Modulation Of Sympathetic Nerve Activity Research Articles

Aging in females is associated with changes in respiratory modulation of sympathetic nerve activity and blood pressure.

Sympathetic nerve activity (SNA) is tightly coupled with the respiratory cycle. In healthy human males, respiratory modulation of SNA does not change with age. However, it is unclear how this modulation is affected by age in females. We investigated whether respiratory sympathetic modulation is altered in healthy postmenopausal (PMF) versus premenopausal female (YF), and younger male (YM) adults, and determined its relationship to resting blood pressure. Muscle SNA (MSNA; microneurography), respiration (transducer belt), ECG, and continuous blood pressure were measured in 12 YF, 13 PMF, and 12 YM healthy volunteers. Respiratory modulation of MSNA was quantified during two phases of the respiratory cycle: mid-late expiration and inspiration/postinspiration. All groups showed respiratory modulation of MSNA (P < 0.0005). There was an interaction between the respiratory phase and group for MSNA [bursts/100 heartbeats (HB) (P = 0.004) and bursts/min (P = 0.029)], with smaller reductions in MSNA during inspiration observed in PMF versus the other groups. Respiratory modulation of blood pressure was also reduced in PMF versus YF (6 [2] vs. 12 [9] mmHg, P = 0.008) and YM (13 [13] mmHg, P = 0.001, median [interquartile range]). The magnitude of respiratory sympathetic modulation was related to resting blood pressure in PMF only, such that individuals with less modulation had greater resting blood pressure. The data indicate that aging in postmenopausal females is associated with less inspiratory inhibition of MSNA. This correlated with a higher resting blood pressure in PMF only. Thus, the reduced modulation of MSNA could contribute to the age-related rise in blood pressure that occurs in females.NEW & NOTEWORTHY The current study demonstrates that respiratory modulation of sympathetic nerve activity (SNA) is reduced in healthy postmenopausal (PMF) versus premenopausal females (YF). Furthermore, respiratory sympathetic modulation was negatively related to resting blood pressure in postmenopausal females, such that blood pressure was greater in individual with less modulation. Reduced respiratory sympathetic modulation may have implications for the autonomic control of blood pressure in aging postmenopausal females, by contributing to age-related sympathetic activation and reducing acute, respiratory-linked blood pressure variation.

Clarification of hypertension mechanisms provided by the research of central circulatory regulation.

Sympathoexcitation, under the regulatory control of the brain, plays a pivotal role in the etiology of hypertension. Within the brainstem, significant structures involved in the modulation of sympathetic nerve activity include the rostral ventrolateral medulla (RVLM), caudal ventrolateral medulla (CVLM), nucleus tractus solitarius (NTS), and paraventricular nucleus (paraventricular). The RVLM, in particular, is recognized as the vasomotor center. Over the past five decades, fundamental investigations on central circulatory regulation have underscored the involvement of nitric oxide (NO), oxidative stress, the renin-angiotensin system, and brain inflammation in regulating the sympathetic nervous system. Notably, numerous significant findings have come to light through chronic experiments conducted in conscious subjects employing radio-telemetry systems, gene transfer techniques, and knockout methodologies. Our research has centered on elucidating the role of NO and angiotensin II type 1 (AT1) receptor-induced oxidative stress within the RVLM and NTS in regulating the sympathetic nervous system. Additionally, we have observed that various orally administered AT1 receptor blockers effectively induce sympathoinhibition by reducing oxidative stress via blockade of the AT1 receptor in the RVLM of hypertensive rats. Recent advances have witnessed the development of several clinical interventions targeting brain mechanisms. Nonetheless, Future and further basic and clinical research are needed.

Chapter 10 - Respiratory–cardiovascular interactions

Much of biology is rhythmical and comprises oscillators that can couple. These have optimized energy efficiency and have been preserved during evolution. The respiratory and cardiovascular systems contain numerous oscillators, and importantly, they couple. This coupling is dynamic but essential for an efficient transmission of neural information critical for the precise linking of breathing and oxygen delivery while permitting adaptive responses to changes in state. The respiratory pattern generator and the neural network responsible for sympathetic and cardiovagal (parasympathetic) tone generation interact at many levels ensuring that cardiac output and regional blood flow match oxygen delivery to the lungs and tissues efficiently. The most classic manifestations of these interactions are respiratory sinus arrhythmia and the respiratory modulation of sympathetic nerve activity. These interactions derive from shared somatic and cardiopulmonary afferent inputs, reciprocal interactions between brainstem networks and inputs from supra-pontine regions. Disrupted respiratory-cardiovascular coupling can result in disease, where it may further the pathophysiological sequelae and be a harbinger of poor outcomes. This has been well documented by diminished respiratory sinus arrhythmia and altered respiratory sympathetic coupling in animal models and/or patients with myocardial infarction, heart failure, diabetes mellitus, and neurological disorders as stroke, brain trauma, Parkinson disease, or epilepsy. Future research needs to assess the therapeutic potential for ameliorating respiratory-cardiovascular coupling in disease.

Respiratory sympathetic modulation is augmented in chronic kidney disease

Respiratory modulation of sympathetic nerve activity (respSNA) was studied in a hypertensive rodent model of chronic kidney disease (CKD) using Lewis Polycystic Kidney (LPK) rats and Lewis controls. In adult animals under in vivo anaesthetised conditions (n = 8–10/strain), respiratory modulation of splanchnic and renal nerve activity was compared under control conditions, and during peripheral (hypoxia), and central, chemoreceptor (hypercapnia) challenge. RespSNA was increased in the LPK vs. Lewis (area under curve (AUC) splanchnic and renal: 8.7 ± 1.1 vs. 3.5 ± 0.5 and 10.6 ± 1.1 vs. 7.1 ± 0.2 μV.s, respectively, P < 0.05). Hypoxia and hypercapnia increased respSNA in both strains but the magnitude of the response was greater in LPK, particularly in response to hypoxia. In juvenile animals studied using a working heart brainstem preparation (n = 7–10/strain), increased respSNA was evident in the LPK (thoracic SNA, AUC: 0.86 ± 0.1 vs. 0.42 ± 0.1 μV.s, P < 0.05), and activation of peripheral chemoreceptors (NaCN) again drove a larger increase in respSNA in the LPK with no difference in the response to hypercapnia. Amplified respSNA occurs in CKD and may contribute to the development of hypertension.

Ghrelin Preserves Ischemia-Induced Vasodilation of Male Rat Coronary Vessels Following β-Adrenergic Receptor Blockade.

Acute myocardial infarction (MI) triggers an adverse increase in cardiac sympathetic nerve activity (SNA). Whereas β-adrenergic receptor (β-AR) blockers are routinely used for the management of MI, they may also counter β-AR-mediated vasodilation of coronary vessels. We have reported that ghrelin prevents sympathetic activation following MI. Whether ghrelin modulates coronary vascular tone following MI, either through the modulation of SNA or directly as a vasoactive mediator, has never been addressed. We used synchrotron microangiography to image coronary perfusion and vessel internal diameter (ID) in anesthetized Sprague-Dawley rats, before and then again 30 minutes after induction of an MI (left coronary artery ligation). Rats were injected with either saline or ghrelin (150 µg/kg, subcutaneously), immediately following the MI or sham surgery. Coronary angiograms were also recorded following β-AR blockade (propranolol, 2 mg/kg, intravenously). Finally, wire myography was used to assess the effect of ghrelin on vascular tone in isolated human internal mammary arteries (IMAs). Acute MI enhanced coronary perfusion to nonischemicregions through dilation of small arterioles (ID 50 to 250 µm) and microvessel recruitment, irrespective of ghrelin treatment. In ghrelin-treated rats, β-AR blockade did not alter the ischemia-induced vasodilation, yet in saline-treated rats, β-AR blockade abolished the vasodilation of small arterioles. Finally, ghrelin caused a dose-dependent vasodilation of IMA rings (preconstricted with phenylephrine). In summary, this study highlights ghrelin as a promising adjunct therapy that can be used in combination with routine β-AR blockade treatment for preserving coronary blood flow and cardiac performance in patients who suffer an acute MI.

Possible Breathing Influences on the Control of Arterial Pressure After Sino-aortic Denervation in Rats.

Surgical removal of the baroreceptor afferents [sino-aortic denervation (SAD)] leads to a lack of inhibitory feedback to sympathetic outflow, which in turn is expected to result in a large increase in mean arterial pressure (MAP). However, few days after surgery, the sympathetic nerve activity (SNA) and MAP of SAD rats return to a range similar to that observed in control rats. In this review, we present experimental evidence suggesting that breathing contributes to control of SNA and MAP following SAD.The purpose of this review was to discuss studies exploring SNA and MAP regulation in SAD rats, highlighting the possible role of breathing in the neural mechanisms of this modulation of SNA. Recent studies show that baroreceptor afferent stimulation or removal (SAD) results in changes in the respiratory pattern. Changes in the neural respiratory network and in the respiratory pattern must be considered among mechanisms involved in the modulation of the MAP after SAD.

Targeting sympathetic glia for treating cardiovascular diseases

Gq G protein-coupled receptor (Gq-GPCR) signaling in glial fibrillary acidic protein-expressing (GFAP + ) glia is essential for neuron-glia interaction in the Central Nervous System (CNS). However, the exploration of the roles of Gq-GPCR signaling in peripheral GFAP + glia has just begun. Our recent study showed that GFAP + glia in the sympathetic ganglia, namely satellite glial cells (SGCs), positively modulate sympathetic-regulated cardiac functions following their Gq-GPCR activation. In this research highlight, we discuss the significance of satellite glial modulation of sympathetic nerve activity (SNA) in both physiology and in diseases. We also present a new experimental strategy for manipulating satellite glial signaling in the sympathetic ganglia using adeno-associated virus (AAV). The success of targeted viral transduction in ganglionic SGCs suggest a strong therapeutic potential of targeting sympathetic glia for the treatment of cardiovascular diseases (CVDs).

Vestibular Modulation of Sympathetic Nerve Activity to Muscle and Skin in Humans.

We review the existence of vestibulosympathetic reflexes in humans. While several methods to activate the human vestibular apparatus have been used, galvanic vestibular stimulation (GVS) is a means of selectively modulating vestibular afferent activity via electrodes over the mastoid processes, causing robust vestibular illusions of side-to-side movement. Sinusoidal GVS (sGVS) causes partial entrainment of sympathetic outflow to muscle and skin. Modulation of muscle sympathetic nerve activity (MSNA) from vestibular inputs competes with baroreceptor inputs, with stronger temporal coupling to the vestibular stimulus being observed at frequencies remote from the cardiac frequency; “super entrainment” was observed in some individuals. Low-frequency (<0.2 Hz) sGVS revealed two peaks of modulation per cycle, with bilateral recordings of MSNA or skin sympathetic nerve activity, providing evidence of lateralization of sympathetic outflow during vestibular stimulation. However, it should be noted that GVS influences the firing of afferents from the entire vestibular apparatus, including the semicircular canals. To identify the specific source of vestibular input responsible for the generation of vestibulosympathetic reflexes, we used low-frequency (<0.2 Hz) sinusoidal linear acceleration of seated or supine subjects to, respectively, target the utricular or saccular components of the otoliths. While others had discounted the semicircular canals, we showed that the contributions of the utricle and saccule to the vestibular modulation of MSNA are very similar. Moreover, that modulation of MSNA occurs at accelerations well below levels at which subjects are able to perceive any motion indicates that, like vestibulospinal control of posture, the vestibular system contributes to the control of blood pressure through potent reflexes in humans.

Opposite Arterial Pressure Responses to Renal Afferent Nerve Stimulation in Unanesthetized Versus Anesthetized Rats: Implications for the Neural‐Renal Axis and Hypertension

Neural control of the kidney remains a primary focus of treatment of cardiovascular and renal disease, including hypertension (HTN). Moreover, recent studies support a role of renal afferent nerves in the modulation of sympathetic nerve activity (SNA), and in turn, arterial pressure (AP). We recently reported resting afferent nerve activity (ARNA) is elevated in the DOCA‐salt hypertensive rat, and that targeted afferent renal nerve ablation attenuates this model of hypertension (Banek et al. Hypertension 2016). These findings suggest that increased ARNA contributes to the pathogenesis of HTN. Previous investigations of the responses of AP and SNA to renal afferent nerve stimulation have been conducted in anesthetized animals have reported a sympatho‐inhibitory response. The present study was designed to measure the acute AP response to increased ARNA in anesthetized and unanesthetized preparations. Male Sprague Dawley rats (300–400g) underwent acute renal afferent stimulation while under 2% isoflurane anesthesia (ISO; n=12) or in the absence of anesthesia following a cortical decerebration (DEC; n=12). Animals were instrumented to measure AP, heart rate (HR), and ARNA. To activate renal afferent nerves, a ureteral catheterization was performed to perfuse the renal pelvis with vehicle 0.9% saline [VEH] or with the TRPV1‐agonist 50μM capsaicin (CAP). Following instrumentation and a 30‐minute stabilization period, ARNA and cardiovascular responses to VEH or CAP stimulation were recorded. Peak responses in ARNA, AP, and HR were quantified and compared between ISO vs. DEC preparations by a Student's t‐test (α=.05). ARNA responses were calculated as percent change from baseline (%ARNA). Data presented as mean±SEM. There was no difference in resting ∫ARNA, AP, or HR prior to afferent stimulation between ISO and DEC groups. VEH perfusion of the renal pelvis elicited no response in both ISO and DEC groups. In contrast, CAP administration resulted in marked increase in %ARNA that was similar in magnitude in both groups (ISO 214±31% vs. DEC 239±40%). More importantly, whereas the CAP‐induced increase in ARNA elicited a depressor response in ISO rats (−17±6mmHg), CAP evoked an opposing pressor response in DEC rats (+54±9mmHg). These findings suggest the existence of a renal afferent nerve‐dependent sympatho‐excitatory reflex in the rat, and anesthesia may directly interfere in this signaling pathway. It is important to note it is unknown whether this acute reflex translates to long‐term regulation of SNA and AP. While the anatomical and biological mechanisms of this reflex remain rudimentary, further studies are underway to chronically monitor afferent nerve activity and blood pressure in conscious freely moving rats to elucidate this important neural‐renal axis.Support or Funding InformationNIH 5R01HL116476; NIH 2T32HL7741

Respiratory modulation of sympathetic nerve activity is enhanced in male rat offspring following uteroplacental insufficiency

Sympathetic nerve activity to the cardiovascular system displays prominent respiratory-related modulation which leads to the generation of rhythmic oscillations in blood pressure called Traube–Hering waves. An amplification of this respiratory modulation of sympathetic activity is observed in hypertension of both genetic, the spontaneously hypertensive rat, and induced, chronic intermittent hypoxia or maternal protein restriction during gestation, origin. Male offspring of mothers with uteroplacental insufficiency, induced by bilateral uterine vessel ligation at 18 days of gestation, are also hypertensive in adulthood. In this study we examined whether these male offspring display altered respiratory modulation of sympathetic activity at pre-hypertensive ages compared to controls. Respiratory, cardiovascular and sympathetic parameters were examined using the working heart–brainstem preparation in 35 day old male rats that had reduced birth weight due to uteroplacental insufficiency. Whilst all respiratory parameters were not different between groups, we observed an enhanced respiratory-related burst of thoracic sympathetic nerve activity and amplified Traube–Hering waves in the growth-restricted group. This group also showed an increased sympathetic and bradycardic response to activation of peripheral chemoreceptors. The observations add support to the view that altered respiratory modulation of sympathetic activity represents a common mechanism involved in the development of several forms of hypertension.

Neuronal and Endothelial Nitric Oxide Synthases in the Paraventricular Nucleus Modulate Sympathetic Overdrive in Insulin-Resistant Rats.

A central mechanism participates in sympathetic overdrive during insulin resistance (IR). Nitric oxide synthase (NOS) and nitric oxide (NO) modulate sympathetic nerve activity (SNA) in the paraventricular nucleus (PVN), which influences the autonomic regulation of cardiovascular responses. The aim of this study was to explore whether the NO system in the PVN is involved in the modulation of SNA in fructose-induced IR rats. Control rats received ordinary drinking water, whereas IR rats received 12.5% fructose-containing drinking water for 12 wks to induce IR. Basal SNA was assessed based on the changes in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in response to chemicals administered to the PVN. We found an increased plasma norepinephrine level but significantly reduced NO content and neuronal NOS (nNOS) and endothelial NOS (eNOS) protein expression levels in the PVN of IR rats compared to Control rats. No difference in inducible NOS (iNOS) protein expression was observed between the two groups. In anesthetized rats, the microinjection of sodium nitroprusside (SNP), an NO donor, or Nω-nitro-L-arginine methyl ester (L-NAME), a non-selective inhibitor of NOS, into the PVN significantly decreased and increased basal SNA, respectively, in both normal and IR rats, but these responses to SNP and L-NAME in IR rats were smaller than those in normal rats. The administration of selective inhibitors of nNOS or eNOS, but not iNOS, to the PVN significantly increased basal SNA in both groups, but these responses were also smaller in IR rats. Moreover, IR rats exhibited reduced nNOS and eNOS activity in the PVN. In conclusion, these data indicate that the decreased protein expression and activity levels of nNOS and eNOS in the PVN lead to a reduction in the NO content in the PVN, thereby contributing to a subsequent enhancement in sympathoexcitation during IR.

Interactive effects of hypoxia, hypercapnia and lung volume on sympathetic nerve activity in humans.

What is the central question of this study? The central question of this study was to investigate the interaction of mild exposures to O2 and CO2 on chemoreflex control of SNA and the modulation of lung volume and respiratory phase on this interaction. What is the main finding and its importance? We demonstrate that the synergistic interaction of oxygen- and carbon dioxide-chemosensitive control of the sympathetic nervous system with hypoxia and hypercapnia exists at very mild excitatory stimuli, is significantly overridden by lung inflation and does not extend to inhibitory modulation by hypocapnia in healthy subjects. These findings demonstrate the important inhibitory modulation of sympathetic nerve activity by lung inflation mechanisms in healthy individuals even in the presence of strong sympathoexcitatory stimuli. We hypothesized that simultaneous stimulation of O2 - and CO2 -sensitive chemoreflexes produces synergistic activation of the sympathetic nervous system and that this effect would be most apparent at low lung volume (expiratory) phases of respiration. Each subject (n = 11) breathed 16 gas mixtures in random order: a 4 × 4 matrix of normoxic to hypoxic (8, 12, 16 and 21% O2 ) combined with normocapnic to hypercapnic gases (0, 2, 4 and 6% CO2). Tidal volume, arterial pressure, heart rate and muscle sympathetic nerve activity (MSNA) were measured continuously before and while breathing each gas mixture for 2 min. Changes in MSNA were determined for each gas mixture. The MSNA was subdivided into low and high lung volume and respiratory phases to investigate further modulation by components of normal respiratory phase. Both hypoxia and hypercapnia increased mean MSNA independently. Mean and low lung volume MSNA increased exponentially with increasing levels of combined hypoxia and hypercapnia and resulted in a significant interaction (P < 0.01). In contrast, MSNA during the high lung volume phase of respiration never increased significantly (P > 0.4). Similar but less pronounced effects were found for expiratory and inspiratory phases of respiration. These effects created marked respiratory periodicity in MSNA at higher levels of combined hypoxia and hypercapnia. Finally, the response to hypoxia was not affected by hypocapnia, suggesting that the interaction occurs only during excitatory chemosensitive stimuli. These data indicate that hypoxia and hypercapnia interact to elicit synergistic sympathoexcitation and that withdrawal of sympathoinhibitory effects of lung inflation exaggerates this chemoreflex interaction.

Respiratory modulation of sympathetic activity is attenuated in adult rats conditioned with chronic hypobaric hypoxia

Respiratory modulation of sympathetic nerve activity (SNA) depends on numerous factors including prior experience. In our studies, exposing naïve adult, male Sprague-Dawley rats to acute intermittent hypoxia (AIH) enhanced respiratory-modulation of splanchnic SNA (sSNA); whereas conditioning them to chronic hypobaric hypoxia (CHH) attenuated modulation. Further, AIH can evoke increased SNA in the absence phrenic long-term facilitation. We hypothesized that AIH would restore respiratory modulation of SNA in CHH rats. In anesthetized, CHH-conditioned (0.5 atm, 2 wks) rats (n=16), we recorded phrenic and sSNA before during and after AIH (8% O2 for 45s every 5min for 1h). At baseline, sSNA was not modulated with respiration. The sSNA was not recruited during a single brief exposure of hypoxia nor after 10 repetitive exposures. Further, the sSNA chemoresponse was not restored 1h after completing AIH. Thus, CHH-conditioning blocked the short-term plasticity expressed in sympatho-respiratory efferent activities and this was associated with reduced respiratory modulation of sympathetic activity and with attenuation of the sympatho-respiratory chemoresponse.

Pulmonary vascular tone is dependent on the central modulation of sympathetic nerve activity following chronic intermittent hypoxia.

Chronic intermittent hypoxia (IH) provokes a centrally mediated increase in sympathetic nerve activity (SNA). Although this sympathetic hyperexcitation has been linked to systemic hypertension, its effect on the pulmonary vasculature is unclear. This study aimed to assess IH-mediated sympathetic excitation in modulating pulmonary vasculature tone, particularly acute hypoxia vasoconstrictor response (HPV), and the central β-adrenergic signaling pathway for facilitating the increase in SNA. Sprague-Dawley rats were exposed to IH (cycle of 4% O2 for 90 s/air for 90 s) for 8 h/day for 6 weeks. Subsequently, rats were anesthetized and either pulmonary SNA was recorded (electrophysiology), or the pulmonary vasculature was visualized using microangiography. Pulmonary sympathetic and vascular responses to acute hypoxia were assessed before and after central β1-adrenergic receptor blockade (Metoprolol, 200 nmol i.c.v.). Chronic IH increased baseline SNA (110% increase), and exacerbated the sympathetic response to acute hypoxia. Moreover, the magnitude of HPV in IH rats was blunted compared to control rats (e.g., 10 and 20% vasoconstriction, respectively). In only the IH rats, β1-receptor blockade with metoprolol attenuated the hypoxia-induced increase in pSNA and exacerbated the magnitude of acute HPV, so that both sympathetic and HPV responses were similar to that of control rats. Interestingly, the expression of β1-receptors within the brainstem was similar between both control and IH rats. These results suggest that the centrally mediated increase in SNA following IH acts to blunt the local vasoconstrictor effect of acute hypoxia, which reflects an inherent difference between vasodilator and vasoconstrictor actions of SNA in pulmonary and systemic circulations.

Differentiated Baroreflex Modulation of Sympathetic Nerve Activity During Deep Brain Stimulation in Humans

Targeted electric deep brain stimulation in midbrain nuclei in humans alters cardiovascular parameters, presumably by modulating autonomic and baroreflex function. Baroreflex modulation of sympathetic outflow is crucial for cardiovascular regulation and is hypothesized to occur at 2 distinct brain locations. The aim of this study was to evaluate sympathetic outflow in humans with deep brain stimulating electrodes during ON and OFF stimulation of specific midbrain nuclei known to regulate cardiovascular function. Multiunit muscle sympathetic nerve activity was recorded in 17 patients undergoing deep brain stimulation for treatment of chronic neuropathic pain (n=7) and Parkinson disease (n=10). Sympathetic outflow was recorded during ON and OFF stimulation. Arterial blood pressure, heart rate, and respiratory frequency were monitored during the recording session, and spontaneous vasomotor and cardiac baroreflex sensitivity were assessed. Head-up tilt testing was performed separately in the patients with Parkinson disease postoperatively. Stimulation of the dorsal most part of the subthalamic nucleus and ventrolateral periaqueductal gray resulted in improved vasomotor baroreflex sensitivity, decreased burst frequency and blood pressure, unchanged burst amplitude distribution, and a reduced fall in blood pressure after tilt. Stimulation of the dorsolateral periaqueductal gray resulted in a shift in burst amplitude distribution toward larger amplitudes, decreased spontaneous beat-to-beat blood pressure variability, and unchanged burst frequency, baroreflex sensitivity, and blood pressure. Our results indicate that a differentiated regulation of sympathetic outflow occurs in the subthalamic nucleus and periaqueductal gray. These results may have implications in our understanding of abnormal sympathetic discharge in cardiovascular disease and provide an opportunity for therapeutic targeting.

Respiratory Modulation of Sympathetic Nerve Activity in Patients with Chronic Heart Failure: From Modeling to Clinical Application

Respiratory Modulation of Sympathetic Nerve Activity in Patients with Chronic Heart Failure: From Modeling to Clinical Application

Abstract 439: Role of Hindbrain Endogenous Melanocortin Receptor Activity in Contributing to Hypertension in SHR

We previously demonstrated that activation of the central nervous system (CNS) melanocortin system plays a key role in the modulation of sympathetic nerve activity (SNA) and blood pressure (BP) regulation. In the present study, we examined whether chronic inhibition of melanocortin-4 receptors (MC4R) in the hindbrain attenuates the elevated blood pressure in spontaneously hypertensive rats (SHR). The long-term cardiovascular and metabolic effects of MC4R antagonism were assessed in SHR and normotensive Wistar-Kyoto (WKY) rats. Male WKY rats (n=6) and SHR (n=7) were implanted with telemetry probes to measure BP and heart rate (HR) 24-hrs/day, and an intracerebroventricular (ICV) cannula was placed into the fourth ventricle (4 th V). After 10 days of recovery and 5 days of control measurements, the MC4R antagonist (SHU-9119, 1 nmol/h, 4 th V) was infused for 10 days followed by a 5-day recovery period. Chronic hindbrain MC4R antagonism significantly increased food intake and body weight in WKY (17±1 to 35±2 g/day and 280±8 to 353±8 g) and SHR (19±2 to 35±2 g/day and 323±7 to 371±11 g). No changes were observed in blood glucose levels (99±4 to 87±4 and 89±5 to 89±4 mg/dl, respectively for WKY and SHR). Chronic SHU-9119 infusion reduced MAP and HR similarly in WKY (-5±1 mmHg and -47±3 bpm) and SHR (-8±3 mmHg and -44±3 bpm). These results suggest that although hindbrain MC4R activity is important for appetite and HR regulation, it does not play a major role in mediating the elevated blood pressure in SHR. (NHLBI-PO1 HL51971/AHA SDG5680016)

Abnormal sympathetic nerve activity in women exposed to cigarette smoke: a potential mechanism to explain increased cardiac risk

In women, cardiac deaths attributable to tobacco exposure have reached the same high levels as men. Normally, sympathetic nerve activity (SNA) fluctuates according to the menstrual phase, but in habitual smokers, SNA levels remain constant. Our purpose is to extend these observations to other groups of women exposed to tobacco smoke and to explore potential mechanisms. We hypothesize that women exposed to secondhand smoke, but not former smokers, have nonfluctuating SNA compared with never smokers, and that impaired baroreflex suppression of SNA, and/or heightened central SNA responses, underlie this nonfluctuating SNA. We also hypothesize that female smokers have impaired nocturnal blood pressure dipping, normally mediated by modulation of SNA. In 49 females (19 never, 12 current, 9 former, 9 passive smokers), SNA was recorded (microneurography) during high- and low-hormone ovarian phases at rest, during pharmacological baroreflex testing, and during the cold pressor test (CPT). Twenty-four hour blood pressure (BP) monitoring was performed. Current and passive smokers, but not former smokers, had a nonfluctuating pattern of SNA, unlike never smokers in whom SNA varied with the menstrual phase. Baroreflex control of SNA was significantly blunted in current smokers, independent of menstrual phase. In passive smokers, SNA response to CPT was markedly increased. Nondipping was unexpectedly high in all groups. SNA does not vary during the menstrual cycle in active and passive smokers, unlike never and former smokers. Baroreflex control of SNA is blunted in current smokers, whereas SNA response to CPT is heightened in passive smokers. Smoking cessation is associated with return of the altered SNA pattern to normal.

Cardiorespiratory coupling of sympathetic outflow in humans: a comparison of respiratory and cardiac modulation of sympathetic nerve activity to skin and muscle

What is the central question of this study?Muscle sympathetic nerve activity (MSNA) is well known to be modulated by the arterial baroreceptors and respiration, but what are the magnitudes of cardiac and respiratory modulation of skin sympathetic nerve activity (SSNA), which primarily subserves thermoregulation?What is the main finding and what is its importance?Using direct microelectrode recordings of MSNA and SSNA in awake humans, we show that the magnitude of respiratory modulation of SSNA is identical to that of MSNA, the primary difference between the two sources of sympathetic outflow being the greater cardiac modulation of MSNA. This emphasises the role of the baroreceptors in entraining sympathetic outflow to muscle. It is well known that microelectrode recordings of skin sympathetic nerve activity (SSNA) in awake human subjects reveal spontaneous bursts of activity with no overt modulation by changes in blood pressure or respiration, in contrast to the clear cardiac and respiratory modulation of muscle sympathetic nerve activity (MSNA). However, cross-correlation analysis has revealed that, like individual muscle vasoconstrictor neurones, the firing of individual cutaneous vasoconstrictor neurones is temporally coupled to both the cardiac and respiratory rhythms during cold-induced cutaneous vasoconstriction, and the same is true of single sudomotor neurones during heat-induced sweating. Here, we used cross-correlation analysis to determine whether SSNA exhibits cardiac and respiratory modulation in thermoneutral conditions and to compare respiratory and cardiac modulation of SSNA with that of MSNA. Oligounitary recordings of spontaneous SSNA (n = 20) and MSNA (n = 18) were obtained during quiet, unrestrained breathing. Respiration was recorded by a strain-gauge transducer around the chest and ECG recorded by surface electrodes. Respiratory and cardiac modulation of SSNA and MSNA were quantified by fitting polynomial equations to the cross-correlation histograms constructed between the sympathetic spikes and respiration or ECG. The amplitude of the respiratory modulation (52.5 ± 3.4%) of SSNA was not significantly different from the amplitude of the cardiac modulation (46.6 ± 3.2%). Both were comparable to the respiratory modulation of MSNA (47.7 ± 4.2%), while cardiac modulation of MSNA was significantly higher (89.8 ± 1.5%). We conclude that SSNA and MSNA share similar levels of respiratory modulation, the primary difference between the two sources of sympathetic outflow being the marked cardiac modulation of MSNA provided by the baroreceptors.

Cannabinoid and GABA modulation of sympathetic nerve activity and blood pressure in the dorsal periaqueductal gray of the rat.

Sympathoexcitation and increased blood pressure evoked by central networks integrating defensive behavior are fundamental to the acute stress response. A balance between excitatory glutamatergic and inhibitory GABAergic neurotransmission in the dorsal periaqueductal gray (dPAG) results in a tonic level of activity in the alerting system. Neuromodulators such as endocannabinoids have been shown to influence the sympathoexcitatory and pressor components of acute stress in the dPAG, exemplified by the defense response as a model, but the mechanism of integration remains unknown. The present study examines the role of GABA and its interaction with endocannabinoids in modulating sympathetic nerve activity and blood pressure related to the defense response. Microinjection of the broad-spectrum excitatory amino acid dl-homocysteic acid (DLH) identified sites of the defense pathway in the dPAG from which an increase in renal sympathetic nerve activity and blood pressure could be evoked, and subsequent microinjections were made at the same site through a multibarrelled micropipette. Blockade of GABAA receptors or microinjection of the cannabinoid 1 receptor agonist anandamide elicited a renal sympathoexcitation and pressor response. Prior microinjection of the GABAA receptor antagonist gabazine attenuated the sympathoexcitation and pressor response associated with anandamide microinjection. In contrast, the sympathetic response to DLH was enhanced by GABAA receptor blockade. These data demonstrate that sympathoexcitatory neurons in the dPAG are under tonic inhibition by GABA and that endocannabinoids modulate this GABAergic neurotransmission to help regulate components of the defense response.