crude ethanolic extract and all fractions did not alter mean arterial pressure when compared with the control group, which received a vehicle. In addition, subchronic (14 days) oral administration of crude ethanolic extract, fractions, and stigmasterol did not alter cardiovascular parameters. In conclusion, our findings demonstrate that oral administration of organic extracts of P. betulinus did not induce cardiovascular alterations.

Blockade of Rostral Ventrolateral Medulla (RVLM) Bombesin Receptor Type 1 Decreases Blood Pressure and Sympathetic Activity in Anesthetized Spontaneously Hypertensive Rats.

Intrathecal injection of bombesin (BBS) promoted hypertensive and sympathoexcitatory effects in normotensive (NT) rats. However, the involvement of rostral ventrolateral medulla (RVLM) in these responses is still unclear. In the present study, we investigated: (1) the effects of BBS injected bilaterally into RVLM on cardiorespiratory and sympathetic activity in NT and spontaneously hypertensive rats (SHR); (2) the contribution of RVLM BBS type 1 receptors (BB1) to the maintenance of hypertension in SHR. Urethane-anesthetized rats (1.2 g · kg(-1), i.v.) were instrumented to record mean arterial pressure (MAP), diaphragm (DIA) motor, and renal sympathetic nerve activity (RSNA). In NT rats and SHR, BBS (0.3 mM) nanoinjected into RVLM increased MAP (33.9 ± 6.6 and 37.1 ± 4.5 mmHg, respectively; p < 0.05) and RSNA (97.8 ± 12.9 and 84.5 ± 18.1%, respectively; p < 0.05). In SHR, BBS also increased DIA burst amplitude (115.3 ± 22.7%; p < 0.05). BB1 receptors antagonist (BIM-23127; 3 mM) reduced MAP (-19.9 ± 4.4 mmHg; p < 0.05) and RSNA (-17.7 ± 3.8%; p < 0.05) in SHR, but not in NT rats (-2.5 ± 2.8 mmHg; -2.7 ± 5.6%, respectively). These results show that BBS can evoke sympathoexcitatory and pressor responses by activating RVLM BB1 receptors. This pathway might be involved in the maintenance of high levels of arterial blood pressure in SHR.

Do the carotid body chemoreceptors mediate cardiovascular and sympathetic adjustments induced by sodium overload in rats?

Acute plasma hypernatremia induces several cardiovascular and sympathetic responses. It is conceivable that these responses contribute to rapid sodium excretion and restoration of normal conditions. Afferent pathways mediating these responses are not entirely understood. The present study analyses the effects of acute carotid chemoreceptor inactivation on cardiovascular and sympathetic responses induced by infusion of hypertonic saline (HS). All experiments were performed on anesthetized male Wistar rats instrumented for recording of arterial blood pressure (ABP), renal blood flow (RBF) and renal sympathetic nerve activity (RSNA). Animals were subjected to sham surgery or carotid chemoreceptor inactivation by bilateral ligation of the carotid body artery (CBA). In sham rats (n=8), intravenous infusion of HS (3 M NaCl, 1.8 ml/kg b.wt.) elicited a transient increase (9±2mmHg) in ABP, and long lasting (30 min) increases in RBF (138±5%) and renal vascular conductance (RVC) (128±5%) with concurrent decrease in RSNA (-19±4%). In rats submitted to CBA ligation (n=8), the pressor response to HS was higher (24±2mmHg; p<0.05). However, RBF and RVC responses to HS infusion were significantly reduced (113±5% and 93±4%, respectively) while RSNA was increased (13±2%). When HS (3M NaCl, 200µl) was administrated into internal carotid artery (ICA), distinct sympathetic and cardiovascular responses were observed. In sham-group, HS infusion (3M NaCl, 200µl) into ICA promoted an increase in ABP (26±8mmHg) and RSNA (29±13%). In CBA rats, ABP (-3±5.6mmHg) remained unaltered despite sympathoinhibition (-37.6±5.4%). These results demonstrate that carotid body chemoreceptors play a role in the development of hemodynamic and sympathetic responses to acute HS infusion.

Does the median preoptic nucleus contribute to sympathetic hyperactivity in spontaneously hypertensive rats?

The present study sought to determine the involvement of median preoptic nucleus (MnPO) in the regulation of the cardiovascular function and renal sympathetic activity in normotensive (NT) and spontaneously hypertensive rats (SHR). MnPO inhibition evoked by Muscimol (4mM) nanoinjections, elicited fall in MAP and renal sympathoinhibition in NT-rats. Surprisingly, in SHRs these responses were greater than in NT-rats. These results demonstrated, for the first time that MnPO was involved in the tonic control of sympathetic activity in NT and SHRs. Furthermore, our data suggest the MnPO involvement in the increased sympathetic outflow and consequent arterial hypertension observed in SHRs.

Involvement of sinoaortic afferents in renal sympathoinhibition and vasodilation induced by acute hypernatremia.

Despite the abundance of evidence that supports the important role of aortic and carotid afferents to short-term regulation of blood pressure and detection of variation in the arterial PO2 , PCO2 and pH, relatively little is known regarding the role of these afferents during changes in the volume and composition of extracellular compartments. The present study sought to determine the involvement of these afferents in the renal vasodilation and sympathoinhibition induced by hypertonic saline (HS) infusion. Sinoaortic-denervated and sham male Wistar rats were anaesthetised with intravenous (i.v.) urethane (1.2 g/kg body weight (bw)) prior to the measurement of the mean arterial pressure (MAP), renal vascular conductance (RVC) and renal sympathetic nerve activity (RSNA). In the sham group, the HS infusion (3 mol/L NaCl, 1.8 mL/kg bw, i.v.) induced transient hypertension (12 ± 4 mmHg from baseline, peak at 10 min; P < 0.05), an increase in RVC (127 ± 9% and 150 ± 13% from baseline, at 20 and 60 min respectively; P < 0.05) and a decrease in RSNA (-34 ± 10% and -29 ± 5% from baseline, at 10 and 60 min respectively; P < 0.05). In sinoaortic-denervated rats, HS infusion promoted a sustained pressor response (30 ± 5 and 17 ± 6 mmHg of baseline values, at 10 and 30 min respectively; P < 0.05) and abolished the increase in RVC (85 ± 8% from baseline, at 10 min) and decrease in RSNA (-4 ± 3% from baseline, at 10 min). These results suggest that aortic and carotid afferents are involved in cardiovascular and renal sympathoinhibition responses induced by acute hypernatremia.

Does the sympathetic nervous system contribute to the pathophysiology of metabolic syndrome?

The metabolic syndrome (MS), formally known as syndrome X, is a clustering of several risk factors such as obesity, hypertension, insulin resistance, and dislypidemia which could lead to the development of diabetes and cardiovascular diseases (CVD). The frequent changes in the definition and diagnostic criteria of MS are indications of the controversy and the challenges surrounding the understanding of this syndrome among researchers. Obesity and insulin resistance are leading risk factors of MS. Moreover, obesity and hypertension are closely associated to the increase and aggravation of oxidative stress. The recommended treatment of MS frequently involves change of lifestyles to prevent weight gain. MS is not only an important screening tool for the identification of individuals at high risk of CVD and diabetes but also an indicator of suitable treatment. As sympathetic disturbances and oxidative stress are often associated with obesity and hypertension, the present review summarizes the role of sympathetic nervous system and oxidative stress in the MS.