Arterial Blood Pressure Responses Research Articles

Real-time closed-loop brainstem stimulation modality for enhancing temporal blood pressure reduction

BackgroundTraditional pharmacological interventions are well tolerated in the management of elevated blood pressure (BP) for individuals with resistant hypertension. Although neuromodulation has been investigated as an alternative solution, its open-loop (OL) modality cannot follow the patient's physiological state. In fact, neuromodulation for controlling highly fluctuating BP necessitates a closed-loop (CL) stimulation modality based on biomarkers to monitor the patient's continuously varying physiological state. ObjectiveBy leveraging its intuitive linkage with BP responses in ongoing efforts aimed at developing a CL system to enhance temporal BP reduction effect, this study proposes a CL neuromodulation modality that controls nucleus tractus solitarius (NTS) activity to effectively reduce BP, thus reflecting continuously varying physiological states. MethodWhile performing neurostimulation targeting the NTS in the rat model, the arterial BP response and neural activity of the NTS were simultaneously measured. To evaluate the temporal BP response effect of CL neurostimulation, OL (constant parameter; 20 Hz, 200 uA) and CL (Initial parameter; 11 Hz, 112 uA) stimulation protocols were performed with stimulation 180 s and rest 600 s, respectively, and examined NTS activity and BP response to the protocols. ResultsIn-vivo experiments for OL versus CL protocol for direct NTS stimulation in rats demonstrated an enhancement in temporal BP reduction via the CL modulation of NTS activity. ConclusionThis study proposes a CL stimulation modality that enhances the effectiveness of BP control using a feedback control algorithm based on neural signals, thereby suggesting a new approach to antihypertensive neuromodulation.

Aging in females has minimal effect on changes in celiac artery blood flow during dynamic light-intensity exercise.

Blood flow to the active muscles and arterial blood pressure (ABP) increase during dynamic exercise, whereas blood flow to inactive organs (e.g., splanchnic organs and inactive limbs) declines. Aging leads to exaggerated ABP responses to exercise in females, but whether this is related to greater splanchnic vasoconstriction is unknown. This study sought to clarify the effect of aging in females on celiac artery blood flow during dynamic light-intensity exercise. Twelve healthy young females (YF: 20 ± 2 yr, mean ± SD) and 12 healthy older females (OF: 71 ± 4 yr) performed dynamic knee-extension and knee-flexion exercises at 30% of heart rate reserve for 4 min. The absolute changes from baseline (Δ) for mean arterial blood pressure (MAP), celiac artery mean blood flow (celMBF), and celiac vascular conductance (celVC) during exercise were calculated. ABP was measured using an automated sphygmomanometer, and celMBF was recorded by Doppler ultrasonography. The increase in MAP during exercise was greater in OF than in YF (YF: +14 ± 7 mmHg, OF: +24 ± 13 mmHg, P = 0.028). The celMBF decreased during exercise in both groups, but there was no significant difference in the response between YF and OF (YF: -93.0 ± 66.1 mL/min, OF: -89.6 ± 64.0 mL/min, P = 0.951). The celVC also decreased during exercise and remained lower than baseline during exercise. However, the response was not different between YF and OF (YF: -1.8 ± 1.0 mL/min/mmHg, OF: -1.5 ± 0.6 mL/min/mmHg, P = 0.517). These results demonstrate that aging in females has minimal influence on splanchnic artery hemodynamic responses during dynamic light-intensity exercise, suggesting that exaggerated ABP responses during exercise in OF are not due to greater splanchnic vasoconstriction.NEW & NOTEWORTHY During exercise, the splanchnic arteries vasoconstrict, contributing to blood flow redistribution and the blood pressure response. Blood pressure responses to exercise are exaggerated with aging in females; however, the physiological mechanism responsible has not been clarified. We show that celiac artery blood flow changes during light-intensity dynamic exercise do not differ with age in females. This indicates the exaggerated blood pressure to exercise with aging is likely not due to a difference in splanchnic vasoconstriction.

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.

Enhancing Endothelial Function with Nutrient-Enriched Table Hen Eggs: A Randomized Study in Patients Recovering from Acute Coronary Syndrome.

This study investigated the effect of consumption of table eggs enriched with n-3 polyunsaturated fatty acids (n-3 PUFA), lutein, vitamin E and selenium on microvascular function, oxidative stress and inflammatory mediators in patients after acute coronary syndrome (ACS). In a prospective, randomized, interventional, double-blind clinical trial, ACS patients were assigned to either the Nutri4 (N=15, mean age: 57.2±9.2 years), or the Control group (N=13; mean age 56.8±9.6 years). The Nutri4 group consumed three enriched hen eggs daily for three weeks, providing approximately 1.785 mg of vitamin E, 0.330 mg of lutein, 0.054 mg of selenium and 438 mg of n-3 PUFAs. Biochemical parameters, including serum lipids, liver enzymes, nutrient concentrations, serum antioxidant enzyme activity (catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD)), and markers of oxidative stress (thiobarbituric acid reactive substances (TBARS) and ferric reducing ability (FRAP)), were assessed before and after the dietary interventions. Additionally, arterial blood pressure, heart rate, body composition, fluid status, anthropometric measurements, and skin microvascular blood flow responses to various stimuli (postocclusive reactive hyperemia (PORH), acetylcholine- (AchID), and sodium nitroprusside- (SNPID)) were measured using laser Doppler flowmetry (LDF) throughout the study. The intake of Nutri4 eggs led to a significant reduction in LDL cholesterol levels, while the levels of total cholesterol remained within the established reference values. Consuming Nutri4 eggs resulted in a 12.7% increase in serum vitamin E levels, an 8.6% increase in selenium levels, and demonstrated a favorable impact on microvascular reactivity, as evidenced by markedly improved PORH and ACh ID. Nutri4 eggs exerted a significant influence on the activity of GPx and SOD, with no observed changes in TBARS or FRAP values. The consumption of Nutri4 eggs positively influenced microvascular function in individuals with ACS, without eliciting adverse effects on oxidative stress.

Postoperative orthostatic intolerance following fast-track unicompartmental knee arthroplasty: incidence and hemodynamics—a prospective observational cohort study

BackgroundEarly postoperative mobilization is essential for early functional recovery but can be inhibited by postoperative orthostatic intolerance (OI). Postoperative OI is common after major surgery, such as total knee arthroplasty (TKA). However, limited data are available after less extensive surgery, such as unicompartmental knee arthroplasty (UKA). We, therefore, investigated the incidence of OI as well as cardiovascular and tissue oxygenation responses during early mobilization after UKA.MethodsThis prospective single-centre observational study included 32 patients undergoing primary UKA. Incidence of OI and cardiovascular and tissue oxygenation responses during mobilization were evaluated preoperatively, at 6 and 24 h after surgery. Perioperative fluid balance, bleeding, surgery duration, postoperative hemoglobin, pain during mobilization and opioid usage were recorded.ResultsDuring mobilization at 6 h after surgery, 4 (14%, 95%CI 4–33%) patients experienced OI; however, no patients terminated the mobilization procedure prematurely. Dizziness and feeling of heat were the most common symptoms. OI was associated with attenuated systolic and mean arterial blood pressure responses in the sitting position (all p < 0.05). At 24 h after surgery, 24 (75%) patients had already been discharged, including three of the four patients with early OI. Only five patients were available for measurements, two of whom experienced OI; one terminated the mobilization procedure due to intolerable symptoms. We observed no statistically significant differences in perioperative fluid balance, bleeding, surgery duration, postoperative hemoglobin, pain, or opioid usage between orthostatic intolerant and tolerant patients.ConclusionsThe incidence of orthostatic intolerance after fast-track unicompartmental knee arthroplasty is low (~ 15%) and is associated with decreased orthostatic pressure responses. Compared to the previously described orthostatic intolerance incidence of ~ 40% following total knee arthroplasty, early orthostatic intolerance is uncommon after unicompartmental knee arthroplasty, suggesting a procedure-specific component.Trial registration: Prospectively registered at ClinicalTrials.gov; registration number: NCT04195360, registration date: 13.12.2019.

Expansion of Psychosocial Distress in Nurses Working in Hemodialysis During Exposure to COVID-19 Pandemic in Bulgaria

Abstract A new type of virus, SARS-CoV-2, has spread globally throughout the world. The COVID-19 epidemic rapidly spread worldwide. The health care system, society and medical professionals have prepared to adapt, train and resist the increased psychosocial pressure. In this situation, the role and place of medical professionals has become noticeably more prominent, and the psychosocial stress of the work environment has increased its impact – progressing to high levels of harmful intensity towards the medical professionals. Focusing within the borders of Bulgaria, it can be argued that the initial two waves of high levels of COVID-19 prevalence were difficult and critical to overcome. The aim of our study is to investigate the impact of psychosocial stress on the functional status examined with the response of arterial blood pressure of nurses, practicing long-term care in hemodialysis clinics and centers during exposure to COVID-19 pandemic. A study was conducted on the subjective assessment of psychological and social risk factors, and arterial systolic and diastolic blood pressure in 2018-2019 (pre-COVID-19 period) and 2020 (COVID-19 period), respectively. The methods used were the NIOSH questionnaire – to assess psychosocial stress at work and to measure blood pressure with a sphygmomanometer. The results showed that the expansion of psychosocial risks from the work environment impacted on the functional status of nurses, with an increase in the level of social support and systolic blood pressure during the COVID-19 compared to the pre-COVID-19 period, and a decrease in the level of control when comparing the same periods. We will monitor and observe these effects with concern in order to respond in a timely manner with effective and practical strategies, policies and programs to counter and prevent psychosocial stress in the workplace. One of the outlined guiding goals and trends for this will be to both preserve and prolong the work life of nurses and to reposition them as a key and significant group for the healthcare system.

Amplified P2X3 pathway activity in muscle afferent dorsal root ganglion neurons and exercise pressor reflex regulation in hindlimb ischaemia-reperfusion.

Hindlimb ischaemia-reperfusion (IR) is among the most prominent pathophysiological conditions observed in peripheral artery disease (PAD). An exaggerated arterial blood pressure (BP) response during exercise is associated with an elevated risk of cardiovascular events in individuals with PAD. However, the precise mechanisms leading to this exaggerated BP response are poorly elucidated. The P2X3 signalling pathway, which plays a key role in modifying the exercise pressor reflex (EPR), is the focus of the present study. We determined the regulatory role of P2X3 on the EPR in a rat model of hindlimb IR. In vivo and in vitro approaches were used to determine the expression and functions of P2X3 in muscle afferent nerves and EPR in IR rats. We found that in IR rats there was (1) upregulation of P2X3 protein expression in the L4-6 dorsal root ganglia (DRG); (2) amplified P2X currents in isolated isolectin B4 (IB4)-positive muscle DRG neurons; and (3) amplification of the P2X-mediated BP response. We further verified that both A-317491 and siRNA knockdown of P2X3 significantly decreased the activity of P2X currents in isolated muscle DRG neurons. Moreover, inhibition of muscle afferents' P2X3 receptor using A-317491 was observed to alleviate the exaggerated BP response induced by static muscle contraction and P2X-induced BP response by α,β-methylene ATP injection. P2X3 signalling pathway activity is amplified in muscle afferent DRG neurons in regulating the EPR following hindlimb IR.

Abstract 12634: Amplified P2x 3 Pathway Activity in IB4 Positive Muscle DRG Neurons and Exercise Pressor Reflex Regulation in Hindlimb Ischemia-Reperfusion

Background: Hindlimb ischemia-reperfusion (IR) represents one of the most prominent pathological conditions observed in peripheral artery disease (PAD). Arterial blood pressure response (BP) during exercise, partly driven by the exaggerated exercise pressor reflex (EPR), is associated with an elevated risk of cardiovascular events in PAD patients. However, the precise underlying mechanisms leading to this exaggerated BP response are poorly elucidated. The purinergic P2X 3 signaling pathway, which plays a key role in modifying the EPR, was the focus of the present study. Objectives: To examine the regulatory role of P2X 3 on the EPR in a rat model of hindlimb IR, which was induced by 6 hours’ ischemia followed by 18 hours’ reperfusion (referred to as IR rats). Results: We found that, in IR rats, there were: 1) upregulation of P2X 3 protein expression in the L4-6 dorsal root ganglion (DRG) (1.48±0.16 in IR rats/n=8 vs. 1.00±0.41 in sham rats/n=9; P&lt;0.05), which was localized in IB4 positive DRG neurons by the method of immunohistochemistry, 2) amplified P2X currents in isolated muscle DRG neurons (P2X transient currents: 1281.64±776.74 pA in IR rats/n=25, vs. 717.91±556.2 pA in sham rats/n=9, P&lt;0.05; and sustain currents: 466.94±168.68 pA in IR rats/n=11, vs. 271.49±200.90 pA in sham rats/n=8, P&lt;0.05); 3) amplification of P2X-mediated BP response (29±8 mmHg in IR rats/n=12 vs. 21±4 mmHg in sham rats/n=7; P&lt;0.05); and 4) alleviation of the exaggerated BP response induced by static muscle contraction (18±8 mmHg in IR +A317491/n=8, vs. 29±11 mmHg in IR/n=7, P&lt;0.05) and P2X-mediated BP response by α, β-me-ATP injection (15±4 mmHg in IR+A317491 /n=6 vs. 23±7 mmHg in IR/n=4, P&lt;0.05) following the inhibition of muscle afferents’ P2X 3 receptor by A-317491. We further verified that both A-317491 and siRNA knockdown of P2X 3 significantly decreased the activity of P2X currents in the isolated muscle DRG neurons (all P&lt;0.05 vs. their respective controls). Conclusion: With the above evidence from multiple approaches, we concluded that the P2X 3 signaling pathway activity is amplified following hindlimb IR via the enhancing expression and activity of P2X 3 receptors in IB4 positive muscle DRG afferents. This contributes to the exacerbated EPR responses in PAD.

Are there Interindividual Responses of Cardiovascular Disease Risk Markers to Acute Exercise? A Replicated Crossover Study.

Using a replicated crossover design, we quantified the response heterogeneity of postprandial cardiovascular disease (CVD) risk marker responses to acute exercise. Twenty men (mean (SD) age, 26 (6) years; BMI, 23.9 (2.4) kg·m-2) completed four, 2-day conditions (two control, two exercise) in randomised orders. On days 1 and 2, participants rested and consumed two high-fat meals over 9-h. Participants ran for 60-mins (61 (7)% of peak oxygen uptake) on day 1 (6.5-7.5 h) of both exercise conditions. Time-averaged total-area-under-the-curve (TAUC) for triacylglycerol (TAG), glucose and insulin were calculated from 11 venous blood samples on day 2. Arterial stiffness and blood pressure responses were calculated from measurements at baseline on day 1 and at 2.5-h on day 2. Consistency of individual differences was explored by correlating the two replicates of control-adjusted exercise responses for each outcome. Within-participant covariate-adjusted linear mixed models quantified participant-by-condition interactions and individual-response SDs. Acute exercise reduced mean TAUC-TAG (-0.27 mmol·L-1 h; Cohen's d = 0.29, P = 0.017) and TAUC-insulin (-24.45 pmol·L-1 h; Cohen's d = 0.35, P = 0.022) vs. control, but led to negligible changes in TAUC-glucose and the vascular outcomes (Cohen's d ≤ 0.41, P ≥ 0.106). Small-to-moderate, but nonsignificant, correlations were observed between the two response replicates (r = -0.40 to 0.15, P ≥ 0.066). We did not detect any individual response heterogeneity. All participant-by-condition interactions were P ≥ 0.137, and all individual-response SDs were small with wide 95% confidence intervals overlapping zero. Large trial-to-trial within-subject variability inhibited detection of consistent inter-individual variability in postprandial metabolic and vascular responses to acute exercise.

Orexin facilitates the hypoxic ventilatory response via the activation of corticotropin-releasing hormone neurons that project to the nucleus of the solitary tract

The paraventricular nucleus of the hypothalamus (PVN) contributes significantly to the peripheral chemoreflex-mediated respiratory and sympathetic responses to hypoxia, in part via reciprocal interactions with nucleus of the solitary tract (nTS). Previously we showed that orexin neurons in the perifornical hypothalamus are activated by hypoxia and facilitate the hypoxic ventilatory response (HVR) in the active phase of the circadian cycle . The neural circuitry through which orexin facilitates the HVR is unknown. Orexin receptors (OxR) are expressed in the PVN, and we recently showed that OxR blockade reduced the activation of both corticotropin-releasing hormone neurons in the PVN as well as nTS neurons. In addition, hypoxia activated orexin neurons projecting to the PVN, but not those projecting to nTS. Here we further explored the hypothesis that orexin facilitates the HVR and arterial blood pressure (ABP) response to hypoxia via the activation of nTS-projecting CRH neurons, and that specific OxR1 knockdown in the PVN would reduce the HVR. To test these hypotheses, we nanoinjected fluorescent retrobeads bilaterally into the nTS to label nTS-projecting neurons. Rats were then exposed to hypoxia (2hrs at 11% O2 during the active phase) following injection of either suvorexant (OxR antagonist; 20 mg/kg i.p.; n=4), or vehicle (DMSO; n=4). Using immunohistochemistry (IHC) we then quantified the number of activated (i.e., Fos-immunoreactive; IR) nTS-projecting CRH neurons. In separate groups of rats we nanoinjected shRNA to knockdown Ox1R expression specifically in the PVN (n=8). PVN of control rats was nanoinjected with scrambled RNA (scRNA; n=3) or aCSF (n=2). Three weeks later, rats were exposed to graded hypoxia (from 21% to 10% inspired O2) over 3-5 minutes to assess the acute HVR and ABP response to different levels of hypoxia. OxR blockade reduced the number of Fos-IR, nTS-projecting CRH neurons by ~32% (drug: p&lt;0.0001). Images confirmed successful targeting of shRNA to PVN, and OxR1 knockdown (by ~50%) was confirmed in subsets of samples by Western Blot and IHC. Ox1R knockdown specifically in the PVN had no effect on resting ventilation, but significantly reduced the HVR (main effect: p=0.02; 22% decrease in VE/VCO2 at 13% O2), due to a reduction in the respiratory frequency response to hypoxia (main effect: p=0.004; 38 breath/min decrease at 13% O2). Ox1R knockdown also decreased ABP (~5 mmHg at all O2 levels; main effect: p=0.0015), but not its response to hypoxia. These data suggest that orexin neurons facilitate the HVR via OxR1 Grants: 5R01HL098602 (EH, DK), 5R01HL136710 (KC) This is the full abstract presented at the American Physiology Summit 2023 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.

Sympathoexcitation and pressor responses induced by acetate, an ethanol metabolite in the hypothalamic paraventricular nucleus involves activation of NMDA receptors in rats

Alcohol abuse plays a crucial role in the prevalence of cardiovascular and neuronal degenerated diseases. However, the central mechanism that mediates these effects are not fully understood. It has been well know that autonomic hypothalamic paraventricular nucleus (PVN) play an important role in regulating sympathetic outflow and arterial blood pressure (ABP). Moreover, it has been demonstrated that the increased glutamatergic activity among PVN neurons contributed to the sympathoexcitation and development of hypertension. Furthermore, we have reported that ethanol and acetate increase sympathetic outflow and arterial pressure, which may involve the activation of NMDA receptors in autonomic central nucleus of amygdala. Combing with the fact that autonomic PVN neurons are abundantly expressed NMDA receptors, we hypothesize that acetate, the metabolic products from alcohol, activates the PVN neurons through the increase in glutamatergic activity and contributes to the sympathoexcitation and development of chronic diseases, such as hypertension. In anesthetized rats, the effect of acetate microinjected in the PVN on the renal sympathetic nerve activity (RSNA) and arterial blood pressure (ABP) was determined. The PVN acetate microinjection increased sympathoexcitatiory and pressor response in a dose dependent dose-dependent (1.5mm, 0.5mm, 2.0mm, 7.5mm) manner, and 2mm of acetate showed a minimum dose evoked a maximal response. To determine the role of acetate-stimulated glutamatergic receptor activation in driving sympathoexcitatory and pressor responses, either 2mm acetate or pre-treatment of Kynurenic acid (KYN, 7.2mm) ionotropic excitatory amino acid receptor blocker, or D-2-amino-5-phosphopentanoate (AP5, 3.0mm), a N-methyl-D-aspartate (NMDA) receptor antagonist, followed by 2mm acetate were microinjected into the PVN of male Sprague Dawley rats (300-500g, n= 6-9/ group). RSNA and ABP responses were compared among vehicle (saline) and 2mm acetate, pre-treatment of KYN and 2mm acetate, or pre-treatment AP5 and 2mm acetate protocols. 2mm acetate significantly increased RSNA (60-70% baseline, p &lt; 0.001) and mean arterial pressure (MAP, 10-12mmHg, p &lt; 0.05). Non-selective glutamatergic receptor antagonist, KYN significantly blocked the sympathoexcitatory (RSNA, p &lt; 0.05) and pressor response (MAP, p &lt; 0.05) evoked by 2mm acetate in the PVN. Furthermore, selective NMDA receptor antagonist, AP5 significantly attenuates the sympathoexcitatory response induced by PVN 2mm acetate (RSNA, P &lt; 0.05 and MAP, p &lt; 0.01). These data indicate acetate can increase glutamatergic activity and excitability of pre-sympathetic PVN neurons via activation of local NMDA receptors. The metabolism of ethanol to acetate following by alcohol consumption may contribute, in part, to the development of neurogenic hypertension and/or other cardiovascular diseases associated with increased sympathetic outflow. R15HL145655, R15HL150703 This is the full abstract presented at the American Physiology Summit 2023 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.

Critical Closing Pressure and Cerebrovascular Resistance Responses to Intracranial Pressure Variations in Neurocritical Patients

BackgroundCritical closing pressure (CrCP) and resistance-area product (RAP) have been conceived as compasses to optimize cerebral perfusion pressure (CPP) and monitor cerebrovascular resistance, respectively. However, for patients with acute brain injury (ABI), the impact of intracranial pressure (ICP) variability on these variables is poorly understood. The present study evaluates the effects of a controlled ICP variation on CrCP and RAP among patients with ABI.MethodsConsecutive neurocritical patients with ICP monitoring were included along with transcranial Doppler and invasive arterial blood pressure monitoring. Internal jugular veins compression was performed for 60 s for the elevation of intracranial blood volume and ICP. Patients were separated in groups according to previous intracranial hypertension severity, with either no skull opening (Sk1), neurosurgical mass lesions evacuation, or decompressive craniectomy (DC) (patients with DC [Sk3]).ResultsAmong 98 included patients, the correlation between change (Δ) in ICP and the corresponding ΔCrCP was strong (group Sk1 r = 0.643 [p = 0.0007], group with neurosurgical mass lesions evacuation r = 0.732 [p < 0.0001], and group Sk3 r = 0.580 [p = 0.003], respectively). Patients from group Sk3 presented a significantly higher ΔRAP (p = 0.005); however, for this group, a higher response in mean arterial pressure (change in mean arterial pressure p = 0.034) was observed. Exclusively, group Sk1 disclosed reduction in ICP before internal jugular veins compression withholding.ConclusionsThis study elucidates that CrCP reliably changes in accordance with ICP, being useful to indicate ideal CPP in neurocritical settings. In the early days after DC, cerebrovascular resistance seems to remain elevated, despite exacerbated arterial blood pressure responses in efforts to maintain CPP stable. Patients with ABI with no need of surgical procedures appear to remain with more effective ICP compensatory mechanisms when compared with those who underwent neurosurgical interventions.

Effects of sex and ageing on the human respiratory muscle metaboreflex.

Intense inspiratory muscle work evokes a sympathetically mediated pressor reflex, termed the respiratory muscle metaboreflex, in which young females demonstrate an attenuated response relative to males. However, the effects of ageing and female sex hormones on the respiratory muscle metaboreflex are unclear. We tested the hypothesis that the pressor response to inspiratory work would be similar between older males and females, and higher relative to their younger counterparts. Healthy, normotensive young (26±3years) males (YM; n=10) and females (YF; n=10), as well as older (64±5years) males (OM; n=10) and females (OF; n=10), performed inspiratory pressure threshold loading (PTL) to task failure. Older adults had a greater mean arterial pressure (MAP) response to PTL than young (P<0.001). YF had a lower MAP compared to YM (+10±6 vs. +19±15mmHg, P=0.026); however, there was no difference observed between OF and OM (+26±11 vs. +27±11mmHg, P=0.162). Older adults had a lower heart rate response to PTL than young (P=0.002). There was no effect of sex between young females and males (+19±9 and +27±11bpm, P=0.186) or older females and males (+17±7 and +20±7bpm, P=0.753). We conclude the respiratory muscle metaboreflex response is heightened in older adults, and the sex effect between older males and post-menopause females is absent, suggesting an effect of circulating sex hormones. KEY POINTS: The arterial blood pressure response to the respiratory muscle metaboreflex is greater in older males and females. Compared to sex-matched young individuals, there is no sex differences in the blood pressure response between older males and post-menopause females. Our results suggest the differences between males and females in the cardiovascular response to high levels of inspiratory muscle work is abolished with reduced circulating female sex hormones.

Exaggerated blood pressure response to static exercise in hindlimb ischemia-reperfusion.

Peripheral artery disease (PAD) reduces the blood flow supply in the affected limbs as one of the significant cardiovascular concerns. Revascularization surgery in the femoral artery plays a central role in treating PAD. Exercise is also a rehabilitation strategy suggested for PAD patients to improve vascular functions. However, the effects of limb ischemia-reperfusion (IR), one of the most predominant complications in revascularization surgery, on exercise-induced arterial blood pressure (BP) response are poorly understood. In the present study, we determined 1) the blood flow status in the hindlimb muscles of rats (plantar muscle, red and white portions of gastrocnemius) with different time points of the hindlimb IR; and 2) the BP response to static muscle contraction in rats at different time points after the blood flow reperfusion procedure. Results of this study indicated that, compared with the Sham group, the blood flow in the hindlimb muscles evaluated by Evans blue concentration was significantly reduced at 6h of femoral artery occlusion (FAO 6h) (vs. sham control, p < 0.05). The decreased blood flow was gradually recovered after the blood flow reperfusion for 18 (IR 18h), 66 (IR 66h), and 114 (IR 114h) hours (p < 0.05 vs. FAO 6h for all IR groups). The response of mean arterial pressure was 20 ± 4mmHg in Sham rats (n = 7); 32 ± 10mmHg in IR 18h rats (n = 10); 27 ± 7mmHg in IR 66h rats (n = 13); 26 ± 4mmHg in IR 114h rats (n = 9) (p < 0.05 vs. Sham for all groups). No significant difference was observed in the peak-developed tension during muscle contraction among all the groups (p > 0.05). In conclusion, static exercise-induced BP response is exaggerated following IR. Whereas the BP response is not statistically significant but tends to decrease with a prolonged IR time, the exaggerated BP response remains through time points from post-IR 18h-114h.

Central command suppresses pressor-evoked bradycardia at the onset of voluntary standing up in conscious cats.

What is the central question of this study? Standing up can cause hypotension and tachycardia. Accumulated evidence poses the simple question, does the cardiac baroreflex operate at the onset of standing up? If the cardiac baroreflex is suppressed, what mechanism is responsible for baroreflex inhibition? What is the main finding and its importance? In cats, we found blunting of cardiac baroreflex sensitivity in the pressor range at the onset of voluntary hindlimb standing, but not of passive hindlimb standing. This finding suggests that central command suppresses pressor-evoked bradycardia at the onset of standing up, probably in advance, to prevent or buffer orthostatic hypotension. It remains unclear whether cardiac baroreflex function is preserved or suppressed at the onset of standing up. To answer the question and, if cardiac baroreflex is suppressed, to investigate the mechanism responsible for the suppression, we compared the sensitivity of the arterial cardiac baroreflex at the onset of voluntary and passive hindlimb standing in conscious cats. Cardiac baroreflex sensitivity was estimated from the maximal slope of the baroreflex curve between the responses of systolic arterial blood pressure and heart rate to a brief occlusion of the abdominal aorta. The systolic arterial blood pressure response to standing up without aortic occlusion was greater in the voluntary case than in the passive case. Cardiac baroreflex sensitivity was clearly decreased at the onset of voluntary standing up compared with rest (P=0.005) and the onset of passive standing up (P=0.007). The cardiac baroreflex sensitivity at the onset of passive standing up was similar to that at rest (P=0.909). The findings suggest that central command would transmit a modulatory signal to the cardiac baroreflex system during the voluntary initiation of standing up. Furthermore, the present data tempt speculation on a close relationship between central inhibition of the cardiac baroreflex and the centrally induced tachycardiac response to standing up.

Impaired hemodynamic response to exercise in patients with peripheral artery disease: evidence of a link to inflammation and oxidative stress.

An exaggerated mean arterial blood pressure (MAP) response to exercise in patients with peripheral artery disease (PAD), likely driven by inflammation and oxidative stress and, perhaps, required to achieve an adequate blood flow response, is well described. However, the blood flow response to exercise in patients with PAD actually remains equivocal. Therefore, eight patients with PAD and eight healthy controls completed 3 min of plantar flexion exercise at both an absolute work rate (WR) (2.7 W, to evaluate blood flow) and a relative intensity (40%WRmax, to evaluate MAP). The exercise-induced change in popliteal artery blood flow (BF, Ultrasound Doppler), MAP (Finapress), and vascular conductance (VC) were quantified. In addition, resting markers of inflammation and oxidative stress were measured in plasma and muscle biopsies. Exercise-induced ΔBF, assessed at 2.7 W, was lower in PAD compared with controls (PAD: 251 ± 150 vs. Controls: 545 ± 187 mL/min, P < 0.001), whereas ΔMAP, assessed at 40%WRmax, was greater for PAD (PAD: 23 ± 14 vs. Controls: 11 ± 6 mmHg, P = 0.028). The exercise-induced ΔVC was lower for PAD during both the absolute WR (PAD: 1.9 ± 1.6 vs. Controls: 4.7 ± 1.9 mL/min/mmHg) and relative intensity exercise (PAD: 1.9 ± 1.8 vs. Controls: 5.0 ± 2.2 mL/min/mmHg) trials (both, P < 0.01). Inflammatory and oxidative stress markers, including plasma interleukin-6 and muscle protein carbonyls, were elevated in PAD (both, P < 0.05), and significantly correlated with the hemodynamic changes during exercise (r = -0.57 to -0.78, P < 0.05). Thus, despite an exaggerated ΔMAP response, patients with PAD exhibit an impaired exercise-induced ΔBF and ΔVC, and both inflammation and oxidative stress likely play a role in this attenuated hemodynamic response.

Sympathoexcitatory responses to renal chemosensitive stimuli are exaggerated at nighttime in rats.

The circadian cycle impacts sympathetic nerve activity (SNA), cardiovascular hemodynamics, and renal function. Activation of renal sensory nerves by chemosensory and mechanosensory stimuli reflexively changes efferent SNA and arterial blood pressure (ABP) to maintain homeostasis. However, it is unclear to what extent circadian cycle influences reflex SNA and ABP responses to renal sensory stimuli. Renal, splanchnic, and lumbar SNA and ABP responses to intrarenal arterial infusion of bradykinin or capsaicin and elevated renal pelvic pressure were measured in male and female Sprague-Dawley rats during nighttime (wakeful/active phase) and daytime (inactive phase). Intrarenal arterial bradykinin infusion significantly increased efferent renal SNA, splanchnic SNA, and ABP but not lumbar SNA. Responses were greater during nighttime versus daytime. Similarly, intrarenal arterial capsaicin infusion significantly increased renal SNA and splanchnic SNA, and responses were again greater during nighttime. Elevated renal pelvic pressure increased renal SNA and splanchnic SNA; however, responses did not differ between daytime and nighttime. Finally, afferent renal nerve activity responses to bradykinin were not different between daytime and nighttime. Thus, renal chemokines elicit greater sympathoexcitatory responses at nighttime that cannot be attributed to differences in afferent renal nerve activity. Collectively, these data suggest that the circadian cycle alters the excitability of central autonomic networks to alter baseline SNA and ABP as well as the magnitude of visceral reflexes.NEW & NOTEWORTHY The current study discovers that the circadian cycle influences sympathetic and hemodynamic responses to activation of renal chemosensitive sensory fibers. Sympathetic responses to intrarenal bradykinin or capsaicin infusion were exaggerated during nighttime (active period), but mechanosensitive responses to elevated renal pelvic pressure were not. Importantly, renal afferent nerve responses were not different between nighttime and daytime. These data suggest that the circadian cycle modulates sympathetic responses to visceral afferent activation.

Intramuscular insulin administration potentiates sympathetic and pressor responses to capsaicin in rats

Insulin centrally activates the sympathetic nervous system. However, little is known about the effects of insulin on peripheral primary sensory neurons. Transient receptor potential vanilloid 1 (TRPV1), of which capsaicin (CAP) is an agonist, is widely expressed in small dorsal root ganglia (DRG) neurons subserving skeletal muscle thin‐fiber afferents expressing sensory nociceptors and/or metabolically sensitive skeletal muscle receptors. Evidence suggests that insulin increases the sensitivity of these sensory receptors as well as translocation of TRPV1 from cytosol to plasma membrane in DRG neurons. We therefore hypothesized that insulin potentiates the responsiveness of thin fiber muscle afferents to TRPV1 activation.PurposeThe aim of this investigation was 1) to examine whether TRPV1 and insulin receptors (IR) are co‐localized in small‐diameter (&lt; 30 µm) DRG neurons subserving thin‐fiber afferents (C‐fibers or A‐delta fibers), and 2) to determine the effects of insulin on renal sympathetic nerve activity (RSNA) and mean arterial blood pressure (MAP) responses to stimulation of TRPV1 by injection of CAP into the arterial supply of the hindlimb in decerebrated rats.MethodsL4‐L6 DRGs were harvested from Sprague‐Dawley rats (n=3, 19 weeks, body weight: 518 ± 6 g). The percentage of neurons that expressed IR and/or isolectin B4 binding (IB4, a C‐fiber neuronal marker) in TRPV1 positive small DRGs neurons were assessed. RSNA and MAP responses to intra‐arterial administration of CAP (0.3 µg/100 µL) were measured in decerebrate Sprague‐Dawley rats (10 ± 1 weeks, body weight: 330 ± 43 g) before and after intramuscular injection of either insulin (5 U/mL, 30 µL) or saline (vehicle control, 30 µL). To avoid insulin/saline spill over into the systemic circulation, a vascular occluder placed around the abdominal aorta was inflated immediately prior to intramuscular administration of insulin or saline.ResultsImmunohistochemical staining demonstrated that 22 % of TRPV1 positive DRG neurons expressed IR and IB4 binding. Intramuscular insulin administration did not change blood glucose as well as plasma insulin levels assessed from the jugular vein. The RSNA response to CAP after insulin administration was significantly greater than post injection of vehicle (vehicle: 25 ± 24, n=9, vs. insulin: 54 ± 32 %, n=8, P=0.04). While the MAP response to CAP was not significantly changed by vehicle injection (before: 26 ± 13 vs. after: 24 ± 12 mmHg, n=18), insulin administration significantly increased MAP responsiveness (before: 24 ± 1 vs. after: 29 ± 15 mmHg, n=22, P=0.01).ConclusionThe data demonstrate that 1) TRPV1 and IR co‐localize on small DRG neurons and 2) intramuscular insulin administration significantly augments sympathetic and pressor responses to chemical stimulation of skeletal muscle afferents. These findings suggest that insulin potentiates TRPV1 responsiveness at the muscle tissue level, possibly contributing to insulin‐induced sympathoexcitation.

Exposure to Repeated Cold Stress Influences Sympathetic and Cardiovascular Responses to Muscle Stretch in Decerebrated Rats

Chronic stress is known to cause adverse physical and mental effects such as pain, chronic fatigue, and depression, and it is strongly related to many diseases and syndromes (e.g., fibromyalgia, chronic fatigue syndrome, and post‐traumatic stress disorder). Evidence suggests that exercise and physical activity in leisure time are effective in improving stress‐induced symptoms. Repeated cold stress (RCS), in which an animal is repeatedly exposed to alternating room and low temperatures, is one of the chronic stress models that induces chronic pain and depression. Mechanical hyperalgesia through thin muscle afferent fibers has also been reported to occur from RCS exposure. Since the muscle afferents have a dual modulatory function in nociception and cardiovascular reflex, we hypothesized that RCS augments the mechanical component of the exercise pressor reflex (the skeletal muscle mechanoreflex), i.e., skeletal muscle afferents‐mediated increases sympathetic nerve activity (SNA) and arterial blood pressure (AP).[Purpose]The purpose of this study was to clarify the impacts of RCS on sympathetic and cardiovascular responses to stimulation of the skeletal muscle mechanoreflex in decerebrated rats.[Methods]Male Sprague‐Dawley rats (body weight: 410 ± 15 g, age: 12 weeks) were exposed to RCS using a homemade automated RCS device. The rats were alternately moved to room temperature (22°C) and cold temperature (4°C) compartments at 30‐min intervals for 5 days. To assess the skeletal muscle mechanoreflex function, we measured mean AP (MAP), heart rate (HR), and renal SNA (RSNA) responses to 30‐s static passive stretching of the hindlimb muscles by in vivo recording from unanesthetized decerebrated rats. Stretching was performed by tracing the maximum tension curve obtained from 30‐s electrical stimulation. Changes (Δ) from baseline to peak values of the measured parameters between control and RCS rats were compared.[Results]Peak tension during the Achilles tendon stretch from baseline was not significantly different between groups (control: Δ929 ± 63 g [n = 6] vs RCS: Δ765 ± 66 g [n = 4], p = 0.17). Importantly, the peak RSNA response in RCS rats (Δ236.3% and Δ242.7%, n = 2) tended to be greater than that in control rats (Δ37.1% and Δ23.9%, n = 2). Moreover, RCS had a significantly (p &lt; 0.05) greater HR response (RCS: Δ3.7 ± 1.0 bpm [n = 4] vs control: Δ0.6 ± 0.5 bpm [n = 6]), and MAP response tended (P = 0.07) to be higher in the RCS group (Δ23 ± 6 mmHg, n = 4) than in the control group (Δ8 ± 4 mmHg, n = 6).[Conclusions]Our preliminary data demonstrate that RCS augments the skeletal muscle mechanoreflex. These results suggest that chronic stress can potentially cause exaggerated cardiovascular responses during physical activity.

Exercise Training Upregulates SK+ Channel Function in the Hypothalamic Paraventricular Nucleus (PVN) of Animals

Increased sympathetic outflow is a hallmark of cardiovascular disease (CVD). Previously, our lab demonstrated that small conductance Ca2+ activated K channels (SK+) expressed in the PVN play a crucial role in regulating sympathetic outflow, and SK+ currents were significantly decreased in rats with salt‐sensitive hypertension (SSH). Since SK+ channels among autonomic PVN neurons play a crucial role in regulating sympathetic outflow in SSH, antihypertensive therapies targeted at upregulating SK+ channel expression in the PVN should be pursued. Exercise is a powerful, non‐pharmacological intervention to treat CVD, however, the interaction between SK+ channels among the hypothalamic PVN and exercise is unknown. The objective is to determine the role of exercise in regulating SK+ channels function and sympathetic outflow as well as arterial blood pressure (ABP) in animals. We hypothesize that exercise upregulates SK+ channel function in the PVN and attenuates sympathetic outflow. To test this hypothesis, Sprague Dawley (SD) rats are divided into sedentary (SED) and exercise (EXT) groups based on their willingness to run on a motorized treadmill. Exercise intensity is determined through a maximum exercise capacity test and rats run at 70% of their exercise capacity speed for 30 minutes 5 days/week for 8‐10 weeks. Then rats are anesthetized and renal sympathetic nerve activity (RSNA) and ABP are recorded following bilateral PVN injections of apamin, a selective SK+ channel blocker (0.25mM, 60nL/side). We found that the RSNA response to PVN apamin trended toward significance in EXT rats compared with SED rats (342.1 ± 164.2 % baseline, n=6 vs 120.9 ± 25.1 % baseline, n=3; p = 0.0598). The corresponding ABP response to apamin was not significantly different in EXT rats compared with SED rats (16.5 ± 5.7 mmHg, n=6 vs 24.6 ± 7.2, n=3; p = 0.1039). Collectively, these results indicate exercise activates PVN SK+ channels function and reduces sympathetic outflow. The improvement of channel function or increase in expression may contribute to the beneficial effects of exercise on reducing sympathetic outflow in patients with CVD, including hypertension.