Arterial Pressure Responses Research Articles

Responses of cerebral blood velocity and tissue oxygenation to low-frequency oscillations during simulated haemorrhagic stress in humans.

What is the central question of this study? Do low-frequency oscillations in arterial pressure and cerebral blood velocity protect cerebral blood velocity and oxygenation during central hypovolaemia? What is the main finding and its importance? Low-frequency oscillations in arterial pressure and cerebral blood velocity attenuate reductions in cerebral oxygen saturation but do not protect absolute cerebral blood velocity during central hypovolaemia. This finding indicates the potential importance of haemodynamic oscillations in maintaining cerebral oxygenation and therefore viability of tissues during challenges to cerebral blood flow and oxygen delivery. Tolerance to both real and simulated haemorrhage varies between individuals. Exaggerated low-frequency (∼0.1Hz) oscillations in mean arterial pressure and brain blood flow [indexed via middle cerebral artery velocity (MCAv)] have been associated with improved tolerance to reduced central blood volume. The mechanism for this association has not been explored. We hypothesized that inducing low-frequency oscillations in arterial pressure and cerebral blood velocity would attenuate reductions in cerebral blood velocity and oxygenation during simulated haemorrhage. Fourteen subjects (11men and three women) were exposed to oscillatory (0.1 and 0.05Hz) and non-oscillatory (0Hz) lower-body negative pressure profiles with an average chamber pressure of -60mmHg (randomized and counterbalanced order). Measurements included arterial pressure and stroke volume via finger photoplethysmography, MCAv via transcranial Doppler ultrasound, and cerebral oxygenation of the frontal lobe via near-infrared spectroscopy. Tolerance was higher during the two oscillatory profiles compared with the 0Hz profile (0.05Hz, P=0.04; 0.1Hz, P=0.09), accompanied by attenuated reductions in stroke volume (P<0.001) and cerebral oxygenation of the frontal lobe (P≤0.02). No differences were observed between profiles for reductions in mean arterial pressure (P=0.17) and MCAv (P=0.30). In partial support of our hypothesis, cerebral oxygenation, but not cerebral blood velocity, was protected during the oscillatory profiles. Interestingly, more subjects tolerated the oscillatory profiles compared with the static 0Hz profile, despite similar arterial pressure responses. These findings emphasize the potential importance of haemodynamic oscillations in maintaining perfusion and oxygenation of cerebral tissues during haemorrhagic stress.

Effect of acute high-phosphate intake on muscle metaboreflex activation and vascular function.

Increased consumption of inorganic phosphate (Pi), an abundant ingredient in processed foods, has been associated with elevated cardiovascular disease risk; however, studies investigating underlying mechanisms are limited. Recently, high dietary Pi was shown to exaggerate the pressor response to static muscle contraction in rodents in part because of overactivation of metabolically sensitive skeletal muscle afferents. Whether acute high Pi consumption affects muscle metaboreflex activation in humans remains unknown. Furthermore, although acute high Pi consumption has been shown to impair vascular function in young healthy men, equivocal results have been reported. Therefore, we hypothesized that acute high Pi consumption augments mean arterial pressure (MAP) responses during muscle metaboreflex activation, impairs endothelial function, and increases arterial stiffness in young healthy men. Subjects performed 35% maximal voluntary contraction static handgrip (HG), followed by postexercise ischemia (PEI) to isolate muscle metaboreflex activation. Resting flow-mediated dilation (FMD) and arterial stiffness were assessed. Measures were made before (pre) and 60 min after (post) subjects consumed either a high-phosphate drink (2,000 mg phosphorus and 1,520 mg sodium) or a sodium drink (1,520 mg sodium; control). MAP responses during HG (preΔ = +23 ± 3 mmHg; postΔ = +21 ± 2 mmHg; P = 0.101) and PEI (preΔ = +21 ± 4 mmHg; postΔ = +18 ± 3 mmHg; P = 0.184) were similar before and after Pi consumption. In contrast, FMD was significantly attenuated following Pi (pre = 5.1 ± 0.5%; post = 3.5 ± 0.5%; P = 0.010), whereas arterial stiffness remained unchanged. There were no changes in any measured variable after control drink consumption. In summary, although the muscle metaboreflex remains unaffected following acute high Pi consumption in young healthy men, endothelial function is impaired. NEW & NOTEWORTHY This study was the first to investigate the influence of acute high-phosphate consumption on the pressor response during isometric handgrip and isolated muscle metaboreflex activation during postexercise ischemia in young healthy humans. We demonstrated that a single high dose of phosphate (2,000 mg) did not augment blood pressure in response to exercise or isolated muscle metaboreflex activation, but endothelial function was blunted in young healthy men.

Water deprivation does not augment sympathetic or pressor responses to sciatic afferent nerve stimulation in rats or to static exercise in humans.

Excess dietary salt intake excites central sympathetic networks, which may be related to plasma hypernatremia. Plasma hypernatremia also occurs following water deprivation (WD). The purpose of this study was to test the hypothesis that WD induces hypernatremia and consequently augments sympathetic and pressor responses to sympathoexcitatory stimuli in rats and humans. Sympathetic nerve activity (SNA) and arterial blood pressure (ABP) responses to sciatic afferent nerve stimulation (2-20 Hz) and chemical stimulation of the rostral ventrolateral medulla (RVLM) were assessed in rats after 48 h of WD and compared with normally hydrated control rats (CON). In a parallel randomized-crossover human experiment (n = 13 healthy young adults), sympathetic (microneurography) and pressor (photoplethysmography) responses to static exercise were compared between 16-h WD and CON conditions. In rats, plasma [Na+] was significantly higher in WD versus CON [136 ± 2 vs. 144 ± 2 (SD) mM, P < 0.01], but sciatic afferent nerve stimulation produced similar increases in renal SNA [5 Hz, 174 ± 34 vs. 169 ± 49% (SD), n = 6-8] and mean ABP [5 Hz, 21 ± 6 vs. 18 ± 7 (SD mmHg, n = 6-8]. RVLM injection of l-glutamate also produced similar increases in SNA and ABP in WD versus CON rats. In humans, WD increased serum [Na+] [140.6 ± 2.1 vs. 142.1 ± 1.9 mM (SD), P = 0.02] but did not augment sympathetic [muscle SNA: change from baseline (Δ) 6 ± 7 vs. 5 ± 7 (SD) bursts/min, P = 0.83] or mean ABP [Δ 12 ± 5 vs. 11 ± 8 (SD) mmHg, P = 0.73; WD vs. CON for all results] responses during the final minute of exercise. These findings suggest that despite eliciting relative hypernatremia, WD does not augment sympathetic or pressor responses to sciatic afferent stimulation in rats or to static exercise in humans. NEW & NOTEWORTHY Excess dietary salt intake excites central sympathetic networks, which may be related to plasma hypernatremia. Plasma hypernatremia also occurs following water deprivation (WD). We sought to determine whether plasma hypernatremia/hyperosmolality induced by WD augments sympathetic and pressor responses to sympathoexcitatory stimuli. Our findings suggest that WD does not augment sympathetic or pressor responses to sciatic afferent nerve stimulation in rats or to static exercise in humans.

AT1 Receptor Mediated Hypertensive Response to Ang II in the Nucleus Tractus Solitarii of Normotensive Rats Involves NO Dependent Local GABA Release.

AimIt is well-established that angiotensin II exerts a dampening effect on the baroreflex within the nucleus tractus solitarii (NTS), the principal brainstem site for termination of baroreceptor afferents and which is densely populated with gamma-aminobutyric acid (GABA)ergic neurons and nerve terminals. The present study was designed to investigate whether local release of GABA is involved in the effects mediated by local angiotensin II within the NTS.MethodsIn vivo microdialysis was used for measurement of extracellular glutamate and GABA levels and for infusion of angiotensin II within the NTS of conscious normotensive Wistar rats. The mean arterial pressure (MAP) and heart rate response to local infusion of angiotensin II were subsequently monitored with a pressure transducer under anesthesia. The angiotensin II type 1 receptor (AT1R) antagonist, candesartan, was used to assess whether responses were AT1R dependent and the nitric oxide (NO) synthase inhibitor, N(ω)-nitro-L-arginine methyl ester (L-NAME), was used to assess the involvement of NO in the evoked responses by infusion of angiotensin II. The MAP and heart rate responses were monitored with a pressure transducer.ResultsLocal infusion into the NTS of angiotensin II induced a significant to ninefold significantly increase in extracellular GABA levels; as well as MAP was increased by 15 mmHg. These responses were both abolished by co-infusion of either, the angiotensin II type 1 receptor antagonist, candesartan, or the NO synthase inhibitor, L-NAME, demonstrating that the effect is not only AT1R dependent but also NO dependent. The pressor response to angiotensin II was reversed by co-infusion with the GABAA receptor antagonist, bicuculline. Local blockade of NO synthase decreased both, GABA and glutamate concentrations.ConclusionOur results suggest that the AT1R mediated hypertensive response to angiotensin II within the NTS in normotensive rats is GABA and NO dependent. Nitric oxide produced within the NTS tonically potentiates local GABA and glutamate release.

Enhancement of excitatory transmission in NTS neurons projecting to ventral medulla of rats exposed to sustained hypoxia is blunted by minocycline.

Rats subjected to sustained hypoxia (SH) present increases in arterial pressure (AP) and in glutamatergic transmission in the nucleus tractus solitarius (NTS) neurons sending projections to ventrolateral medulla (VLM). Treatment with minocycline, a microglial inhibitor, attenuated the increase in AP in response to SH. The increase in the amplitude of glutamatergic postsynaptic currents in the NTS-VLM neurons, induced by postsynaptic mechanisms, was blunted by minocycline treatment. The number of microglial cells was increased in the NTS of vehicle-treated SH rats but not in the NTS of minocycline-treated rats. The data show that microglial recruitment/proliferation induced by SH is associated with the enhancement of excitatory neurotransmission in NTS-VLM neurons, which may contribute to the observed increase in AP. Short-term sustained hypoxia (SH) produces significant autonomic and respiratory adjustments and triggers activation of microglia, the resident immune cells in the brain. SH also enhances glutamatergic neurotransmission in the NTS. Here we evaluated the role of microglial activation induced by SH on the cardiovascular changes and mainly on glutamatergic neurotransmission in NTS neurons sending projections to the ventrolateral medulla (NTS-VLM), using a microglia inhibitor (minocycline). Direct measurement of arterial pressure (AP) in freely moving rats showed that SH (24h, fraction of inspired oxygen ( ) 0.1) in vehicle and minocycline (30mg/kg i.p. for 3days)-treated groups produced a significant increase in AP in relation to control groups under normoxic conditions, but this increase was significantly lower in minocycline-treated rats. Whole-cell patch-clamp recordings revealed that the active properties of the membrane were comparable among the groups. Nevertheless, the amplitudes of glutamatergic postsynaptic currents, evoked by tractus solitarius stimulation, were increased in NTS-VLM neurons of SH rats. Changes in asynchronous glutamatergic currents indicated that the observed increase in amplitude was due to postsynaptic mechanisms. These changes were blunted in the SH group previously treated with minocycline. Using immunofluorescence, we found that the number of microglial cells was increased in the NTS of vehicle-treated SH rats but not in the NTS neurons of minocycline-treated rats. Our data support the concept that microglial activation induced by SH is associated with the enhancement of excitatory neurotransmission in NTS-VLM neurons, which may contribute to the increase in AP observed in this experimental model.

Role of Ryanodine Type 2 Receptors in Elementary Ca2+ Signaling in Arteries and Vascular Adaptive Responses.

BackgroundHypertension is the major risk factor for cardiovascular disease, the most common cause of death worldwide. Resistance arteries are capable of adapting their diameter independently in response to pressure and flow‐associated shear stress. Ryanodine receptors (RyRs) are major Ca2+‐release channels in the sarcoplasmic reticulum membrane of myocytes that contribute to the regulation of contractility. Vascular smooth muscle cells exhibit 3 different RyR isoforms (RyR1, RyR2, and RyR3), but the impact of individual RyR isoforms on adaptive vascular responses is largely unknown. Herein, we generated tamoxifen‐inducible smooth muscle cell–specific RyR2‐deficient mice and tested the hypothesis that vascular smooth muscle cell RyR2s play a specific role in elementary Ca2+ signaling and adaptive vascular responses to vascular pressure and/or flow.Methods and ResultsTargeted deletion of the Ryr2 gene resulted in a complete loss of sarcoplasmic reticulum–mediated Ca2+‐release events and associated Ca2+‐activated, large‐conductance K+ channel currents in peripheral arteries, leading to increased myogenic tone and systemic blood pressure. In the absence of RyR2, the pulmonary artery pressure response to sustained hypoxia was enhanced, but flow‐dependent effects, including blood flow recovery in ischemic hind limbs, were unaffected.ConclusionsOur results establish that RyR2‐mediated Ca2+‐release events in VSCMs specifically regulate myogenic tone (systemic circulation) and arterial adaptation in response to changes in pressure (hypoxic lung model), but not flow. They further suggest that vascular smooth muscle cell–expressed RyR2 deserves scrutiny as a therapeutic target for the treatment of vascular responses in hypertension and chronic vascular diseases.

Endothelium-dependent adaptation of arterial wall viscosity during blood flow increase is impaired in essential hypertension

Background and aimsArterial wall viscosity (AWV) is regulated by endothelium-derived NO and epoxyeicosatrienoic acids (EETs) under baseline physiological conditions. Whether these factors regulate AWV during blood flow increase and whether this mechanism is affected in essential hypertensive patients (HT) remain unknown. MethodsThe evolution of radial artery diameter, wall thickness and arterial pressure in response to an increase in flow induced by hand skin heating were measured in 18 untreated HT and 14 normotensive controls (NT) during local infusion of saline and the respective pharmacological inhibitors of NO-synthase and EETs synthesis by cytochrome P450, L-NMMA and/or fluconazole. AWV was estimated by the ratio of the viscous energy dissipated (WV) to the elastic energy stored (WE) obtained from the pressure-diameter relationship. Concomitant changes in operating conditions, which influence the AWV, were taken into account by calculating the midwall stress. ResultsBaseline WV and WE were higher in HT than in NT but WV/WE was similar. In saline condition, WV/WE increased in HT during heating but not in NT. In the presence of L-NMMA and/or fluconazole, WV/WE increased during heating in NT. In contrast, these inhibitors did not modify the increase in WV/WE during heating in HT compared to saline. In all conditions, a larger increase in WV than WE was responsible for the increase in WV/WE. ConclusionsThe release of NO and EETs maintains a stable AWV during flow increase and this endothelial adaptive regulation is lost during essential hypertension, which may promote excessive viscous energy dissipation and cardiovascular uncoupling. Restoration of EETs availability with inhibitors of soluble epoxide hydrolase could thus constitute a promising pharmacological approach to restore the endothelial adaptive regulation of AWV.

Combined V1a and V1b Receptor Activation Within the Paraventricular Nucleus Contributes to Sympathoexcitation and Hypertension in Rats Exposed to Chronic Mild Unpredictable Stress

The paraventricular nucleus (PVN) in the brain has been recognized as a major integrative center for neurohumoral regulation which receives a broad array of afferent inputs. As such, the function of the PVN becomes even more important in times of physical or physiological stress. Two distinct neuronal populations we are interested in include the magnocellular and parvocellular neurons. Specifically, we are interested in deciphering how intranuclearly released vasopressin (AVP) from the magnocellular neurons acts upon the parvocellular pre‐sympathetic neurons and glia that are richly endowed with V1a and V1b receptors in a rat model of depression. It has been demonstrated that V1a receptor activation depolarizes PVN pre‐sympathetic neurons and initiates an action potential, which puts forth a signaling cascade that increases sympathetic nerve activity, arterial pressure and heart rate. Additionally, we previously published that renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) responses to AVP microinjected in the PVN is significantly attenuated when the rats were pretreated with V1b receptor antagonist nelivaptan. In this study, we set out to identify differences in baseline RSNA, MAP and HR between rats exposed to the chronic mild unpredictable stress protocol (CMS) and their normal counterparts, as well as their responses to AVP microinjected into the PVN in the presence of the V1a receptor antagonist, Manning compound, and the V1b receptor inhibitor, nelivaptan. We observed that baseline MAP is higher in CMS rats (110 ± 2 mmHg vs. 115 ± 1 mmHg; P &lt; 0.05). Furthermore, in control rats, combined inhibition of AVP with nelivaptan and Manning compound resulted in near complete abolition of the rise in MAP and baroreflex‐mediated decreases in HR and RSNA. CMS rats exhibited exaggerated baseline RSNA, 43.6 ± 9.97 μV.ms compared with control rats, 8.04 ± 3.24 μV.ms (P &lt; 0.025). PVN AVP injection increased RSNA by 52.1 ± 3.3 %baseline in controls and was blocked by the dual blockade. RSNA did not increase significantly after PVN AVP in CMS rats and V1a receptor and V1b receptor blockade did not change this response. CMS rats displayed higher baseline RSNA 43.6 ± 9.9 μV.ms vs control rats 8.0 ± 3.9 μV.ms P &lt; 0.025). Moreover, dual blockade significantly decreased RSNA from baseline values only in CMS rats: −12.6 ± 0.4 μV.ms compared with control rats −1.1 ± 0.6 μV.ms (P &lt; 0.05). These findings are consistent with the concept that arterial pressure and RSNA are increased during chronic stress via dendritic release of AVP within the PVN thereby contributing to sympathoexcitation and hypertension.Support or Funding InformationDepartment of Veterans Affairs Merit Award to NFRThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Both Dietary Salt Restriction and Excess Dietary Salt Intake Exaggerate Cardiovascular Reflex Responses to Activation of the Sciatic Afferents, Aortic Depressor Nerve, and Vagal Afferents

Excess dietary salt intake exaggerates sympathetic nerve activity (SNA) and arterial blood pressure (ABP) responses to several cardiovascular reflexes in salt‐resistant animals. Recently, observational cohort studies suggest that salt restriction increases cardiovascular morbidity/mortality in several cardiovascular diseases, and the relationship between cardiovascular morbidity and dietary salt intake resembles a J‐shaped curve. However, little evidence exists to document the impact of salt restriction on cardiovascular reflex responses and whether this relationship resembles a J‐shaped curve. Thus, the aim of the present study was to determine whether salt restriction affects SNA and ABP responses to activation of sciatic afferents, the aortic depressor nerve, and cervical vagal afferents. To address this hypothesis, male Sprague‐Dawley rats were fed low (0.01% NaCl, D17010, Research diets), normal (0.1% NaCl, D17020, Research Diets), and high (4.0% NaCl, D17013, Research Diets) salt diet for 14–21 days. Then, reflex responses were measured in Inactin‐anesthetized animals. Baseline mean ABP was not different across groups (low: 112±4, normal: 101±5, high: 109±3mmHg; P&gt;0.1 overall ANOVA). Electrical stimulation of sciatic afferents (1ms pulse, 500uA, 5s duration, 2–20Hz) produced frequency‐dependent increases in ABP. Interestingly, the pressor response to sciatic nerve stimulation was significantly greater in rats fed low and high versus normal NaCl (5Hz; low: 22±4, normal: 12±2, high: 27±2 mmHg, n=5–10, P&lt;0.05). Activation of the aortic depressor nerve (2ms pulse, 500uA, 15s duration, 2–20Hz) produced frequency‐dependent decreases in ABP. The depressor response to aortic nerve stimulation was significantly greater in rats fed low and high versus normal NaCl (5Hz; low: −29±6, normal: −11±3, high: −29±4 mmHg; n=3–7, P&lt;0.05). Finally, electrical stimulation of the cervical vagal afferents (1ms pulse, 500uA, 5s duration, 2–20Hz) produced frequency‐dependent decreases in ABP. Again, the depressor response to vagal nerve stimulation was significantly greater in rats fed low and high versus normal NaCl (5Hz; low: −25±3, normal: −15±2, high: −29±2 mmHg; n=5–10, P&lt;0.05). Simultaneous recordings of lumbar, renal, and splanchnic SNA followed the changes in ABP across low, normal, and high NaCl diets. The present findings showed that both dietary salt restriction and excess dietary salt intake exaggerates sympathetic and cardiovascular responses. These cardiovascular responses to activation of sciatic afferents, the aortic depressor nerve, and vagal afferents as a function of dietary salt resemble a J‐shaped curve.Support or Funding InformationNIH R01 HL128388 (WBF, SDS)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Heat treatment attenuates the exaggerated exercise pressor reflex in rats with peripheral artery disease

Femoral artery occlusion in rats has been used to study human peripheral artery disease (PAD). The responses of blood pressure (BP) and sympathetic nerve activity are exaggerated during static exercise in PAD rats with femoral artery occlusion. The purpose of the current study was to examine if heat treatment (a prior heat exposure) has beneficial effects on the exaggerated exercise pressor reflex in PAD rats. Basal muscle temperature (Tm) was 35.6±0.1 °C in control rats (n=3); and 34.2±0.1 °C in PAD rats (n=5; P&lt;0.05 vs. control rats). As Tm was increased by ~1.5 °C and this was maintained for 30 min, core temperature was not altered in control group and PAD group. The heat treatment was performed 2 times daily for 3 days. Then we examined the BP response to static muscle contraction. The greater mean arterial pressure (MAP) response was observed in PAD rats (31±5 mmHg in PAD rats/n=6 vs. 22±3 mmHg in control rats/n=8; P&lt;0.05). Heat treatment attenuated amplification of BP response in PAD rats (MAP response: 24±3 mmHg in PAD rats with heat treatment/n=5; P&lt;0.05 vs. no heat treatment). Note that no significant difference in developed muscle tension during muscle contraction was seen in control rats and PAD rats with heat treatment or without heat treatment (P&gt;0.05). Our data support the hypothesis that a prior heat exposure plays an inhibitory role in modifying exaggeration of the exercise pressor reflex in PAD.Support or Funding InformationNIH P01 HL134609This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Denervation of carotid chemoreceptors decreases blood pressure in an ovine model of renovascular hypertension

BackgroundHypertension is a major health problem of pandemic proportions that is often inadequately controlled, warranting development of new treatments. There is increasing evidence that hypertension is initiated and maintained by elevated sympathetic nerve activity. There is also strong evidence that aberrant afferent signalling from carotid chemoreceptors promotes sympathoexcitation and hypertension. We hypothesized that hypertension is associated with activation of carotid chemoreceptors and that carotid sinus denervation (CSD) would reduce blood pressure.MethodsAdult ewes either underwent unilateral renal artery clipping or sham surgery. Three weeks later, baroreflex control of heart rate was examined and the contribution of sympathetic mechanisms to hypertension was determined using hexamethonium (125 mg/hr). The mean arterial pressure and renal blood flow response to activation of carotid chemoreceptors was determined in both groups. In a second surgery conducted in hypertensive animals only, the carotid sinus nerve was severed bilaterally (CSD) (n=6) or left intact (sham, n=6) and the effect on blood pressure was examined.ResultsUnilateral renal artery clipping induced hypertension (mean arterial pressure 109 ± 2 vs 91 ± 3 mmHg in shams, p&lt;0.001). The pressor response and the renal vasoconstriction response to chemoreceptor activation was augmented in hypertensive animals compared to the normal group (for e.g. MAP response, 15 ± 1 vs 7 ± 2 mmHg, p&lt;0.05). CSD decreased MAP (−17 ± 1 vs +2 ± 1 mmHg in shams, p&lt;0.0001) and shifted the heart rate baroreflex curve to the left. The contribution of the autonomic nerves to hypertension was elevated in hypertensive animals compared to normal (−19 ± 2 vs −11 ± 2 mmHg, p&lt;0.05) and CSD reduced this contribution.DiscussionIn conclusion, we have shown that hypertension in our large animal model is associated with activation of carotid chemoreceptors and that bilateral CSD lowers arterial pressure. Our data implicates the carotid chemoreceptors in the maintenance of renovascular hypertension.Support or Funding InformationFunded by the University of Auckland Faculty Research Development Fund and the Health Research Council of New Zealand.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Accelerated Early Oxygen Kinetics in the Medial Gastrocnemius of PAD Patients During Light‐Intensity Plantar Flexion

Peripheral arterial disease (PAD) is a systemic vascular disease characterized by impaired skeletal muscle perfusion and mitochondrial respiration. Symptoms most often manifest during moderate‐intensity exercise, such as brisk walking. While the effect of PAD on oxygen transport after the onset of symptoms is well established, the contributions of convective and diffusive oxygen transport to early‐phase muscular work are less clear.PurposeThe aim of this study was to determine if oxygen transport kinetics are altered in the affected muscles of PAD patients during early stage, pre‐symptomatic exercise.MethodsTo answer this question, 5 patients with bilateral PAD and 5 healthy age‐matched controls performed graded dynamic plantar flexion exercise in the bore of a 3T MRI scanner. Exercise began at a workload of 2 kg and increased by 2 kg every 2 minutes for a total of 10 minutes, or until fatigue. Within each 2‐minute stage, subjects performed plantar flexion at a cadence of 30 contractions per minute for a total of 110 seconds. During the final 10 seconds of each stage, a custom fMRI sequence was used to simultaneously examine perfusion, T2* relaxation time (an index of tissue oxygenation), and venous oxygen saturation (SvO2) in the medial gastrocnemius. This imaging protocol consisted of a gradient‐recalled‐echo sequence interleaved into the post labeling delay of a pulsed‐arterial‐spin‐labeling sequence (acquisition time=3.2 seconds). Heart rate and blood pressure were also collected during the final minute of each stage using an automated MRI‐compatible brachial blood pressure cuff.ResultsAs has been reported elsewhere, the peak mean arterial pressure response was augmented in PAD patients (+14.34 mmHg, P=0.03). For fMRI data, multi‐factorial analyses of variance with repeated measures indicated significant group by time interactions for perfusion (F(1,8)=10.671, P=0.01) and T2* relaxation time (F(1,8)=5.285, P=0.05). After eliminating a matched‐pair due to the presence of an outlier, results also indicated a trend towards a significant group by time interaction for SvO2 (F(1,6)=5.629, P=0.055). These interactions can be explained by an initial attenuation in T2* in the PAD group compared to controls at 2 kg (mean diff=1.6±0.7 AU, P=0.05); which was followed by a significant increase in perfusion at 4 kg in the PAD group but not controls (mean diff=17.8±5.4 AU, P=0.01). SvO2 also tended to be lower at 4 kg in the PAD group compared to the control group (mean diff=13.2±5.5%, respectively, P=0.055).ConclusionsOur results indicate that oxygen transport kinetics are accelerated during the early phases of pre‐symptomatic plantar flexion exercise in PAD patients. We postulate that this may be a compensatory mechanism to the reduced total perfusion and mitochondrial capacity previously reported in PAD patients, and may also be partially mediated by the augmented pressor response to exercise.Support or Funding InformationThis research was supported NIH P01 HL134609 (PI‐Sinoway).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Thermoregulation through the glutamatergic neurons in vestibular nucleus complex

The vestibular system is one of the sensory systems which contributes to the sense of balance and spatial orientation. This also participates in the autonomic nervous response, which stimulation of the peripheral vestibular organs induces sympathoexcitation. This response is observed in both rodents and human beings, and we have reported that vestibular system contributes to the arterial pressure response during postural change as one of the feedforward control system (Morita, Abe et al., Sci Rep, 2016). In the other autonomic nervous responses, stimulation of the otolith organs in the inner ear induces hypothermia; exposure to the hypergravity environment decreases body temperature by 8 degree Celsius in mice. This response was attenuated by vestibular lesion or genetic deletion of otolith. In order to elucidate the central mechanism of hypergravity‐induced hypothermia, we examined the role of Vglut2, Vgat and ChAT neurons in vestibular nucleus complex (VNC) on thermoregulation in mice. We used Vglut2‐cre, Vgat‐cre, and ChAT‐cre mice to manipulate each neuron in VNC. Based on the previous work (Abe et al., Nat Neurosci, 2017), AAV‐DIO type viral vector was injected in VNC to express photo sensors (channelrhodopsin or archaerhodopsin) for optogenetics or hM3D(Gq) for chemogenetics. Unilateral photostimulation of the Vglut2 neurons in VNC induced body tilt to the ipsilateral side, while photoinhibition induced body tilt to the contralateral side. In Vgat‐cre mice, opposite response was observed compared with Vglut2‐cre mouse. Photostimulation of ChAT neurons did not show any responses. Chemogenetics stimulation of Vglut2 neurons showed hypothermia with increasing in activity, while Vgat stimulation increased body temperature with decreasing in activity. Deletion of Vglut2 neurons in VNC using AAV2–DIO–taCasp3–TEVp attenuated hypothermia induced by hypergravity exposure. On the other hand, hypothermia was still observed by deletion of Vgat neurons in VNC. Interestingly, chemogenetics stimulation of Vglut2 neurons in VNC 2 days before hypergravity exposure, the hypothermia was attenuated. Taken together, hypothermia induced by hypergravity exposure is due to activation of Vglut2 neurons in VNC.Support or Funding InformationGrant‐in‐Aid for Scientific Research on Innovative Areas 15H05940 (HM) and 18H04974 (CA), Grant‐in‐Aid for Scientific Research (C) 18K06850 (HM), The Takeda Science Foundation (CA), The Uehara Memorial Foundation (CA), Kato Memorial Bioscience Foundation (CA), The Nakatomi Foundation (CA)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Exercise-Induced Alterations in Sympathetic-Somatomotor Coupling in Incomplete Spinal Cord Injury.

The aim of this study was to understand how high- and low-intensity locomotor training (LT) affects sympathetic-somatomotor (SS) coupling in people with incomplete spinal cord injury (SCI). Proper coupling between sympathetic and somatomotor systems allows controlled regulation of cardiovascular responses to exercise. In people with SCI, altered connectivity between descending pathways and spinal segments impairs sympathetic and somatomotor coordination, which may have deleterious effects during exercise and limit rehabilitation outcomes. We postulated that high-intensity LT, which repeatedly engages SS systems, would alter SS coupling. Thirteen individuals (50 ± 7.2 years) with motor incomplete spinal cord injuries (American Spinal Injury Association Impairment Scale C or D; injury level >T6) participated in a locomotor treadmill training program. Patients were randomized into either a high-intensity (high-LT; 70-85% of maximum predicted heart rate; n = 6) group or a low-intensity (low-LT; 50-65% of maximum predicted heart rate; n = 7) group and completed up to 20 LT training sessions over 4-6 weeks, 3-5 days/week. Before and after taining, we tested SS coupling by eliciting reflexive sympathetic activity through a cold stimulation, noxious stimulation, and a mental math task while we measured tendon reflexes, blood pressure, and heart rate. Participants who completed high- versus low-LT exhibited significant decreases in reflex torques during triggered sympathetic activity (cold: -83 vs. 13%, p < 0.01; pain: -65 vs. 54%, p < 0.05; mental math: -43 vs. 41%; p < 0.05). Mean arterial pressure responses to sympathetic stimuli were slightly higher following high- versus low-LT (cold: 30 vs. -1.5%; pain: 6 vs. -12%; mental math: 5 vs. 7%), although differences were not statistically significant. These results suggest that high-LT may be advantageous to low-LT to improve SS coupling in people with incomplete SCI.

Maternal Engineered Nanomaterial Inhalation During Gestation Disrupts Vascular Kisspeptin Reactivity.

Maternal engineered nanomaterial (ENM) inhalation is associated with uterine vascular impairments and endocrine disruption that may lead to altered gestational outcomes. We have shown that nano-titanium dioxide (nano-TiO2) inhalation impairs endothelium-dependent uterine arteriolar dilation in pregnant rats. However, the mechanism underlying this dysfunction is unknown. Due to its role as a potent vasoconstrictor and essential reproductive hormone, we examined how kisspeptin is involved in nano-TiO2-induced vascular dysfunction and placental efficiency. Pregnant Sprague Dawley rats were exposed (gestational day [GD] 10) to nano-TiO2 aerosols (cumulative dose = 525 ± 16 μg; n = 8) or sham exposed (n = 6) and sacrificed on GD 20. Plasma was collected to evaluate estrogen (E2), progesterone (P4), prolactin (PRL), corticosterone (CORT), and kisspeptin. Pup and placental weights were measured to calculate placental efficiency (grams fetus/gram placental). Additionally, pressure myography was used to determine uterine artery vascular reactivity. Contractile responses were assessed via cumulative additions of kisspeptin (1 × 10-9 to 1 × 10-4 M). Estrogen was decreased at GD 20 in exposed (11.08 ± 3 pg/ml) versus sham-control rats (66.97 ± 3 pg/ml), whereas there were no differences in P4, PRL, CORT, or kisspeptin. Placental weights were increased in exposed (0.99 ± 0.03 g) versus sham-control rats (0.70 ± 0.04 g), whereas pup weights (4.01 ± 0.47 g vs 4.15 ± 0.15 g) and placental efficiency (4.5 ± 0.2 vs 6.4 ± 0.5) were decreased in exposed rats. Maternal ENM inhalation exposure augmented uterine artery vasoconstrictor responses to kisspeptin (91.2%±2.0 vs 98.6%±0.10). These studies represent initial evidence that pulmonary maternal ENM exposure perturbs the normal gestational endocrine vascular axis via a kisspeptin-dependent mechanism, and decreased placental, which may adversely affect health outcomes.

Exaggerated mechanoreflex in early-stage type 1 diabetic rats: role of Piezo channels.

Recent findings have shown that muscle contraction evokes an exaggerated pressor response in type 1 diabetes mellitus (T1DM) rats; however, it is not known whether the mechanoreflex, which is commonly stimulated by stretching the Achilles tendon, contributes to this abnormal response. Furthermore, the role of mechano-gated Piezo channels, found on thin-fiber afferent endings, in evoking the mechanoreflex in T1DM is also unknown. Therefore, in male and female streptozotocin (STZ, 50 mg/kg)-induced T1DM and healthy control (CTL) rats, we examined the pressor and cardioaccelerator responses to tendon stretch during the early stage of the disease. To determine the role of Piezo channels, GsMTx-4, a selective Piezo channel inhibitor, was injected into the arterial supply of the hindlimb. At 1 wk after STZ injection in anesthetized, decerebrate rats, we stretched the Achilles tendon for 30 s and measured pressor and cardioaccelerator responses. We then compared pressor and cardioaccelerator responses to tendon stretch before and after GsMTx-4 injection (10 µg/100 ml). We found that the pressor (change in mean arterial pressure) response [41 ± 5 mmHg (n = 15) for STZ and 18 ± 3 mmHg (n = 11) for CTL (P < 0.01)] and cardioaccelerator (change in heart rate) response [18 ± 4 beats/min for STZ (n = 15) and 8 ± 2 beats/min (n = 11) for CTL (P < 0.05)] to tendon stretch were exaggerated in STZ rats. Local injection of GsMTx-4 attenuated the pressor [55 ± 7 mmHg (n = 6) before and 27 ± 9 mmHg (n = 6) after GsMTx-4 (P < 0.01)], but not the cardioaccelerator, response to tendon stretch in STZ rats and had no effect on either response in CTL rats. These data suggest that T1DM exaggerates the mechanoreflex response to tendon stretch and that Piezo channels play a role in this exaggeration.

Central Administration of Insulin Combined With Resistin Reduces Renal Sympathetic Nerve Activity in Rats Fed a High Fat Diet.

Insulin receptors are widely distributed in the central nervous system and their activation by insulin elicits renal sympatho-excitatory effects. Resistin, an adipokine, promotes resistance to the metabolic effects of insulin. Resistin also induces increases in renal sympathetic nerve activity (RSNA) by acting in the brain, but whether it can influence insulin’s actions on RSNA is unknown. In the present study we investigated, in male Sprague-Dawley rats (7–8 weeks of age), the effects of central administration of insulin combined with resistin on RSNA following a normal diet (ND) and a high fat diet (HFD) (22% fat), since HFD can reportedly attenuate insulin’s actions. RSNA, mean arterial pressure (MAP) and heart rate (HR) responses were monitored and recorded before and for 180 min after intracerebroventricular injection of saline (control) (n = 5 HFD and ND), resistin (7 μg; n = 4 ND, n = 5 HFD), insulin (500 mU; n = 6 ND, n = 5 HFD), and the combination of both resistin and insulin (n = 7 ND, n = 5 HFD). The key finding of the present study was that when resistin and insulin were combined there was no increase in RSNA induced in rats fed a normal diet or the high fat diet. This contrasted with the sympatho-excitatory RSNA effects of the hormones when each was administered alone in rats fed the ND and the HFD.

Cerebral and skeletal muscle feed artery vasoconstrictor responses in a mouse model with greater large elastic artery stiffness.

What is the central question of this study? Greater large artery stiffness is associated with dysfunctional resistance artery vasodilatory responses, impaired memory and greater risk of Alzheimer's disease. However, it is unknown whether stiffer large arteries affect cerebral and skeletal muscle feed artery responses to vasoconstrictors. What is the main finding and its importance? In a mouse model with greater large artery stiffness (Eln+/- ), we find an exacerbated vasoconstrictor response to angiotensinII in cerebral arteries, but not skeletal muscle feed arteries, thus implicating altered cerebral artery angiotensinII responsiveness in the poor brain outcomes associated with greater large artery stiffness. Greater stiffness of the large elastic arteries is associated with end-organ damage and dysfunction. At the same time, resistance artery vasoconstrictor responsiveness influences vascular tone and organ blood flow. However, it is unknown whether large elastic artery stiffness modulates the responsiveness to vasoconstrictors in resistance arteries of the cerebral or skeletal muscle circulations. We previously described the elastin haploinsufficient (Eln+/- ) mouse as a model with greater aortic stiffness, but with similar cerebral and skeletal muscle feed artery stiffness to wild-type (Eln+/+ ) mice. Here, we used this model to examine the relationship between large elastic artery stiffness and resistance artery vasoconstrictor responses. In middle cerebral arteries (MCAs), vasoconstriction in response to angiotensinII (AngII) was ∼40% greater in Eln+/- compared with Eln+/+ mice (P=0.02), and this group difference was ameliorated by losartan, indicating a role for AngII type1 receptors (AT1Rs). In gastrocnemius feed arteries, Eln+/- and Eln+/+ mice did not differ in the response to AngII. In addition, the vasoconstrictor responses to noradrenaline, endothelin-1 and potassium chloride were not different between Eln+/- and Eln+/+ mice for either MCAs or gastrocnemius feed arteries. The MCA AT1R gene expression did not differ between groups, whereas AngII type2 receptor gene expression was ∼50% lower in MCAs from Eln+/- versus Eln+/+ mice (P=0.01). In conclusion, greater large elastic artery stiffness is associated with an exacerbated vasoconstriction response to AngII in cerebral arteries, but is not associated with the responses to other vasoconstrictors in either cerebral or skeletal muscle feed arteries.

Current use of vasopressors in septic shock

BackgroundVasopressors are commonly applied to restore and maintain blood pressure in patients with sepsis. We aimed to evaluate the current practice and therapeutic goals regarding vasopressor use in septic shock as a basis for future studies and to provide some recommendations on their use.MethodsFrom November 2016 to April 2017, an anonymous web-based survey on the use of vasoactive drugs was accessible to members of the European Society of Intensive Care Medicine (ESICM). A total of 17 questions focused on the profile of respondents, triggering factors, first choice agent, dosing, timing, targets, additional treatments, and effects of vasopressors. We investigated whether the answers complied with current guidelines. In addition, a group of 34 international ESICM experts was asked to formulate recommendations for the use of vasopressors based on 6 questions with sub-questions (total 14).ResultsA total of 839 physicians from 82 countries (65% main specialty/activity intensive care) responded. The main trigger for vasopressor use was an insufficient mean arterial pressure (MAP) response to initial fluid resuscitation (83%). The first-line vasopressor was norepinephrine (97%), targeting predominantly a MAP > 60–65 mmHg (70%), with higher targets in patients with chronic arterial hypertension (79%). The experts agreed on 10 recommendations, 9 of which were based on unanimous or strong (≥ 80%) agreement. They recommended not to delay vasopressor treatment until fluid resuscitation is completed but rather to start with norepinephrine early to achieve a target MAP of ≥ 65 mmHg.ConclusionReported vasopressor use in septic shock is compliant with contemporary guidelines. Future studies should focus on individualized treatment targets including earlier use of vasopressors.

Blunted Nighttime Sympathetic Nervous System Response to Stress Among Thai Men with Positive Family History of Sudden Unexplained Nocturnal Death Syndrome.

Sudden unexplained nocturnal death syndrome (SUNDS) is prominent among northeast Thai men. This study tests the hypothesis that Thai men with positive family history of SUNDS display abnormal diurnal, autonomic nervous system responses to stress. Healthy northeast Thai men (20-49 years old) lived in the same rural area were divided into two groups based on their positive (PF) or negative family (NF1) history of SUNDS. A second control included Thai men with an NF history of SUNDS from a non-endemic area (NF2). All data were collected at 4:00-6:00 AM (nighttime) and 4:00-6:00 PM (daytime). All three groups displayed nighttime decreases in mean arterial pressure, heart rate, and blood glucose. Furthermore, all subjects displayed similar glucose tolerance and electrolyte balance. The tachycardic responses to a four-minute step test were similar among groups in the daytime, but the nighttime responses were significantly blunted in the PF group compared to either control group (about 20 bpm less). Tachycardic responses to a cold pressor test tended to decrease more during the nighttime in the PF compared to NF1 and NF2 groups, but the difference was not significant. Arterial pressure responses to the exercise were similar among the three groups during the nighttime, whereas in the NF2, daytime mean arterial pressures increased more than those in the other groups. The present data suggest that Thai men with a PF history of SUNDS display blunted sympathetic nervous system responses to stress during the nighttime, a potential factor that may trigger cardiac arrhythmias and contribute to SUNDS.