Sympathetic Control Of Blood Pressure Research Articles

Antioxidant-induced modulation of sympathetic transduction to arterial blood pressure in humans

Purpose: Excess plasma free fatty acids (FAA) promote oxidative stress and an increase in peripheral resistance. Therefore, we tested the hypothesis that excess FAA limits sympathetic control of arterial blood pressure (BP) and that sympathetic control would be restored during co-administration of ascorbic acid, which is an antioxidant with vasodilatory properties. Methods: A 20% IV fat emulsion (Intralipid) was administered for 2 hours to 5 lean, healthy adults with and without co-infusion of ascorbic acid (separate visits) in a double-blinded, crossover study design. Sympathetic control of BP was examined by determining the BP response to individual bursts of muscle sympathetic nerve activity (MSNA) (microneurography). Briefly, beat-to-beat mean arterial pressure (MAP) was measured continuously (finger cuff) and signal-averaged over 15 cardiac cycles following each detected burst of MSNA over a 10-min resting period. Results: In contrast to our hypothesis, no change was observed in sympathetic transduction during lipid infusion (1.5 ± 0.4 vs. 1.4 ± 3 mmHg, P=0.75). However, co-infusion of ascorbic acid significantly increased sympathetic transduction compared with baseline (1.5 ± 0.4 vs. 2.0 ± 3 mmHg, P=0.04), in addition to reducing peripheral resistance (0.73 ± 0.11 vs. 0.53 ± 12 mmHg·min·mL−1, P=0.07). MSNA and MAP were not significantly changed during the 2-hr infusions. Conclusions: These preliminary findings suggest that excess FAA do not modulate sympathetic transduction in lean, healthy adults. However, ascorbic acid infusion reduces peripheral resistance and increases sympathetic transduction, demonstrating an inverse relation between peripheral resistance and sympathetic transduction in healthy adults. Funding and support: R01HL159370-01 (S.W.H.). This work was also supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (# UL1TR002366) The contents are solely the responsibility of the authors and do not necessarily represent the offcial views of the NIH or NCATS. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Role of Ovarian Hormones on proBDNF Levels in the Rostral Ventrolateral Medulla: Influences Related to Neuronal Plasticity and Sympathetic Control of Blood Pressure

Introduction: Rates of cardiovascular disease (CVD) are lower in females of reproductive age when compared to age-matched males. However, at the onset of menopause, a period characterized by decreases in ovarian hormones, there is a marked and dramatic rise in the incidence of CVD in females. Therefore, the presence of ovarian hormones may serve a cardioprotective role due to actions on several target organs, including the brain. In the brainstem, the rostral ventrolateral medulla (RVLM) has been implicated in CVD due to its direct impact on blood pressure. The RVLM also contains receptors for both the pro- and mature forms of brain-derived neurotrophic factor (proBDNF and mBDNF), a key neurotrophin which has been linked to ovarian hormones by the existence of an estrogen response element (ERE) on the bdnf gene. While mBDNF positively influences neuroplasticity by increasing connectivity between neurons (i.e., increased dendritic branching). Alternatively, proBDNF can decrease neuronal excitability—and potentially reduce RVLM overactivity—via structural actions which oppose those enacted by mBDNF. Ovarian hormones may modulate neuronal activity in the RVLM via ERE-mediated effects on proBDNF expression, providing a mechanism for the “cardioprotective” effects observed in females of reproductive age. Hypothesis: We hypothesized that the presence of ovarian hormones maintains proBDNF levels in the RVLM, minimizing activation of the RVLM, thus conferring cardioprotection. Methods: Four-week-old female Sprague-Dawley rats received ovariectomy (OVX) or sham surgery (n=5 and n=4, respectively). Rats were sacrificed at 16 weeks of age and the hindbrain was cut into 80μm coronal sections, from which the RVLM was isolated by tissue punches. Using the caudal pole of the facial nucelus as a landmark, punches were pooled into 4 discrete rostrocaudal subregions. Western blotting was performed to determine proBDNF levels in the RVLM relative to the loading control GAPDH. Results: Average proBDNF expression appeared higher in the RVLM of sham versus OVX females at all rostrocaudal levels; however, this difference did not reach statistical significance (p=0.169, main effect), perhaps due to lower sample sizes. There were no significant rostrocaudal variations in proBDNF expression (p=0.598, main effect), nor was there a significant interaction between main effects (p=0.687). Conclusions: These results suggest that the presence of ovarian hormones may maintain proBDNF expression in the RVLM; however, greater sample sizes will likely provide more definitive conclusions. Additionally, future studies could also address potential sex differences by examining the influence of ovarian hormones on expression of mBDNF. We anticipate our studies will illuminate the relationship between ovarian hormones and cardioprotection via the RVLM, thus providing insight into sex differences in CVD. R01-HL161233, APS and WSU Summer Undergraduate Research Fellowships. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Molecular organization of adrenergic and noradrenergic neurons in the mouse ventrolateral medulla

Catecholaminergic neurons in the ventrolateral medulla (VLM) regulate many important aspects of physiology, including the sympathetic control of blood pressure, glucose homeostasis, immune function, and the neuroendocrine responses to inflammation and stress. Previous studies have parsed catecholaminergic VLM neurons into distinct sub-populations based on neurochemical content, connectivity, and distinct response to the activation of autonomic reflexes. However, there is no consensus for the molecular organization of catecholaminergic neurons. In this study, we used high-throughput single nuclei RNA sequencing combined with anatomically- and genetically-targeted cell-sorting of spinally-projecting and catecholaminergic neurons to systematically characterize C1 and A1 neurons in the mouse VLM. Our results, based on an analysis of 894 catecholaminergic neurons derived from a dataset of 114,805 single-nuclei transcriptomes, indicate that the VLM contains 7 molecularly distinct subpopulations of catecholaminergic neurons, including 5 adrenergic subtypes and 2 noradrenergic subtypes identified by the expression of enzymes involved in the production of catecholamine ( Th, Dbh) and the vesicular transporters for glutamate ( Slc6a17) and noradrenaline ( Slc6a2). Neurons with projections to the spinal cord were present in 4 of 5 adrenergic cell clusters, and 1 noradrenergic cell cluster. We histologically verified two novel markers of the adrenergic ( Hk2) and noradrenergic ( Eya1) neurons using RNA fluorescent in situ hybridization. Hk2 expression was found primarily in Dbh+ neurons in the rostral VLM, including both bulbospinal and non-bulbospinal neurons, as well as majority of Pnmt+ neurons in the rostral VLM and C2/C3 regions. Eya1 co-localized with Dbh and Slc6a2 consistently in the caudal VLM, aligning with the location of the A1 neurons, whereas Eya1 signal was diffuse in the rostral VLM. Collectively, this shows that Hk2 expression is enriched in adrenergic neurons as judged by conventional criteria irrespective of the cell's location in the medulla, whereas Eya1 is enriched in brainstem noradrenergic neurons and provides a marker for A1 neurons. These data show molecularly distinct adrenergic and noradrenergic neurons are spatially intermixed in the VLM, and provides novel gene markers for distinct subtypes of catecholaminergic neurons that can be used to dissect the function in future studies. This work was supported by National Institute of Health (NIH) R01 HL148004 to SBGA; and R01 HL153916, Pathway to Stop Diabetes Initiator Award 1-18-INI-14, and UVA 3Cavaliers grant to JNC. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sympathetic Neural Mechanisms in Hypertension: Recent Insights.

To examine published and unpublished data documenting the role of sympathetic neural factors in the pathogenesis of different hypertensive phenotypes. These phenotypes relate to attended or unattended blood pressure measurements, to nighttime blood pressure profile alterations, and to resistant, pseudoresistant, and refractory hypertension. Results of original clinical studies as well as of recent meta-analyses based on the behavior of different sympathetic biomarkers in various hypertensive forms will be also discussed. Studies performed in the past decade have shown that office blood pressure measurements, including in recent years those characterizing unattended or attended blood pressure assessment, are associated with profound changes in the behavior of different sympathetic biomarkers. This is the case for the clinical hypertensive phenotypes characterized by alterations in the nocturnal blood pressure profile and by sleep duration abnormalities. This is also the case for the clinical conditions defined as resistant, refractory, and pseudoresistant hypertension. Data reviewed in the present paper highlight the relevance of sympathetic neural factors in the development and progression of different clinical hypertensive phenotypes. This suggests that a common hallmark of the majority of the essential hypertensive states detectable in current clinical practice is represented by the alteration in the sympathetic blood pressure control.

Endothelial leptin receptor is dispensable for leptin-induced sympatho-activation and hypertension in male mice

Leptin plays a crucial role in blood pressure (BP) regulation, notably in the context of obesity through central sympatho-mediated pressor effects. Leptin also relaxes arteries via endothelial (EC) leptin receptor (LepREC)-mediated increases in nitric oxide (NO) bioavailability. Herein, we investigated whether leptin-mediated increases in NO bioavailability represent a buffering mechanism against leptin-induced sympatho-activation. We tested the direct contribution of LepREC to BP regulation in physiological conditions and in response to chronic leptin infusion using mice deficient in LepREC. LepREC deficiency did not alter baseline metabolic profile nor leptin-induced reduction in adiposity and increases in energy expenditure. LepREC−/− mice demonstrated no increase in baseline BP and heart rate (HR) (MAP: LepREC+/+:94.7 ± 1.6, LepREC−/−:95.1 ± 1.8 mmHg; HR:LepREC+/+:492.4 ± 11.7, LepREC−/−:509.5 ± 13.4 bpm) nor in response to leptin (MAP, LepREC+/+:101.1 ± 1.7, LepREC−/−:101.7 ± 1.8 mmHg; HR, LepREC+/+:535.6 ± 11.1, LepREC−/−:539.3 ± 14.2 bpm). Moreover, baseline neurogenic control of BP and HR was preserved in LepREC−/− mice as well as leptin-mediated increases in sympathetic control of BP and HR and decreases in vagal tone. Remarkably, LepREC deficiency did not alter endothelium-dependent relaxation in resistance vessels, nor NO contribution to vasodilatation. Lastly, leptin induced similar increases in adrenergic contractility in mesenteric arteries from both LepREC+/+ and LepREC−/− mice. Collectively, these results demonstrate that the NO buffering effects of leptin are absent in resistance arteries and do not contribute to BP regulation. We provide further evidence that leptin-mediated hypertension involves increased vascular sympatho-activation and extend these findings by demonstrating for the first time that increased cardiac sympatho-activation and reduced vagal tone also contribute to leptin-mediated hypertension.

A sympathetic view of blood pressure control at high altitude: new insights from microneurographic studies

New Findings What is the topic of the review? Sympathoexcitation and sympathetic control of blood pressure at high altitude. What advances does it highlight? Sustained sympathoexcitation is fundamental to integrative control of blood pressure in humans exposed to chronic hypoxia. The largest gaps in current knowledge are in understanding the complex mechanisms by which central sympathetic outflow is regulated at high altitude. High altitude (HA) hypoxia is a potent activator of the sympathetic nervous system, eliciting increases in sympathetic vasomotor activity. Microneurographic evidence of HA sympathoexcitation dates back to the late 20th century, yet only recently have the characteristics and underpinning mechanisms been explored in detail. This review summarises recent findings and highlights the importance of HA sympathoexcitation for the regulation of blood pressure in lowlanders and indigenous highlanders. In addition, this review identifies gaps in our knowledge and corresponding avenues for future study.

What is the role of ascorbic acid in norepinephrine synthesis and orthostatic hypotension?

Ascorbic acid (ascorbate) participates in critical steps of the biosynthesis of norepinephrine, including those mediated by tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH). For example, DBH is responsible for the conversion of dopamine into norepinephrine in noradrenergic terminals and requires the activity of the ascorbate-coupled cytochrome b561 protein (CYB561). The recent identification of 2 families harboring CYB561 gene mutations manifested with longstanding orthostatic hypotension (OH)1,2 resembling the phenotype of DBH deficiency3,4 emphasizes the important role of ascorbic acid–related processes in sympathetic control of blood pressure.

Identification of the human sympathetic connectome involved in blood pressure regulation

We review our recent data obtained on the cortical and subcortical components of the human sympathetic connectome - the network of regions involved in the sympathetic control of blood pressure. Specifically, we functionally identified the human homologue of the rostral ventrolateral medulla (RVLM), the primary premotor sympathetic nucleus in the medulla responsible for generating sympathetic vasoconstrictor drive. By performing functional magnetic resonance imaging (fMRI) of the brain at the same time as recording muscle sympathetic nerve activity (MSNA), via a microlectrode inserted into the common peroneal nerve, we are able to identify areas of the brain involved in the generation of sympathetic outflow to the muscle vascular bed, a major contributor to blood pressure regulation. Together with functional connectivity analysis of areas identified through MSNA-coupled fMRI, we have established key components of the human sympathetic connectome and their roles in the control of blood pressure. Whilst our studies confirm the role of lower brainstem regions such as the NTS, CVLM and RVLM in baroreflex control of MSNA, our findings indicate that the insula – hypothalamus – PAG – RVLM circuitry is tightly coupled to MSNA at rest. This fits with data obtained from experimental animals, but also emphasizes the role of areas above the brainstem in the regulation of blood pressure.

Hemodynamic Response to Gabapentin in Conscious Spontaneously Hypertensive Rats.

Ligands of auxiliary α2δ subunit of voltage-dependent calcium channels (VDCCs) decrease elevated L-type VDCCs surface expression in arterial myocytes and arterial constriction in spontaneously hypertensive rats (SHR). However, their effect on blood pressure (BP) is unclear. In this study, we investigated the hemodynamic response to acute and chronic administration of gabapentin, a ligand of auxiliary α2δ subunit of VDCCs, in adult SHR with established neurogenic hypertension. The acute gabapentin administration lowered BP and heart rate more in conscious SHR than Wistar-Kyoto rats. Both nifedipine (L-type VDCCs blocker) and ω-conotoxin GVIA (N-type VDCCs blocker) also decreased BP more in SHR, but only gabapentin and ω-conotoxin GVIA abolished the nitroprusside-induced reflex tachycardia of baroreceptor-heart rate control. Hypotensive effect of gabapentin was accompanied by a reduction of (1) plasma norepinephrine level, (2) depressor response to ganglionic blocker pentolinium, (3) power of low frequency component of systolic BP variability, and (4) pressor response of mesenteric vascular bed to periarterial nerve stimulation, suggesting the decrease of peripheral sympathetic nerve transmission. Moreover, gabapentin effects on BP and baroreflex were absent in sympathectomized rats. In conclusion, the acute (but not chronic) administration of gabapentin lowered BP more in SHR than in Wistar-Kyoto rats. Besides the known L-type VDCCs involvement in the vascular effect of gabapentin, our data revealed the important role of N-type VDCCs in acute gabapentin effect on sympathetic control of BP. Gabapentin-induced changes of sympathetic nerve transmission indicated major hemodynamic mechanism of the acute response to this drug.

Plasticity of sympathetic post‐ganglionic neuron after spinal cord injury

Autonomic dysreflexia (AD) is a hypertensive crisis seen in high‐thoracic spinal cord injured (ht‐SCI) patients normally triggered by noxious stimuli below the injury level. Previous animal research on mechanisms underlying AD have mostly focused on neural plasticity within the injured spinal cord. No studies have assessed whether there is also plasticity in the sympathetic post‐ganglionic neurons (SPNs) ‐ the final neural element responsible for vasoconstriction.Thoracic sympathetic post‐ganglionic neurons (tSPNs) are located in paravertebral ganglia and provide the dominant sympathetic control of blood pressure. Their cellular properties are understudied. The few previous ex vivo studies used sharp electrodes that likely leads to significant impalement injury‐induced changes [1, 2]. We undertook whole‐cell patch clamp recordings in an adult mouse tSPN ex vivo preparation. Compared to earlier reports using sharp electrodes, we observed an order of magnitude greater passive membrane properties (cell resistance and membrane time constant) and repetitive rather than phasic firing properties. Together these observations support much greater excitability and integrative actions of tSPNs than previously assumed.Using the same methodology we then studied whether these neurons undergo plastic changes after high‐thoracic (T2) spinal cord transection (ht‐SCI), an animal model of AD. Recordings were obtained from T3‐T9 tSPNs at 3 weeks and 6 weeks post injury. Preliminary data suggest that early after injury (3 weeks), tSPNs are hypo‐active compared to normal animal, including more hyperpolarized resting membrane potential and higher rheobase and threshold voltage. At 6 weeks post‐SCI, tSPN passive membrane properties are similar to control mice. However, several neurons show spontaneously unstable membrane potential (55% of recorded neurons), which is rarely seen in control. Evidences that tSPNs may become more excitable include lower rheobase and threshold voltage values on average and an increased incidence of nifedipine sensitive persistent inward currents (PIC; 69% of recorded neurons after SCI has PIC comparing to 22% in control). Also, tSPNs appear to receive more frequent spontaneous cholinergic synaptic input after SCI.Support or Funding InformationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of fragrance inhalation of essential oil on control of blood pressure and muscle sympathetic nerve activity in humans

AimsWe recently reported that inhalation of fragrance of Grapefruit essential oil increased blood pressure (BP) while that of Marjoram essential oil decreased BP in humans. In this study, we investigated the effects of fragrance inhalation of Grapefruit and Marjoram essential oil on control of BP and muscle sympathetic nerve activity (MSNA), and also cardiovagal and sympathetic baroreflex function.MethodsThirteen healthy subjects participated in each trial of this study. The experiment was performed in the supine position. Subjects breathed blank air through a face mask for 10 min as baseline. Then, they inhaled air with the fragrance of Grapefruit or Marjoram essential oil from Douglas bags for 10 min. Throughout the trial, MSNA (peroneal nerve, microneurography), beat‐by‐beat heart rate and BP, and breath‐by‐breath respiratory variables were recorded continuously.ResultsBy inhalation of the fragrance of Grapefruit essential oil, diastolic BP increased at 8 to 10 min of inhalation (64 ± 9 mmHg) compared to baseline (62 ± 9 mmHg), whereas MSNA burst rate remained unchanged at the period of inhalation (14.2 ± 8.5 bursts/min) from baseline (13.2 ± 7.0 bursts/min). Cardiovagal (10.8 ± 5.6 vs. 11.9 ± 9.6 ms/mmHg) or sympathetic baroreflex sensitivity (−0.84 ± 0.61 vs. −1.03 ± 0.78 au/mmHg) remained unchanged from baseline at the period of inhalation. On the other hand, by inhalation of the fragrance of Marjoram essential oil, diastolic BP increased at 8 to 10 min of inhalation (61 ± 7 mmHg) compared to baseline (60 ± 8 mmHg) against our previous studies, while MSNA burst rate remained unchanged at the period of inhalation (14.0 ± 8.5 bursts/min) from baseline (12.0 ± 9.4 bursts/min). Cardiovagal (12.0 ± 7.3 vs. 14.9 ± 13.1 ms/mmHg) or sympathetic baroreflex sensitivity (−1.06 ± 0.65 vs. −0.97 ± 0.54 au/mmHg) remained unchanged from baseline at the period of inhalation. Heart rate and respiratory variables remained unchanged in both trials.ConclusionsThe fragrance stimulation of Grapefruit essential oil increased BP without increase in MSNA nor modulating cardiovagal and sympathetic control of BP in humans.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The dawn of cardiovascular neuroprosthetics: Epidural spinal cord stimulation acutely restores cardiovascular function in persons with clinically complete spinal cord injury

INTRODUCTIONNeuroprosthetic electrical stimulation of the lumbosacral spinal cord with surgical implants has the capacity to excite dormant neuronal circuitry that has lost supraspinal control due to a spinal cord injury. Very recently, this intervention was even shown to elicit involuntary and voluntary stepping‐like movement of skeletal muscles previously thought to be paralyzed.OBJECTIVEConsidering that autonomic and cardiovascular dysfunctions are the leading cause of death after spinal cord injury, and a higher health priority than walking again by these individuals, we set out to explore if lumbosacral electrical stimulation of the spinal cord could be harnessed to regulate the cardiovascular system after spinal cord injury.METHODSThree of the first individuals with cervical spinal cord injury to be implanted worldwide were assessed in the present study, all of whom presented with cardiovascular dysfunction, in the form of severe orthostatic hypotension as well as impaired cardiac and cerebral regulation. A 16‐electrode array (Fig A) paddle was implanted over the lower lumbar/sacral spinal cord segments and connected to an electrical stimulation unit (both Medtronic). At least one month after implantation, we developed a cardiovascular optimized stimulation paradigm, that excited sympathetic preganglionic neurons but did not elicit skeletal muscle contraction (confirmed with electromyography; Fig A). We measured beat‐by‐beat blood pressure (photoplethysmography), cardiac function (echocardiography), and cerebral blood flow regulation (transcranial Doppler), in the supine position and in response to sit‐up, as well as cognitive function (Stroop test) with and without (in randomized order) cardiovascular optimized stimulation. Statistics on only one to three individuals is not typically recommended and was not performed.RESULTSTargeted cardiovascular electrical stimulation resulted in: [1] abrogated orthostatic hypotension (–39mmHg and severe presyncope vs. −8mmHg and absence of symptoms; Fig A,B); [2] maintained stroke volume (−32ml vs. −8ml; Fig 1E) and cerebral blood flow (−25 cm/s vs. −6cm/s; Fig B) during sit‐up; and [3] restored neurovascular coupling Fig C (+0% vs. 18%); and Stroop performance (P3–P2 time: 42s vs. 21s). Increased low‐frequency power of systolic blood pressure oscillations suggest supraspinal medullary sympathetic control of blood pressure is restored Fig D.CONCLUSIONSNeuroprosthetic modulation of spinal cord circuitry caudal to injury can restore normal autonomic control, which challenges our dogmatic understanding of the inherent functionality of the autonomic pathways in the spinal cord after injury. This data may represent the dawn of a new age for neuroprosthetic management of autonomic and cardiovascular heath.Support or Funding InformationCraig Neilsen Foundation, Rick Hansen Institute, Helmsley Foundation Research Trust.

Unintended Consequences: Renal Denervation Attenuates Hypertension Development but Impairs Glucose Metabolism in Female Fawn‐Hooded Hypertensive Rats

For both men and women, hypertension (HTN) is the highest risk factor for cardiovascular disease and stroke – the two leading causes of morbidity and mortality throughout the world. Though HTN etiology remains debated, altered sympathetic nervous activity, particularly to the kidney (RSNA), is regarded as a primary contributor to the development and maintenance of HTN. Ablation of renal sympathetic nerves (RDNx) reportedly prevents and/or reverses several forms of experimental hypertension. Several off‐target improvements are also reported, such as glucose metabolism. However, an overwhelming majority of these experimental models and mechanisms focus only on responses in male subjects. Moreover, the sex differences in sympathetic control of blood pressure in hypertension remain poorly defined. In this study, we assessed the role of RDNx to prevent hypertension development and metabolic dysfunction in the Fawn‐Hooded Hypertensive (FHH) rat model. We hypothesized that RDNx would attenuate the development of HTN, and improve glucose handling in female and male rats. FHH rats (10 weeks old) underwent sham or bilateral RDNx surgeries (n=5/group). For the following six weeks, 24‐hour mean arterial pressure (MAP) was monitored by radiotelemetry. Glucose handling was assessed biweekly by glucose tolerance test (GTT). Cardiovascular data was averaged weekly, and analyzed by two‐way ANOVA with a Bonferroni post‐hoc test (α=.05). Data presented as mean ± SEM. Six weeks post‐treatment, RDNx attenuated the HTN in the females (p<.05) vs. sham controls (107±5 vs. 118±3). Interestingly, no difference in MAP between RDNx and sham males was observed (129±2 vs. 125±1mmHg). Regarding glucose metabolism, baseline fasting blood glucose (FBG) and glucose tolerance (GT) were similar between males and females prior to RDNx. After six weeks, FBG in female sham FHH (100.9±2.3mg/dL) was higher (p<.05) than male shams (89.2±2.7mg/dL). Likewise, GT was impaired in female rats compared to male shams. In contrast to our hypothesis, RDNx worsened the FBG (110±2.6mg/dL) and GT in female vs. female shams. No effect of time or RDNx on glucose handling was observed males. In summary, RDNx attenuated HTN development in female FHH rats; however, glucose metabolism was impaired by RDNx in females but not in males. These results suggest that sex may need to be considered in the use of RDNx to treat HTN. These findings are clinically important in that RDNx responses may be partially dependent on sex, and may result in negative outcomes such as impaired glucose metabolism in females. Further examination of sex differences in the responses to RDNx is underway.Support or Funding InformationNIH 5R01HL116476; NIH 2T32HL7741

Sympathetic regulation of blood pressure in normotension and hypertension: when sex matters.

What is the topic of this review? Hypertension is a major problem in Western society. Risk of hypertension increases with age, especially in women, who have lower risk compared with men until menopause. This review outlines the sex differences in the sympathetic control of blood pressure and how these mechanisms change with age. What advances does it highlight? It has recently been recognized that men and women regulate blood pressure by different physiological mechanisms. This is important for both the understanding and the clinical management of individual patients with hypertension. This review summarizes recent advances in understanding how the regulation of blood pressure in hypertension by the sympathetic nervous system differs between men and women. The sympathetic nervous system has a central role in the regulation of arterial blood pressure (BP) and in the development of hypertension in humans. Recent evidence points to differences between the sexes in the integrative mechanisms by which BP is controlled, suggesting that the development of hypertension may follow distinct pathways in women compared with men. An important aspect of sympathetic control of BP is its substantial interindividual variability. In healthy young men, the variability in sympathetic nerve activity (SNA) is balanced by variability in cardiac output and vascular adrenergic responses, such that BP remains similar, and normal, across a severalfold range of resting SNA values. In young women, variability in resting SNA is similar to that seen in men, but the 'balancing' mechanisms are strikingly different; women exhibit greater β-adrenergic vasodilatation compared with men, which minimizes the pressor effects of a given level of SNA. Ageing is associated with increased SNA and a loss of the balancing factors seen in younger people, leading to an increased risk of hypertension in older people. Loss of oestrogen with menopause in women appears to be linked mechanistically with the decrease in β-adrenergic vasodilatation and the increased risk of hypertension in older women. Other important factors contributing to hypertension via sympathetic mechanisms are obesity and arterial stiffening, both of which increase with ageing. We conclude with a discussion of important areas in which more work is needed to understand and manage appropriately the sex-specific mechanisms in the development and maintenance of hypertension.

Cardiac phenylethanolamine N-methyltransferase: localization and regulation of gene expression in the spontaneously hypertensive rat.

Phenylethanolamine N-methyltransferase (PNMT) is the terminal enzyme in the catecholamine biosynthetic pathway responsible for adrenaline biosynthesis. Adrenaline is involved in the sympathetic control of blood pressure; it augments cardiac function by increasing stroke volume and cardiac output. Genetic mapping studies have linked the PNMT gene to hypertension. This study examined the expression of cardiac PNMT and changes in its transcriptional regulators in the spontaneously hypertensive (SHR) and wild type Wistar-Kyoto (WKY) rats. SHR exhibit elevated levels of corticosterone, and lower levels of the cytokine IL-1β, revealing systemic differences between SHR and WKY. PNMT mRNA was significantly increased in all chambers of the heart in the SHR, with the greatest increase in the right atrium. Transcriptional regulators of the PNMT promoter show elevated expression of Egr-1, Sp1, AP-2, and GR mRNA in all chambers of the SHR heart, while protein levels of Sp1, Egr-1, and GR were elevated only in the right atrium. Interestingly, only AP-2 protein-DNA binding was increased, suggesting it may be a key regulator of cardiac PNMT in SHR. This study provides the first insights into the molecular mechanisms involved in the dysregulation of cardiac PNMT in a genetic model of hypertension.

Abstract 132: Leptin-mediated Aldosterone Secretion Causes Hypertension in Obese Females

Obesity causes hypertension (HTN) in males and females. While leptin contributes to obesity-induced HTN by increasing sympathetic activity, in males, it is unknown whether similar mechanisms trigger HTN in obese females. Females secrete 3 to 4 times more leptin than males, but do not exhibit high sympathetic tone with obesity. They however show inappropriately high aldosterone levels that positively correlate with adiposity and blood pressure (BP). Here we hypothesized that leptin induces HTN by increasing aldosterone production in obese females. Hypersensitivity to leptin, in lean mice deficient in protein tyrosine phosphatase 1B (PTP1B) or high leptin levels, in obese Agouti (Ay/a) mice induced HTN (WT: 115±2; KO: 124±2; a/a: 113±1; Ay/a: 128±7mmHg, p<0.05) but did not increase sympathetic control of BP (response to ganglionic blockade). Leptin sensitization and obesity however elevated plasma aldosterone levels and adrenal aldosterone synthase (CYP11B2) expression, in females. Chronic leptin (KO+AA: 115±5; Ay/a+AA: 114±5mmHg) or mineralocorticoid (KO+spiro:111±5; Ay/a+spiro: 121±6mmHg) receptors inhibition restored BP to baseline levels in females PTP1B KO and obese agouti mice. Leptin or leptin receptor deficiency in female ob/ob and db/db mice, abolished obesity-induced increases in adrenal CYP11B2 and plasma aldosterone while chronic leptin infusion in female mice triggered a dose-dependent increase in adrenal CYP11B2 and plasma aldosterone levels. Leptin-mediated aldosterone secretion was independent of changes in plasma angiotensin II, potassium and corticosterone (index of ACTH levels) and preserved in the presence of losartan or α and β-adrenergic receptors antagonists. Stimulation of human adrenocortical cells with leptin dose-dependently increased CYP11B2 expression and aldosterone production. While investigating the interaction between percentage of body fat, leptin and aldosterone levels in young healthy adult Caucasians we reported a positive correlation between adiposity and aldosterone, and between leptin and aldosterone in adult women only. Together these data suggest that leptin directly regulates aldosterone secretion and that leptin induces HTN via aldosterone dependent mechanisms in obese females.

The circulating level of leptin and blood pressure in patients with multiple system atrophy

Patients with multiple system atrophy (MSA) frequently exhibit orthostatic hypotension (OH). Leptin, an adipose-derived hormone, contributes to the sympathetic control of blood pressure (BP), and loss of leptin may cause OH. We aimed to clarify the relationship between leptin and OH in MSA. Serum leptin levels were measured in 36 patients with MSA, 25 patients with other atypical parkinsonian disorders (APDs), including progressive supranuclear palsy-Richardson syndrome and corticobasal syndrome, and 26 control subjects. Blood samples were obtained after fasting for 12h. In MSA patients, baseline BP was measured in the recumbent position after a 3-min rest, and orthostatic changes in BP were evaluated after 0–3min of standing. Serum leptin levels did not differ significantly between MSA patients (5.9±0.8ng/ml), other APD patients (5.2±0.8ng/ml), and controls (6.1±1.3ng/ml; P=0.8). In MSA patients, serum leptin levels correlated significantly with body mass index (P=0.01), but not baseline BPs (systolic BP, P=0.20; diastolic BP, P=0.44) or orthostatic drop in BP (systolic BP, P=0.13; diastolic BP, P=0.58). Our observations indicated that the circulating level of leptin was preserved, and OH occurred independent of the leptin level in MSA patients.

Leptin into the rostral ventral lateral medulla (RVLM) augments renal sympathetic nerve activity and blood pressure.

Leptin is a hormone released from adipose tissue. While this hormone normally acts to reduce feeding behavior and increase energy expenditure, in obesity, resistance to these effects occurs even though the hormone is released in large amounts. Although leptin no longer works to suppress feeding in the obese, leptin retains its potent effects on other autonomic functions such as blood pressure regulation. Leptin has been associated with hypertension and increased sympathetic autonomic activity. Therefore, leptin is emerging as a major contributor to the hypertensive state observed in obesity. Sympathetic control of blood pressure is maintained principally by autonomic reflex control circuits in the caudal brainstem. The rostral ventral-lateral medulla (RVLM) is the primary regulator of the sympathetic nervous system, sending excitatory fibers to sympathetic preganglionic neurons to regulate sympathetic control over resistance vessels and blood pressure. Previous studies from our laboratory have shown that neurons in the ventral lateral medulla express leptin receptors (ObRb). Our present study using pseudo-rabies multi-synaptic retrograde tract tracing and immunohistochemical methods revealed that neurons within the RVLM that send sympathetic projections to the kidney express leptin receptors. Acute microinjection of leptin (1 and 3 μg; 40 nL) into the RVLM evoked a significant increase in Mean Arterial Pressure (MAP) and renal sympathetic nerve activity (RSNA). When the 3 μg dose of leptin was preceded with a leptin antagonist, (SLAN-4; 1 ng), it attenuated the cardiovascular response of leptin. Taken together, these data suggest that leptin's actions within the RVLM may influence blood pressure and renal sympathetic nerve activity.

Chronic intermittent hypoxia increases sympathetic control of blood pressure: role of neuronal activity in the hypothalamic paraventricular nucleus

Like humans with sleep apnea, rats exposed to chronic intermittent hypoxia (CIH) experience arterial hypoxemias and develop hypertension characterized by exaggerated sympathetic nerve activity (SNA). To gain insights into the poorly understood mechanisms that initiate sleep apnea/CIH-associated hypertension, experiments were performed in rats exposed to CIH for only 7 days. Compared with sham-treated normoxic control rats, CIH-exposed rats (n = 8 rats/group) had significantly increased hematocrit (P < 0.001) and mean arterial pressure (MAP; P < 0.05). Blockade of ganglionic transmission caused a significantly (P < 0.05) greater reduction of MAP in rats exposed to CIH than control rats (n = 8 rats/group), indicating a greater contribution of SNA in the support of MAP even at this early stage of CIH hypertension. Chemical inhibition of neuronal discharge in the hypothalamic paraventricular nucleus (PVN) (100 pmol muscimol) had no effect on renal SNA but reduced lumbar SNA (P < 0.005) and MAP (P < 0.05) more in CIH-exposed rats (n = 8) than control rats (n = 7), indicating that CIH increased the contribution of PVN neuronal activity in the support of lumbar SNA and MAP. Because CIH activates brain regions controlling body fluid homeostasis, the effects of internal carotid artery injection of hypertonic saline were tested and determined to increase lumbar SNA more (P < 0.05) in CIH-exposed rats than in control rats (n = 9 rats/group). We conclude that neurogenic mechanisms are activated early in the development of CIH hypertension such that elevated MAP relies on increased sympathetic tonus and ongoing PVN neuronal activity. The increased sensitivity of Na(+)/osmosensitive circuitry in CIH-exposed rats suggests that early neuroadaptive responses among body fluid regulatory neurons could contribute to the initiation of CIH hypertension.

Individual differences in the cardiovascular responses to tonic muscle pain: parallel increases or decreases in muscle sympathetic nerve activity, blood pressure and heart rate

We recently showed that acute muscle pain, induced by bolus intramuscular injection of hypertonic saline, causes a sustained increase in muscle sympathetic nerve activity (MSNA) and a modest increase in blood pressure and heart rate. However, it is not known whether long-lasting (tonic) pain, which more closely resembles chronic pain, causes a sustained increase in MSNA and blood pressure. We tested this hypothesis by recording MSNA in 12 healthy subjects. Tonic pain was induced for ~60 min by slow intramuscular infusion of hypertonic saline (7%) into the ipsilateral tibialis anterior muscle. Pain was sustained at a tolerable level (5/10 to 6/10 on a visual analog scale). Seven subjects showed progressive increases in mean MSNA amplitude during tonic pain, increasing to 154 ± 17% (SEM) at 45 min and remaining essentially constant for the duration of the infusion. In these subjects, blood pressure and heart rate also increased. Conversely, for the other five subjects MSNA showed a progressive decline, with a peak fall of 67 ± 11% at 40 min; blood pressure and heart rate also fell in these subjects. We conclude that tonic muscle pain has long-lasting effects on the sympathetic control of blood pressure, causing a sustained increase in some subjects yet a sustained decrease in others. This may have implications for individual differences in the cardiovascular consequences of chronic pain.