Sympathetic Vasomotor Activity Research Articles

On the Regulation of Arterial Blood Pressure by an Intracranial Baroreceptor

Introduction: There is significant evidence for the existence of an intracranial baroreceptor mechanism(s) capable of sensing physiological changes in cerebral blood flow (Marina et al., 2020). However, little is known about the sensitivity of this mechanism to changes in brain perfusion and its interaction with inputs from the peripheral (arterial) baroreceptors. The aim of this study was to characterise the cardiovascular responses to physiological changes in cerebral perfusion induced by experimental manipulations of intracranial pressure (ICP). Methods: The experiments were performed in adult Sprague-Dawley rats (250–300 g), anesthetized with urethane (induction: 1.3 g kg−1, i.p.; maintenance: 10–25 mg kg−1 h−1, i.v.). The femoral artery and vein were cannulated for measurement of arterial blood pressure (ABP) and administration of anaesthetic. The trachea was cannulated, and the animal was mechanically ventilated. The lateral cerebral ventricles were cannulated and connected via saline-filled catheters to a pressure transducer to record ICP and to a “water column” to allow controlled manipulation of ICP. The experiments included the denervation of the arterial baroceptors, stimulation of the aortic depressor nerve and recording of renal sympathetic nerve activity. Results: The resting ICP in rats anesthetized with urethane was 6.2 ± 0.7 mmHg (n=8). Following a small craniotomy that reduced ICP to 0 mmHg, ABP decreased by 11.2 mmHg (n=6) within 30 min. Restoring the integrity of the intracranial space increased ABP to the baseline level. Progressive increases in ABP were observed in response to experimentally-induced increases in ICP by 5, 10, 15 and 20 mmHg, revealing a linear relationship between ICP and systemic arterial pressure within the physiological range of ICP changes. In the absence of inputs from the arterial baroceptors (bilateral sino-aortic denervation and vagotomy) the ABP responses to ICP increases were preserved. Analysis of the ABP and heart rate responses to the electrical stimulation of the aortic depressor nerve suggested baroreflex re-setting at raised ICP. Renal nerve recordings demonstrated increased sympathetic activity at raised ICP (172 ± 34.91 % at 20 mmHg ICP (p=0.003; n=7) with markedly enhanced bursts of activity during the inspiratory phase of the respiratory cycle. Conclusion: These data demonstrate that the intracranial baroceptor mechanism is highly sensitive to changes in cerebral perfusion within the physiological range and suggest that cerebral blood flow is an important determinant of systemic ABP. The data suggest that at raised ICP the baroreflex control of sympathetic vasomotor activity is reset and provides effective control of arterial blood pressure at a higher level required to compensate for reduced brain perfusion. Marina, N., Christie, I.N., Korsak, A., Doronin, M., Brazhe, A., Hosford, P.S., Wells, J.A., Sheikhbahaei, S., Humoud, I., Paton, J.F. and Lythgoe, M.F., 2020. Astrocytes monitor cerebral perfusion and control systemic circulation to maintain brain blood flow. Nature Communications, 11(1), 131. This PhD Studentship is funded by the British Heart Foundation. 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.

Brain α2δ-1-Bound NMDA Receptors Drive Calcineurin Inhibitor-Induced Hypertension.

Calcineurin is highly enriched in immune T cells and the nervous system. Calcineurin inhibitors, including cyclosporine and tacrolimus (FK506), are the cornerstone of immunosuppressive regimens for preserving transplanted organs and tissues. However, these drugs often cause persistent hypertension owing to excess sympathetic outflow, which is maintained by N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory input to the hypothalamic paraventricular nucleus (PVN). It is unclear how calcineurin inhibitors increase NMDAR activity in the PVN to augment sympathetic vasomotor activity. α2δ-1 (encoded by the Cacna2d1 gene), known colloquially as a calcium channel subunit, is a newly discovered NMDAR-interacting protein. In this study, we determined whether α2δ-1 plays a role in calcineurin inhibitor-induced synaptic NMDAR hyperactivity in the PVN and hypertension development. Immunoblotting and coimmunoprecipitation assays were used to quantify synaptic protein levels and the physical interaction between GluN1 (the obligatory NMDAR subunit) and α2δ-1. Whole-cell patch-clamp recordings of retrogradely labeled, spinally projecting PVN were conducted in perfused brain slices to measure presynaptic and postsynaptic NMDAR activity. Radio-telemetry was implanted in rodents to continuously record arterial blood pressure in conscious states. Prolonged treatment with FK506 in rats significantly increased protein levels of α2δ-1, GluN1, and the α2δ-1-GluN1 complex in PVN synaptosomes. These effects were blocked by inhibiting α2δ-1 with gabapentin or interrupting the α2δ-1-NMDAR interaction with an α2δ-1 C-terminus peptide. Treatment with FK506 potentiated the activity of presynaptic and postsynaptic NMDARs in spinally projecting PVN neurons; such effects were abolished by gabapentin, Cacna2d1 knockout, or α2δ-1 C-terminus peptide. Furthermore, microinjection of α2δ-1 C-terminus peptide into the PVN diminished renal sympathetic nerve discharges and arterial blood pressure that had been increased by FK506 treatment. Remarkably, concurrent administration of gabapentin prevented the development of FK506-induced hypertension in rats. Additionally, FK506 treatment induced sustained hypertension in wild-type mice but not in Cacna2d1 knockout mice. α2δ-1 is essential for calcineurin inhibitor-induced increases in synaptic NMDAR activity in PVN presympathetic neurons and sympathetic outflow. Thus, α2δ-1 and α2δ-1-bound NMDARs represent new targets for treating calcineurin inhibitor-induced hypertension. Gabapentinoids (gabapentin and pregabalin) could be repurposed for treating calcineurin inhibitor-induced neurogenic hypertension.

Frequency-coded patterns of sympathetic vasomotor activity are differentially evoked by the paraventricular nucleus of the hypothalamus in the Goldblatt hypertension model.

The paraventricular nucleus of the hypothalamus (PVN) contains premotor neurons involved in the control of sympathetic vasomotor activity. It is known that the stimulation of specific areas of the PVN can lead to distinct response patterns at different target territories. The underlying mechanisms, however, are still unclear. Recent evidence from sympathetic nerve recording suggests that relevant information is coded in the power distribution of the signal along the frequency range. In the present study, we addressed the hypothesis that the PVN is capable of organizing specific spectral patterns of sympathetic vasomotor activation to distinct territories in both normal and hypertensive animals. To test it, we investigated the territorially differential changes in the frequency parameters of the renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively), before and after disinhibition of the PVN by bicuculline microinjection. Subjects were control and Goldblatt rats, a sympathetic overactivity-characterized model of neurogenic hypertension (2K1C). Additionally, considering the importance of angiotensin II type 1 receptors (AT1) in the sympathetic responses triggered by bicuculline in the PVN, we also investigated the impact of angiotensin AT1 receptors blockade in the spectral features of the rSNA and sSNA activity. The results revealed that each nerve activity (renal and splanchnic) presents its own electrophysiological pattern of frequency-coded rhythm in each group (control, 2K1C, and 2K1C treated with AT1 antagonist losartan) in basal condition and after bicuculline microinjection, but with no significant differences regarding total power comparison among groups. Additionally, the losartan 2K1C treated group showed no decrease in the hypertensive response triggered by bicuculline when compared to the non-treated 2K1C group. However, their spectral patterns of sympathetic nerve activity were different from the other two groups (control and 2K1C), suggesting that the blockade of AT1 receptors does not totally recover the basal levels of neither the autonomic responses nor the electrophysiological patterns in Goldblatt rats, but act on their spectral frequency distribution. The results suggest that the differential responses evoked by the PVN were preferentially coded in frequency, but not in the global power of the vasomotor sympathetic responses, indicating that the PVN is able to independently control the frequency and the power of sympathetic discharges to different territories.

Blood-brain barrier lesion - a novel determinant of autonomic imbalance in heart failure and the effects of exercise training.

Heart failure (HF) is characterized by reduced ventricular function, compensatory activation of neurohormonal mechanisms and marked autonomic imbalance. Exercise training (T) is effective to reduce neurohormonal activation but the mechanism underlying the autonomic dysfunction remains elusive. Knowing that blood-brain barrier (BBB) lesion contributes to autonomic imbalance, we sought now to investigate its involvement in HF- and exercise-induced changes of autonomic control. Wistar rats submitted to coronary artery ligation or SHAM surgery were assigned to T or sedentary (S) protocol for 8 weeks. After hemodynamic/autonomic recordings and evaluation of BBB permeability, brains were harvesting for ultrastructural analysis of BBB constituents, measurement of vesicles trafficking and tight junction's (TJ) tightness across the BBB (transmission electron microscopy) and caveolin-1 and claudin-5 immunofluorescence within autonomic brain areas. HF-S rats vs. SHAM-S exhibited reduced blood pressure, augmented vasomotor sympathetic activity, increased pressure and reduced heart rate variability, and, depressed reflex sensitivity. HF-S also presented increased caveolin-1 expression, augmented vesicle trafficking and a weak TJ (reduced TJ extension/capillary border), which determined increased BBB permeability. In contrast, exercise restored BBB permeability, reduced caveolin-1 content, normalized vesicles counting/capillary, augmented claudin-5 expression, increased TJ tightness and selectivity simultaneously with the normalization of both blood pressure and autonomic balance. Data indicate that BBB dysfunction within autonomic nuclei (increased transcytosis and weak TJ allowing entrance of plasma constituents into the brain parenchyma) underlies the autonomic imbalance in HF. Data also disclose that exercise training corrects both transcytosis and paracellular transport and improves autonomic control even in the persistence of cardiac dysfunction.

Hypertension depresses but exercise training restores both Mfsd2a expression and blood-brain barrier function within PVN capillaries.

Hypertension augments while exercise training corrects the increased vesicle trafficking (transcytosis) across the blood-brain barrier (BBB) within preautonomic areas and the autonomic imbalance. There is no information on a possible mechanism(s) conditioning these effects. Knowing that Mfsd2a is the major transporter of docosahexaenoic acid (DHA) and that Mfsd2a knockout mice exhibited leaky BBB, we sought to identify its possible involvement in hypertension- and exercise-induced transcytosis across the BBB. Spontaneously hypertensive rats (SHR) and Wistar rats were submitted to treadmill training (T) or kept sedentary (S) for 4 wk. Resting hemodynamic/autonomic parameters were recorded in conscious chronically cannulated rats. BBB permeability within the hypothalamic paraventricular nucleus (PVN) was evaluated in anesthetized rats. Brains were harvested for Mfsd2a and caveolin-1 (an essential protein for vesicle formation) expression. SHR-S versus Wistar-S exhibited elevated arterial pressure (AP) and heart rate (HR), increased vasomotor sympathetic activity, reduced cardiac parasympathetic activity, greater pressure variability, reduced HR variability, and depressed baroreflex control. SHR-S also showed increased BBB permeability, reduced Mfsd2a, and increased caveolin-1 expression. SHR-T versus SHR-S exhibited increased Mfsd2a density, reduced caveolin-1 protein expression, and normalized PVN BBB permeability, which were accompanied by resting bradycardia, partial AP drop, reduced sympathetic and normalized cardiac parasympathetic activity, increased HR variability, and reduced pressure variability. No changes were observed in Wistar-T versus Wistar-S. Training is an efficient tool to rescue Mfsd2a expression, which by transporting DHA into the endothelial cell reduces caveolin-1 availability and vesicles' formation. Exercise-induced Mfsd2a normalization is an important mechanism to correct both BBB function and autonomic control in hypertensive subjects.

Trained hypertensive rats exhibit decreased transcellular vesicle trafficking, increased tight junctions' density, restored blood-brain barrier permeability and normalized autonomic control of the circulation.

Introduction: Chronic hypertension is accompanied by either blood-brain barrier (BBB) leakage and autonomic dysfunction. There is no consensus on the mechanism determining increased BBB permeability within autonomic areas. While some reports suggested tight junction's breakdown, others indicated the involvement of transcytosis rather than paracellular transport changes. Interestingly, exercise training was able to restore both BBB permeability and autonomic control of the circulation. We sought now to clarify the mechanism(s) governing hypertension- and exercise-induced BBB permeability. Methods: Spontaneously hypertensive rats (SHR) and normotensive controls submitted to 4-week aerobic training (T) or sedentary protocol (S) were chronically cannulated for baseline hemodynamic and autonomic recordings and evaluation of BBB permeability. Brains were harvested for measurement of BBB function (FITC-10kDa leakage), ultrastructural analysis of BBB constituents (transmission electron microscopy) and caveolin-1 expression (immunofluorescence). Results: In SHR-S the increased pressure, augmented sympathetic vasomotor activity, higher sympathetic and lower parasympathetic modulation of the heart and the reduced baroreflex sensitivity were accompanied by robust FITC-10kDa leakage, large increase in transcytotic vesicles number/capillary, but no change in tight junctions' density within the paraventricular nucleus of the hypothalamus, the nucleus of the solitary tract and the rostral ventrolateral medulla. SHR-T exhibited restored BBB permeability and normalized vesicles counting/capillary simultaneously with a normal autonomic modulation of heart and vessels, resting bradycardia and partial pressure reduction. Caveolin-1 expression ratified the counting of transcellular, not other cytoplasmatic vesicles. Additionally, T caused in both groups significant increases in tight junctions' extension/capillary border. Discussion: Data indicate that transcytosis, not the paracellular transport, is the primary mechanism underlying both hypertension- and exercise-induced BBB permeability changes within autonomic areas. The reduced BBB permeability contributes to normalize the autonomic control of the circulation, which suppresses pressure variability and reduces the occurrence of end-organ damage in the trained SHR. Data also disclose that hypertension does not change but exercise training strengthens the resistance of the paracellular pathway in both strains.

Evaluation of Sympathetic Vasomotor Activity of the Brachial Arteries Using Doppler Ultrasound.

BACKGROUND The sympathetic nervous system is principally accountable for peripheral artery regulation, and its effect is that vasospasm occurs in the medium and large arteries of the extremities, resulting in decreased flow of blood. Because of this information of how the body works, our goal is to create a noninvasive and repeatable self-test model that uses Doppler ultrasound examination. MATERIAL AND METHODS The study was conducted on 31 healthy and active participants who volunteered for the study. Written informed consent was obtained from all participants. The baseline diameter and flow rates of the brachial artery from 2 cm superior to the antecubital fossa were determined using a Doppler probe, which remained stationary throughout the experiment, allowing for continuous measurements. Then, to activate the sympathetic fibers, an electrical stimulus was applied for 5 s with an intensity of 10 mA and frequency of 1 Hz at the level of the median nerve at the wrist via the bipolar stimulation electrode. Immediately following the sixth stimulation, the artery diameter and flow rates were assessed again. RESULTS Following the stimulation, a statistically significant decrease in flow rate was observed (P<0.001). Moreover, stimulation resulted in a statistically significant reduction in the diameter of the brachial artery (P<0.001). CONCLUSIONS Our research suggests that Doppler ultrasonography can be routinely used to detect the normal and abnormal functioning of the peripheral sympathetic nervous system.

Disparate Roles of Oxidative Stress in Rostral Ventrolateral Medulla in Age-Dependent Susceptibility to Hypertension Induced by Systemic l-NAME Treatment in Rats.

This study aims to investigate whether tissue oxidative stress in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons reside, plays an active role in age-dependent susceptibility to hypertension in response to nitric oxide (NO) deficiency induced by systemic l-NAME treatment, and to decipher the underlying molecular mechanisms. Systolic blood pressure (SBP) and heart rate (HR) in conscious rats were recorded, along with measurements of plasma and RVLM level of NO and reactive oxygen species (ROS), and expression of mRNA and protein involved in ROS production and clearance, in both young and adult rats subjected to intraperitoneal (i.p.) infusion of l-NAME. Pharmacological treatments were administered by oral gavage or intracisternal infusion. Gene silencing of target mRNA was made by bilateral microinjection into RVLM of lentivirus that encodes a short hairpin RNA (shRNA) to knock down gene expression of NADPH oxidase activator 1 (Noxa1). We found that i.p. infusion of l-NAME resulted in increases in SBP, sympathetic neurogenic vasomotor activity, and plasma norepinephrine levels in an age-dependent manner. Systemic l-NAME also evoked oxidative stress in RVLM of adult, but not young rats, accompanied by augmented enzyme activity of NADPH oxidase and reduced mitochondrial electron transport enzyme activities. Treatment with L-arginine via oral gavage or infusion into the cistern magna (i.c.), but not i.c. tempol or mitoQ10, significantly offset the l-NAME-induced hypertension in young rats. On the other hand, all treatments appreciably reduced l-NAME-induced hypertension in adult rats. The mRNA microarray analysis revealed that four genes involved in ROS production and clearance were differentially expressed in RVLM in an age-related manner. Of them, Noxa1, and GPx2 were upregulated and Duox2 and Ucp3 were downregulated. Systemic l-NAME treatment caused greater upregulation of Noxa1, but not Ucp3, mRNA expression in RVLM of adult rats. Gene silencing of Noxa1 in RVLM effectively alleviated oxidative stress and protected adult rats against l-NAME-induced hypertension. These data together suggest that hypertension induced by systemic l-NAME treatment in young rats is mediated primarily by NO deficiency that occurs both in vascular smooth muscle cells and RVLM. On the other hand, enhanced augmentation of oxidative stress in RVLM may contribute to the heightened susceptibility of adult rats to hypertension induced by systemic l-NAME treatment.

Differential effects of estrogen receptors in the rostral ventrolateral medulla in Goldblatt hypertension

Previous studies have shown that 17β-estradiol plays a cardioprotective role in the central nervous system (CNS) of male rats. The aim of the present study was to determine the influence of 17β-estradiol on sympathetic vasomotor activity and blood pressure in a renovascular hypertensive Goldblatt two-kidney one-clip (2K-1C) male rat model. We also determined the influence of angiotensin II AT1 receptor on the expression of estrogen receptors (ERα, ERβ, and G protein-coupled ER (GPER)) in the rostral ventrolateral medulla (RVLM) of Goldblatt rats. Experiments were performed in Goldblatt and age-matched control rats six weeks after clipping of renal artery to induce hypertension. Microinjection of 17β-estradiol into the RVLM led to a greater reduction in mean arterial pressure and renal sympathetic nerve activity in controls than in 2K-1C rats. Microinjection of the GPER agonist G-1 into the RVLM led to a significantly greater increase in mean arterial pressure and renal sympathetic nerve activity in 2K-1C rats. Expression levels of estrogen receptors GPER and ERα, but not ERβ, were significantly higher in the RVLM of 2K-1C rats than in that of the control rats. Chronic treatment with losartan significantly reduced the expression levels of estrogen receptors in the RVLM of 2K-1C rats. Taken altogether, the data suggest that the imbalance of actions between ERα and GPER, particularly with the predominance of GPER in the RVLM, contributes to sympathetic overactivation in male rats with Goldblatt hypertension. AT1-Angiotensin II receptor in the RVLM upregulated estrogen receptor expression in male Goldblatt rats.

Neonatal stress and loss of ovarian hormones: a novel multidisciplinary approach to understand the coincidence of cardiorespiratory and metabolic disorders in females

IntroductionIn women, the prevalence of sleep apnea (SA) rises 3‐fold at menopause and most patients also present hypertension and obesity. While the “protective effects” of ovarian hormones are well documented, we do not know why the loss of ovarian hormones leads to SA and related cardiovascular and metabolic disorders only in a subpopulation of women. Because neonatal stress is a major cause of adult diseases, we tested the hypothesis that loss of ovarian function reveals the latent effects of stress on cardiorespiratory and metabolic control. To do so, we subjected female rats to neonatal maternal separation (NMS), a translational model of early life stress.MethodologyRat pups subjected to NMS were placed in a temperature‐controlled incubator 3h/day from postnatal day 3 to 12; controls (CTRL) were undisturbed. The effects of loss of ovarian function were tested using a surgical approach (ovariectomy; OVX, animals with 8 weeks old) and aging (40 weeks old). Measurements of ventilation (by whole body plethysmography), blood pressure (by tail cuff plethysmography), and body composition (by nuclear magnetic resonance) were made. We also harvested brains from 8 weeks old females (SHAM versus OVX). Then, we compared the expression of FosB, a transcription factor that indicates neuronal activity. The number of FosB expressing neurons was counted in the paraventricular nucleus of the hypothalamus (PVH), the main structure regulating the hypothalamic pituitary adrenal (HPA) axis.ResultsNMS does not affect the incidence of apneic events in all groups. At 8 weeks, mean arterial pressure (MAP) of NMS females was 5% lower than CTRL. In addition, NMS females had 10% more body mass compared to CTRL. At 40 weeks, the MAP of NMS females was 15% higher than CTRL. In both ages, NMS presented 4% more fat, and 4% less lean tissue. OVX did not affect cardiorespiratory function but augmented the number of neurons expressing FosB in the PVH by 55% in NMS, not in CTRL females.DiscussionThe hypotension observed in young (8 weeks) NMS females was unexpected but is consistent with the fact that hypotension is a common comorbidity of depression. PVH dysfunction contributes to the increase of sympathetic vasomotor activity, characteristic of multiple forms of hypertension. Additionally, the chronic activation of the HPA axis can leads to obesity. The increased expression of FosB in OVX NMS animals indicate that ovarian hormones prevents the stress‐related rise of activity of the HPA axis. At 40 weeks old, the fact that NMS animals were obese and hypertensive indicates that those effects are age dependent. The emergence of dysregulation on the stress neuroaxis is a plausible mechanism to explain those results. Together, these data indicate that neonatal stress may explain why a subpopulation of women are at risk of developing cardiorespiratory and metabolic disturbance at menopause. Ongoing experiments will evaluate the incidence of SA in older animals (60 weeks old) and exploring the underlying mechanisms.

Patterns of renal and splanchnic sympathetic vasomotor activity in an animal model of survival to experimental sepsis.

Sepsis causes long-term disability, such as immune dysfunction, neuropsychological disorders, persistent inflammation, catabolism, and immunosuppression, leading to a high risk of death in survivors, although the contributing factors of mortality are unknown. The purpose of this experimental study in rats was to examine renal (rSNA) and splanchnic (sSNA) sympathetic nerve activity, as well as baroreflex sensitivity, in acute and chronic post-sepsis periods. The rats were divided into two groups: control group with naïve Wistar rats and sepsis group with 2-mL intravenous inoculation of Escherichia coli at 108 CFU/mL. Basal mean arterial pressure, heart rate, rSNA, sSNA, and baroreflex sensitivity were evaluated in all groups at the acute (6 h) and chronic periods (1 and 3 months). Basal rSNA and sSNA were significantly reduced in the surviving rats, as was their baroreflex sensitivity, for both pressor and hypotensive responses, and this effect lasted for up to 3 months. A single episode of sepsis in rats was enough to induce long-term alterations in renal and splanchnic sympathetic vasomotor nerve activity, representing a possible systemic event that needs to be elucidated. These findings showed that post-sepsis impairment of sympathetic vasomotor response may be one of the critical components in the inability of sepsis survivors to respond effectively to new etiological illness factors, thereby increasing their risk of post-sepsis morbidity.

Perfusion of Brain Preautonomic Areas in Hypertension: Compensatory Absence of Capillary Rarefaction and Protective Effects of Exercise Training.

Remodeling of capillary rarefaction and deleterious arteries are characteristic hallmarks of hypertension that are partially corrected by exercise training. In addition, experimental evidence showed capillary rarefaction within the brain cortex and reduced cerebral blood flow. There is no information on hypertension- and exercise-induced effects on capillary profile and function within preautonomic nuclei. We sought now to evaluate the effects of hypertension and exercise training (T) on the capillary network within hypothalamic paraventricular (PVN) and solitary tract (NTS) nuclei, and on the remodeling of brain arteries. Age-matched spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY), submitted to moderate T or kept sedentary (S) for three months, were chronically cannulated for hemodynamic recordings at rest. Rats were anesthetized for i.v. administration of fluorescein isothiocyanate (FITC)-dextran (capillary volume/density measurements) or 4% paraformaldehyde perfusion (basilar, middle, and posterior arteries' morphometry) followed by brain harvesting and processing. Other groups of conscious rats had carotid blood flow (CBF, ultrasound flowmeter) acquired simultaneously with hemodynamic recordings at rest and exercise. SHR-S exhibited elevated pressure and heart rate, reduced CBF, increased wall/lumen ratio of arteries, but no capillary rarefaction within the PVN and NTS. T improved performance gain and caused resting bradycardia in both groups; reduction of pressure and sympathetic vasomotor activity and normalization of the wall/lumen ratio were only observed in SHR-T. T groups responded with marked PVN and NTS capillary angiogenesis and augmented CBF during exercise; to avoid overperfusion at rest, reduced basal CBF was observed only in WKY-T. Data indicated that the absence of SHR-S capillary rarefaction and the intense SHR-T angiogenesis within autonomic areas associated with correction of deleterious arteries' remodeling are essential adjustments to hypertension and exercise training, respectively. These adaptive responses maintain adequate baseline perfusion in SHR-S and SHR-T preautonomic nuclei, augmenting it in exercised rats when a well-coordinated autonomic control is required.

Renal sympathetic activation triggered by the rostral ventrolateral medulla is dependent of spinal cord AT1 receptors in Goldblatt hypertensive rats

Spinal cord neurons contribute to elevated sympathetic vasomotor activity in renovascular hypertension (2K1C), particularly, increased actions of angiotensin II. However, the origin of these spinal angiotensinergic inputs remains unclear. The present study aimed to investigate the role of spinal angiotensin II type 1 receptor (AT1) receptors in the sympathoexcitatory responses evoked by the activation of the rostral ventrolateral medulla (RVLM) in control and 2K1C Goldblatt rats. Hypertension was induced by clipping of the left renal artery. After 6 weeks, a catheter (PE-10) filled with losartan was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anesthetized rats. The effects of glutamate microinjection into the RVLM on blood pressure (BP), heart rate (HR), and renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively) were evaluated in the presence or absence of spinal AT1 blockade. Tachycardic, pressor, and renal sympathoexcitatory effects caused by RVLM activation were significantly blunted by losartan in 2K1C rats, but not in control rats. However, no differences were found in the gene expression of angiotensin-converting enzyme, angiotensinogen, and renin in the spinal cord segments between the groups. In conclusion, acute sympathoexcitation induced by RVLM activation is dependent on the spinal AT1 receptor in Goldblatt, but not in control, rats. The involvement of other central cardiovascular nuclei in spinal angiotensinergic actions, as well as the source of angiotensin II, remains to be determined in the Goldblatt model.

Stimulation of Locus Coeruleus Inhibits the Cardiogenic Sympathetic Afferent Reflex in Rats

Ischemic stimulation of cardiac sensory afferents causes chest pain and an increase in sympathetic vasomotor activity. This sympathetic reflex, which increases blood pressure and heart rate, is referred to as the cardiogenic sympathetic afferent reflex (CSAR). While the CSAR may be important for the maintenance of blood perfusion of vital organs, the increased sympathetic activity may also be detrimental because it further increases the oxygen demand of the ischemic myocardium. While the brain stem nuclei, such as the nucleus tractus solitarius and rostral ventrolateral medulla have been shown to play an important role in the CSAR, the role of other brain stem nuclei and the sources that regulate sympathetic activity in the CSAR are still not clear. We have previously characterized the role of hypothalamic nuclei in the CSAR and have shown that acute chemical inhibition of the paraventricular nucleus but not the dorsomedial hypothalamus attenuates the CSAR. However, little is known regarding other brain stem sites involved in the regulation of sympathetic activity. In this study, we tested the hypothesis that “stimulation of the locus coeruleus (LC) attenuates the CSAR in rats”. Renal sympathetic nerve activity (RSNA), blood pressure, and heart rate were recorded in anesthetized and cervically vagotomized rats during epicardial application of bradykinin (BK 10 μg/ml). Unilateral microinjection of glutamate (2.5 nmol in 50 nl), was used to stimulate the LC. Vehicle injection into the LC had no significant effect (n=10, P > 0.05) on blood pressure, heart rate, or RSNA. In vehicle-injected rats, epicardial BK application significantly increased (P < 0.05) RSNA to 253.5 ± 19.0% of baseline, heart rate from 335.7 ± 14.0 to 351.4 ± 10.5 bpm, and blood pressure from 103.4 ± 3.5 mmHg to 131.4 ± 4.1 mmHg. In a separate group of rats (n=10) glutamate microinjection into the LC significantly (P < 0.05) reduced basal RSNA to 40.2 ± 7.0% of baseline and blood pressure to 60.4 ± 5.0 mmHg, but did not significantly decrease heart rate (329.3 ± 12.5 bpm, P > 0.05). In this group of rats, although epicardial BK application significantly increased (P < 0.05) RSNA to 118.3 ± 19.3% of baseline and blood pressure to 129.5 ± 6.6 mmHg the reflex response to epicardial BK application on RSNA, blood pressure, and heart rate, was significantly attenuated (P < 0.05) compared with the respective controls. These results suggest that the brain stem pathways involving LC inputs to sympathetic vasomotor pathways are important for the regulation of the CSAR.

The dynamic activity of C1 neurons determines the level of blood pressure during hemorrhage in freely behaving rats

Background Adrenergic neurons in the rostral ventrolateral medulla (RVLM), called C1 neurons, regulate vasomotor sympathetic nerve activity (SNA) and blood pressure (BP), and are thought to contribute to BP homeostasis during hemorrhage. In unanesthetized rats, hemorrhage has two sequential phases: 1) compensated, when SNA is markedly elevated and BP is maintained at nearly normal levels and 2) decompensated, when SNA is suppressed, and BP falls dramatically. We hypothesize that dynamic changes in C1 neuron activity determines the level of SNA and BP during hemorrhage. Aim To measure C1 neuron activity during hypotensive hemorrhage in non-anesthetized freely behaving rats. Methods The real-time activity of C1 neurons was monitored using a genetically encoded calcium indicator, jGCaMP7s, with in vivo fiber photometry in non-anesthetized rats. A virus carrying a Cre-dependent GCaMP7 transgene (pGP-AAV1-syn-FLEX-jGCaMP7s-WPRE) was injected in the RVLM of adult female and male Th-Cre rats and an optic fiber was implanted at the site of injection. Four weeks later, rats were instrumented for BP measurements and vascular access for blood withdrawal. The next day, the activity of C1 neurons was measured while the rats were subjected to a controlled hypotensive hemorrhage (18 ml/kg of blood withdrawal over 20 minutes, rate 0.3-0.5 ml/min). Isosbestic-corrected fluorescence (DF/F0) is expressed as a Z-score based on a baseline recording period expressed as mean ± SD. Tests include Student's t-test or repeated measures one-way ANOVA. Differences were considered significant at p<0.05. Results Four weeks after the injection, GCaMP7 was expressed selectively in C1 neurons (76 ± 12 % of GCaMP7-positive neurons expressed tyrosine hydroxylase and PNMT). Transient hypotension induced by intravenous sodium nitroprusside (SNP) activated C1 neurons (from -0.3 ± 0.6 to 11.3 ± 4 A.U., p=0.0002, n=8), whereas elevations in BP induced by intravenous phenylephrine (PE) did not consistently reduce C1 neuron activity (from 0.1 ± 0.3 to -0.9 ± 2.3 A.U., p=0.343, n=7). During hemorrhage, the activity of C1 neurons increases during the compensated phase (when BP is stable despite the blood loss) in relation to the pre-hemorrhage period (from 0.17 ± 0.8 to 5.2 ± 2.1 A.U., p=0.0006, n=8). At the onset of the decompensated phase, the activity of C1 neurons drops dramatically in relation to the compensated phase (from 5.2 ± 2.1 to 2.9 ± 2.8 A.U., p=0.0017, n=8). Conclusions Our results indicate that C1 neurons have low resting activity and are very sensitive to hypotension in quite awake freely behaving rats. And the activation of C1 neurons is critical for BP stability during compensated hemorrhage and their inhibition contributes to the reduction in SNA and hypotension during decompensated hemorrhage.

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.

Renal Sensory Activity Regulates the γ-Aminobutyric Acidergic Inputs to the Paraventricular Nucleus of the Hypothalamus in Goldblatt Hypertension.

Renal sensory activity is centrally integrated within brain nuclei involved in the control of cardiovascular function, suggesting that renal afferents regulate basal and reflex sympathetic vasomotor activity. Evidence has shown that renal deafferentation (DAx) evokes a hypotensive and sympathoinhibitory effect in experimental models of cardiovascular diseases; however, the underlying mechanisms involved in this phenomenon need to be clarified, especially those related to central aspects. We aimed to investigate the role of renal afferents in the control of γ-aminobutyric acid (GABA)ergic inputs to the paraventricular nucleus (PVN) of the hypothalamus in renovascular hypertensive (2K1C) rats and their influence in the regulation of cardiovascular function. Hypertension was induced by clipping the left renal artery. After 4 weeks, renal DAx was performed by exposing the left renal nerve to a 33 mM capsaicin solution for 15 min. After 2 weeks of DAx, microinjection of muscimol into the PVN was performed in order to evaluate the influence of GABAergic activity in the PVN and its contribution to the control of renal sympathetic nerve activity (rSNA) and blood pressure (BP). Muscimol microinjected into the PVN triggered a higher drop in BP and rSNA in the 2K1C rats and renal DAx mitigated these responses. These results suggest that renal afferents are involved in the GABAergic changes found in the PVN of 2K1C rats. Although the functional significance of this phenomenon needs to be clarified, it is reasonable to speculate that GABAergic alterations occur to mitigate microglia activation-induced sympathoexcitation in the PVN of 2K1C rats.

Clinical Practice: Should we Radically Alter our Sedation of Critical Care Patients, Especially Given the COVID-19 Pandemics?

The high number of patients infected with the SARS-CoV-2 virus requiring care for ARDS puts sedation in the critical care unit (CCU) to the edge. Depth of sedation has evolved over the last 40 years (no-sedation, deep sedation, daily emergence, minimal sedation, etc.). Most guidelines now recommend determining the depth of sedation and minimizing the use of benzodiazepines and opioids. The broader use of alpha-2 adrenergic agonists (‘alpha-2 agonists’) led to sedation regimens beginning at admission to the CCU that contrast with hypnotics+opioids (“conventional“ sedation), with major consequences for cognition, ventilation and circulatory performance. The same doses of alpha-2 agonists used for ‘cooperative’ sedation (ataraxia, analgognosia) elicit no respiratory depression but modify the autonomic nervous system (cardiac parasympathetic activation, attenuation of excessive cardiac and vasomotor sympathetic activity). Alpha-2 agonists should be selected only in patients who benefit from their effects (‘personalized’ indications, as opposed to a ‘one size fits all’ approach). Then, titration to effect is required, especially in the setting of systemic hypotension and/or hypovolemia. Since no general guidelines exist for the use of alpha-2 agonists for CCU sedation, our clinical experience is summarized for the benefit of physicians in clinical situations in which a recommendation might never exist (refractory delirium tremens; unstable, hypovolemic, hypotensive patients, etc.). Because the physiology of alpha-2 receptors and the pharmacology of alpha-2 agonists lead to personalized indications, some details are offered. Since interactions between conventional sedatives and alpha-2 agonists have received little attention, these interactions are addressed. Within the existing guidelines for CCU sedation, this article could facilitate the use of alpha-2 agonists as effective and safe sedation while awaiting large, multicentre trials and more evidence-based medicine.

The involvement of renal afferents in the maintenance of cardiorenal diseases.

Elevated sympathetic vasomotor activity is a common feature of cardiorenal diseases. Therefore, the sympathetic nervous system is an important therapeutic target, particularly the fibers innervating the kidneys. In fact, renal denervation has been applied clinically and shown promising results in patients with hypertension and chronic kidney disease. However, the underlying mechanisms involved in the cardiorenal protection induced by renal denervation have not yet been fully clarified. This mini-review highlights historical and recent aspects related to the role of renal sensory fibers in the control of cardiorenal function under normal conditions and in experimental models of cardiovascular disease. Results have demonstrated that alterations in renal sensory function participate in the maintenance of elevated sympathetic vasomotor activity and cardiorenal changes; as such, renal sensory fibers may be a potential therapeutic target for the treatment of cardiorenal diseases. Although it has not yet been applied in clinical practice, selective afferent renal denervation may be promising, since such an approach maintains efferent activity and can provide more refined control of renal function compared with total renal denervation. However, more studies are needed to understand the mechanisms by which renal afferents partially contribute to such changes, in addition to the need to evaluate the safety and advantages of the approach for application in the clinical practice.

Role of spinal neurons in the maintenance of elevated sympathetic activity: a novel therapeutic target?

The control of sympathetic vasomotor activity involves a complex network within the brain and spinal circuits. An extensive range of studies has indicated that sympathoexcitation is a common feature in several cardiovascular diseases and that strategies to reduce sympathetic vasomotor overactivity in such conditions can be beneficial. In the present mini-review, we present evidence supporting the spinal cord as a potential therapeutic target to mitigate sympathetic vasomotor overactivity in cardiovascular diseases, focusing mainly on the actions of spinal angiotensin II on the control of sympathetic preganglionic neuronal activity.