Autonomic Control Of Blood Pressure Research Articles

Circadian rhythm of blood pressure in patients with drug-resistant mesial temporal lobe epilepsy

ObjectiveTo determine whether patients with drug-resistant mesial temporal lobe epilepsy present with an alteration in the autonomic circadian regulation of blood pressure. MethodsA prospective case‒control study was designed, with a case group comprising patients with drug-resistant mesial temporal lobe epilepsy and a control group comprising healthy volunteers. Twenty-four-hour outpatient blood pressure monitoring was performed to assess the existence of a normal (dipping) or altered (non-dipping) circadian pattern. In addition, analytical and ultrasound parameters (carotid intima-media thickness) of vascular risk and sleep quality were evaluated. ResultsTwenty-four subjects were recruited in each study group, amongst whom no demographic differences or history of vascular risk were observed. A higher percentage of participants with a non-dipping pattern was observed in the group of patients with epilepsy (62.5% vs. 12.5, p = 0.001). In the case group, significant differences were also observed in carotid intima-media thickness, with a greater probability of presenting with pathological values (p = 0.022). ConclusionThe results suggest a disorder of the central autonomic control of blood pressure in patients with drug-resistant mesial temporal lobe epilepsy, with a greater probability of developing an alteration of the circadian rhythm of blood pressure. This dysfunction may be a factor involved in the increased cardiovascular risk in this population.

Abstract P232: Endothelin B Receptor Modulation Of Diurnal Blood Pressure Amplitude During High Salt Diet

High salt diet can alter baroreflex sensitivity. We have previously shown that rats deficient in endothelin B receptors (ET B -R) demonstrate an exaggerated diurnal blood pressure amplitude similar to that seen in rats with sinoaortic denervation fed a high salt diet. However, it remains unclear if ET B -R influence on baroreflex function is due to sensory or efferent mechanisms of autonomic blood pressure control. We employed selective ET B -R antagonism using A192621 in ET B -R deficient rats (ET B -def) that only express functional ET B -R on efferent nerves and transgenic controls (TG) to isolate the role of efferent vs sensory pathways. Rats with telemetry were fed a normal salt diet (0.49% NaCl) during baseline and osmotic minipump infusion of 10 mg/kg/day A192621 or vehicle. After one week of infusion, animals were fed a high salt (4.0% NaCl) diet. Selective ET B -R blockade increased 24 hr MAP in TG animals during normal salt diet (+16.4 ± 1.0 mmHg from baseline; n = 10; p < 0.001) but had no effect on ET B -def (-1.2 ± 1.8 mmHg; n = 7; p > 0.99 ). A192621 treated TG rats did not exhibit a further increase in pressure following high salt diet (+5.5 ± 1.3 mmHg; n = 6; p = 0.25), but both vehicle and A192621 treated ET B -def rats displayed a salt-sensitive increase in MAP (+15.9 ± 4.2 and +14.4 ± 4.5 mmHg; n = 3 and 4; p = 0.003 and 0.001, respectively). A192621 treatment had no significant effect on MAP amplitude (light-dark difference) in any group during normal salt diet. However, during high salt, A192621 treated TG animals had an increase in MAP amplitude (+9.7 ± 0.7 mmHg; n = 6; p = 0.002), and vehicle had no effect (+0.8 ± 0.8 mmHg; n = 5; p = 0.97). Both A192621 and vehicle treated ET B -def rats had a similar increase in amplitude following high salt diet (+9.3 ± 0.6 and +8.6 ± 1.4; n = 4 and 3; p = 0.001 and 0.018, respectively). In summary, antagonism of ET B -R increased MAP only in TG rats but did not have an effect on diurnal amplitude during normal salt in any group. Antagonism of ET B -R during high salt diet caused TG rats to exhibit a similarly high diurnal amplitude as ET B -def rats. These data suggest that blocking ET B -R on baroreflex sensory pathways are the mitigating cause for increased diurnal blood pressure rhythms during high salt diet.

The Stress Hormone ACTH Causes a Prolonged Reduction in Heart Rate Variability

Hypoglycemia is a complex stressor that activates multiple hormonal systems and the sympathetic nervous system. Hypoglycemia also impairs autonomic control of blood pressure. It is possible that stress hormones produced during hypoglycemia (such as ACTH) play a role in the attenuation of autonomic function after recurrent hypoglycemia known as “cardiovascular hypoglycemia‐associated autonomic failure”. Prior work from this placebo‐controlled cross‐over study has shown that ACTH infusion reduces Modified Oxford baroreflex gain and that the reduction persists to the following day. The purpose of this analysis was to determine whether measures of heart rate variability (HRV) demonstrate a similar pattern. In the original study, men and women aged 18 – 55 years (n = 22) completed 2 study visits (ACTH or placebo in random order) with a 1–3‐month washout period between. A study visit consisted of a 3‐day/2‐night inpatient stay with the infusion occurring on day 2. Standard HRV measures from 3 minutes of 0.1 Hz breathing (6 breaths/minute) were collected on each of the 3 days. Overall HRV (time or frequency domain), as well as low frequency HRV, were reduced on the infusion day and the day after by ACTH, with no effect on blood pressure variability. Low‐frequency transfer function gain was similarly reduced, but only on day 3. In addition, these frequency domain gains were significantly correlated with the Modified Oxford derived gains. These results suggests that the ACTH impairment of autonomic control of blood pressure is reflected in HRV measures.

Loss of Female Sex Hormones Does Not Further Elevate Blood Pressure in Obese Female Mice but Preserves the Contribution of Leptin to Hypertension

Obesity, which is a major risk factor for hypertension and cardiovascular disease, abolishes the cardioprotective effects of female sex hormones and predisposes women to hypertension. Although 40% of postmenopausal women are obese and 75% are hypertensive, the mechanisms whereby obesity and menopause interact to elevate blood pressure (BP) remains unknown. Formerly, our laboratory demonstrated that hypertension involves leptin‐mediated increases in aldosterone production in obese female mice of reproductive age. Herein, we hypothesized that loss of female sex hormones with ovariectomy (OVX) will further elevate BP and impairs vascular function in obese female mice. Obese agouti yellow mice (Ay) on a KK background and lean controls underwent OVX or sham surgery at 12‐week of age. At 15 weeks, mice were implanted with radiotelemeters to record BP under baseline conditions and in response to leptin receptor blockade (Allo‐Aca, 0.05mg/kg/day s.c. osmotic minipump). To ascertain the effects of OVX on autonomic control of BP, we recorded BP and heart rate (HR) responses to ganglionic blockade (hexamethonium), atropine, and propranolol. At 18 weeks, mice were euthanized and mesenteric arteries isolated to measure endothelial function via wire myography. Obesity significantly increased mean arterial pressure (MAP), systolic BP, diastolic BP, and HR but OVX did not further elevate BP. Interestingly, obesity also disrupted circadian rhythm. Unexpectedly, OVX significantly reduced MAP response to ganglionic blockade (2‐way ANOVA, P<0.05) in obese mice but preserved HR responses to propranolol and atropine respectively suggesting lower neurogenic control of BP. Allo‐Aca treatment significantly decreased (2‐way ANOVA, P<0.05) MAP in both sham and OVX obese mice, indicating BP elevation remains leptin‐dependent. Obesity significantly impaired relaxation to acetylcholine (2‐way ANOVA, P<0.05) but OVX did not further impair relaxation. Compared to lean controls, LNAME further reduced (2‐way ANOVA, P=0.054) relaxation responses to acetylcholine in obese OVX mice suggesting greater contribution of nitric oxide synthase activity to vascular relaxation. Quantitative real‐time PCR showed a trend for decreased adrenal aldosterone synthase (CYP11B2) expression in obese OVX mice. Interestingly, menopause induced a similar decrease in CYP11B2 expression in human adrenal tissue collected from kidney donors with elevated BMIs (postmenopausal 56 yo female: BMI 27.4, vs. premenopausal 43 yo female, BMI 32). Quantification of mouse plasma aldosterone levels via LC‐MS revealed no significant difference in circulating aldosterone levels, suggesting that tissue(s) other than the adrenals could potentially produce aldosterone in obese OVX mice. Plasma analysis also revealed Allo‐Aca treatment increased ANG II, ANG I and ANG 1‐7 in obese mice. In conclusion, these data suggest that obesity‐associated hypertension remains leptin dependent in the absence of female sex hormone and that female sex steroids play limited role in the control of the development of hypertension associated with obesity.

Direct evidence of VEGF-mediated neuroregulation and afferent explanation of blood pressure dysregulation during angiogenic therapy

Abstract Objective Oncocardiology is increasingly hot research field/topic in the clinical management of cancer with anti-angiogenic therapy of vascular endothelial growth factor (VEGF) that may cause cardiovascular toxicity, such as hypertension via vascular dysfunction and attenuation of eNOS/NO signaling in the baroreflex afferent pathway. The aim of the current study was to evaluate the potential roles of VEGF/VEGF receptors (VEGFRs) expressed in the baroreflex afferent pathway in autonomic control of blood pressure (BP) regulation. Methods The distribution and expression of VEGF/VEGFRs were detected in the nodose ganglia (NG) and nucleus of tractus solitary (NTS) using immunostaining and molecular approaches. The direct role of VEGF was tested by NG microinjection under physiological and hypertensive conditions. Results Immunostaining data showed that either VEGF or VEGFR2/VEGFR3 was clearly detected in the NG and NTS of adult male rats. Microinjection of VEGF directly into the NG reduced the mean blood pressure (MBP) dose-dependently, which was less dramatic in renovascular hypertension (RVH) rats, suggesting the VEGF-mediated depressor response by direct activation of the 1st-order baroreceptor neurons in the NG under both normal and disease conditions. Notably, this reduced depressor response in RVH rats was directly caused by the downregulation of VEGFR2, which compensated the up regulation of VEGF/VEGFR3 in the NG during the development of hypertension. Conclusion It demonstrated for the first time that the BP-lowering property of VEGF/VEGFRs signaling via the activation of baroreflex afferent function may be a common target/pathway leading to BP dysregulation in anti-angiogenic therapy.

Central Administration of Hydrogen Sulfide Donor NaHS Reduces Iba1-Positive Cells in the PVN and Attenuates Rodent Angiotensin II Hypertension.

Hydrogen sulfide (H2S) is a gaseous signaling molecule with neuromodulatory, anti-inflammatory, and anti-hypertensive effects. Here, we investigate whether chronic intracerebroventricular (ICV) infusion of sodium hydrosulfide (NaHS), an H2S donor, can alleviate angiotensin II (Ang II)–induced hypertension (HTN), improve autonomic function, and impact microglia in the paraventricular nucleus (PVN) of the hypothalamus, a brain region associated with autonomic control of blood pressure (BP) and neuroinflammation in HTN. Chronic delivery of Ang II (200 ng/kg/min, subcutaneous) for 4 weeks produced a typical increase in BP and sympathetic drive and elevated the number of ionized calcium binding adaptor molecule 1–positive (Iba1+) cells in the PVN of male, Sprague–Dawley rats. ICV co-infusion of NaHS (at 30 and/or 60 nmol/h) significantly attenuated these effects of Ang II. Ang II also increased the abundance of cecal Deltaproteobacteria and Desulfovibrionales, among others, which was prevented by ICV NaHS co-infusion at 30 and 60 nmol/h. We observed no differences in circulating H2S between the groups. Our results suggest that central H2S may alleviate rodent HTN independently from circulating H2S via effects on autonomic nervous system and PVN microglia.

Low-frequency component of photoplethysmogram reflects the autonomic control of blood pressure

The question of how much information the photoplethysmogram (PPG) signal contains on the autonomic regulation of blood pressure (BP) remains unsolved. This study aims to compare the low-frequency (LF) and high-frequency components of PPG and BP and assess their correlation with oscillations in interbeat (RR) intervals at similar frequencies. The PPG signal from the distal phalanx of the right index finger recorded using a reflective PPG sensor at green light, the BP signal from the left hand recorded using a Finometer, and RR intervals were analyzed. These signals were simultaneously recorded within 15 min in a supine resting condition in 17 healthy subjects (12 males and 5 females) aged 33 ± 9 years (mean ± SD). The study revealed the high coherence of LF components of PPG and BP with the LF component of RR intervals. The high-frequency components of these signals had low coherence. The analysis of the signal instantaneous phases revealed the presence of high-phase coherence between the LF components of PPG and BP. It is shown that the LF component of PPG is determined not only by local myogenic activity but also reflects the processes of autonomic control of BP.

Brain Cellular Senescence as a Potential Mediator of Angiotensin II‐Induced Hypertension

Hypertension affects 1 in 3 US adults and is a leading risk factor for heart attack and stroke. The peptide hormone angiotensin II (Ang II) is a well-recognized driver of hypertension, particularly through its sympathoexcitatory actions within the central nervous system (CNS). Although a number of pro-hypertensive CNS mechanisms (i.e. neurogenic hypertension) have been elucidated, including oxidative and endoplasmic reticulum stress, how these mechanisms translate into long-term alterations in CNS circuits remains unclear. Intriguingly, stress-associated pathways can culminate in cellular senescence and the senescence-associated secretory phenotype (SASP). Chronic senescence/SASP leads to marked changes in cell metabolism, macromolecule damage, and a pro-inflammatory environment. Based on this, we hypothesized that CNS cellular senescence may be a key contributor to neurogenic hypertension. We first performed a proof-of-principle experiment to determine if CNS cellular senescence is involved in blood pressure regulation. C57Bl/6J male mice were fitted with intracerebroventricular (ICV) cannulas and underwent implantation of radiotelemeters for conscious recording of cardiovascular parameters. Following surgical recovery, the senescence inducing agent doxorubicin (0.00125 mg) or vehicle control was administered daily over three days (n=3/group). Daily ICV administration of doxorubicin resulted in marked elevations in mean arterial blood pressure within 48 hours that were sustained throughout the study (72 hours: 107±1 vs. 123±1 mmHg; ICV vehicle vs. doxorubicin, p<0.05). Relative to controls, ganglionic blockade (i.p. chlorisondamine 12 mg/kg) elicited a greater fall in blood pressure in doxorubicin-treated animals (Δ-11±4 vs. Δ-56±6 mmHg; ICV vehicle vs. doxorubicin, p<0.05). Given these findings that CNS cellular senescence is associated with a hypertensive phenotype, likely through alterations in autonomic control of blood pressure, we next profiled cellular senescence in key cardioregulatory nuclei during hypertension development. Male C57Bl/6J mice were implanted with subcutaneous osmotic minipumps for chronic infusion of Ang II (600 ng/kg/min). Brains were collected at baseline and after 14 days of Ang II infusion (n=4-5/group) and micropunches of cardiovascular and autonomic nuclei including the organum vasculosum lamina terminalis (OVLT), subfornical organ (SFO), and paraventricular nucleus of the hypothalamus (PVN) were collected. Two-week infusion of Ang II resulted in a robust increase in the key senescent gene p16 (CDKN2A) in the SFO (6.1±0.8 fold baseline, p<0.05). Interestingly, Ang II-induced hypertension was not associated with changes in p16 in the OVLT (2.2±0.7 fold baseline, p=0.2) and PVN (1.5±0.4 fold baseline, p=0.4). Additionally, Ang II-induced senescence in the SFO was paralleled by the upregulation of SASP indicators (e.g. Interleukin-1α: 6.5±1.4 fold baseline, p<0.05). Together, these findings indicate that: 1) CNS cellular senescence is pro-hypertensive; and 2) Ang II elicits cellular senescence/SASP in the SFO. Collectively, our data may point to brain cellular senescence as a novel mediator of hypertension.

Assessment of Alamandine in Pulmonary Fibrosis and Respiratory Mechanics in Rodents.

Introduction Pulmonary fibrosis (PF) is characterized by an accelerated decline in pulmonary function and has limited treatment options. Alamandine (ALA) is a recently described protective peptide of the renin-angiotensin system (RAS) with essential tasks in several conditions. Our group previously demonstrated that ALA is reduced by 365% in the plasma of patients with idiopathic PF, and thus, it is plausible to believe that stimulation of this peptide could represent an important therapeutic target. In this sense, this study investigates the effects of ALA in an experimental model of PF. Materials and Methods Bleomycin (BLM) was administrated in Wistar rats, and these fibrotic animals were treated with ALA for 14 days. Body weight, histology, respiratory, and hemodynamic parameters were analyzed to study the effects of ALA. Results ALA treatment attenuated the development of fibrosis (P < 0.0001), reduced respiratory system elastance (P < 0.0001), and preserved weight gain (P < 0.0001) in fibrotic animals without affecting the autonomic control of blood pressure and heart rate. Conclusion The data from this study demonstrate the potential of ALA to alleviate pulmonary fibrosis and improve respiratory system mechanics in vivo. The promising results encourage more detailed investigations of the potential of ALA as a future and efficient antifibrotic.

Central and peripheral modulation of exercise pressor reflex sensitivity after nonfatiguing work.

Autonomic blood pressure control is fundamentally altered during a single bout of exercise, as evidenced by the downward resetting of the baroreflex following exercise (postexercise hypotension). However, it is unclear if an acute bout of exercise is also associated with a change in the sensitivity of the exercise pressor response to a controlled stimulus, such as a static contraction. This study tested the hypothesis that the blood pressure response to a controlled static contraction would be attenuated after unilateral cycling of the contralateral (opposite) leg, but preserved after cycling of the ipsilateral (same) leg. To test this, the blood pressure response to 90 s of isometric plantar flexion [50% maximal voluntary contraction (MVC)] was compared before and after 20 min of contralateral and ipsilateral single-leg cycling at 20% peak oxygen consumption and rest (control) in 10 healthy subjects (three males and seven females). The mean arterial pressure response was significantly attenuated after contralateral single-leg cycling (+9.8 ± 7.5% ∆mmHg vs. +6.7 ± 6.6% ∆mmHg pre and postexercise, respectively, P = 0.04) and rest (+9.0 ± 7.5% ∆mmHg vs. +6.6 ± 5.2% ∆mmHg pre and postexercise, respectively, P = 0.03). In contrast, the pressor response nonsignificantly increased following ipsilateral single-leg cycling (+5.5 ± 5.2% ∆mmHg vs. +8.9 ± 7.2% ∆mmHg pre and postexercise, respectively, P = 0.08). The heart rate, leg blood flow, and leg conductance responses to plantar flexion were not affected by any condition (P ≥ 0.12). These results are consistent with the notion that peripheral, but not central mechanisms promote exercise pressor reflex sensitivity after exercise.

Symptom severity impacts sympathetic dysregulation and inflammation in post-traumatic stress disorder (PTSD)

Post-traumatic stress disorder (PTSD) is associated with a greater risk of incident hypertension and cardiovascular disease. Inflammation, impaired baroreflex sensitivity (BRS) decreased parasympathetic nervous system (PNS) and overactive sympathetic nervous system (SNS) activity are suggested as contributing mechanisms. Increasing severity of PTSD symptoms has been linked to greater cardiovascular risk; however, the impact of PTSD symptom severity on inflammation and autonomic control of blood pressure has not yet been explored. We hypothesized that increasing PTSD symptom severity is linked to higher inflammation, greater SNS activity, lower PNS reactivity and impaired BRS. Seventy Veterans participated in this study: 28 with severe PTSD ((Clinical Administered PTSD Scale (CAPS) > 60; S-PTSD), 16 with moderate PTSD (CAPS ≥ 45 ≤ 60; M-PTSD) and 26 Controls (CAPS < 45; NO-PTSD). We recorded continuous blood pressure (BP), heart rate (HR) via EKG, heart rate variability (HRV) markers reflecting PNS and muscle sympathetic nerve activity (MSNA) at rest, during arterial baroreflex sensitivity (BRS) testing via the modified Oxford technique, and during 3 min of mental stress via mental arithmetic. Blood samples were analyzed for 12 biomarkers of systemic and vascular inflammation. While BP was comparable between severity groups, HR tended to be higher (p = 0.055) in S-PTSD (76 ± 2 beats/min) than in Controls (67 ± 2 beats/min) but comparable to M-PTSD (70 ± 3 beats/min). There were no differences in resting HRV and MSNA between groups; however, cardiovagal BRS was blunted (p = 0.021) in S-PTSD (10 ± 1 ms/mmHg) compared to controls (16 ± 3 ms/mmHg) but comparable to M-PTSD (12 ± 2 ms/mmHg). Veterans in the S-PTSD group had a higher (p < 0.001) combined inflammatory score compared to both M-PTSD and NO-PTSD. Likewise, while mental stress induced similar SNS and cardiovascular responses between the groups, there was a greater reduction in HRV in S-PTSD compared to both M-PTSD and NO-PTSD. In summary, individuals with severe PTSD symptoms have higher inflammation, greater impairment of BRS, a trend towards higher resting HR and exaggerated PNS withdrawal at the onset of mental stress that may contribute to cardiovascular risk in severe PTSD.

Long‐Term Effects of Device‐Guided Slow Breathing on Autonomic Control of Blood Pressure at Rest and During Stress in Post‐Traumatic Stress Disorder

Post‐traumatic stress disorder (PTSD) is characterized by augmented sympathetic nervous system (SNS) reactivity, impaired baroreflex sensitivity (BRS), and an increased risk for developing hypertension and cardiovascular disease. We recently showed that device‐guided slow breathing (DGB) using the RESPeRATE device acutely lowers blood pressure (BP) and muscle sympathetic activity (MSNA) and improves sympathetic BRS in PTSD. The aim of this study was to determine if long‐term daily DGB leads to sustained improvements in resting MSNA, BP, sympathetic BRS, and neurocirculatory reactivity during mental stress in combat veterans with PTSD. 19 post 9/11 veterans with PTSD (age, 36±2 years) were enrolled and randomized to either 8 weeks of DGB (n=9) versus an identical Sham device (n=10) for 15 minutes daily. Using biofeedback and musical tones, DGB guided respiratory rate (RR) to a subphysiologic rate of 5–6 breaths/min, while Sham guided RR to a normal rate of 12–14 breaths/min. BP, heart rate (HR), RR and MSNA were measured at rest and during 3 minutes of mental arithmetic (MA). Sympathetic and cardiovagal BRS were assessed with pharmacologic manipulation of BP using the modified Oxford technique. All physiologic measures were obtained before, and after 8 weeks of breathing intervention. Age, BMI, BP and HR were similar between the groups, while baseline MSNA at rest was greater in the DGB group pre‐intervention (p=0.048). Contrary to our hypothesis, there was no difference in the change in resting systolic BP (visit*group, p=0.097), diastolic BP (visit*group, p=0.571), HR (visit*group, p=0.323) and RR (visit*group, p=0.304) after 8 weeks of DGB versus Sham. There was a trend towards a difference in change in resting MSNA between the groups (visit*group, p=0.081). However, contrary to our hypothesis, there was no change in resting MSNA from pre to post 8 weeks of DGB (19±4 vs 20±2 burst/min, p&gt;0.05), while there was an increase in resting MSNA after 8 weeks of Sham (9±2 vs 19±3 burst/min, p&lt;0.001). There was no difference in change in cardiovagal BRS between the groups (visit*group, p= 0.139). Meanwhile, sympathetic BRS (visit*group, p=0.031) was not altered by 8 weeks of DGB (−1.47±0.5 vs 1.13±0.4, p=0.401), but improved with 8 weeks of Sham (−0.63±0.3 vs 1.45±0.4, p=0.032). During stress, neural and hemodynamic responses to MA (time*visit*group, p &gt;0.05 for BP, HR and MSNA) were not different between the treatment groups. In summary, although our previous data showed that DGB acutely improves SNS activity and regulation in PTSD, we observed no sustained improvements in resting MSNA, BRS, hemodynamics, or neurocirculatory reactivity during mental stress with long‐term DGB in PTSD.Support or Funding InformationSupported by NIH HL‐098744, NIH DK‐00756, VA Merit I01CX001065, AHA 15CSA24340001This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Blood pressure variability, heart functionality, and left ventricular tissue alterations in a protocol of severe hemorrhagic shock and resuscitation.

Autonomic control of blood pressure (BP) and heart rate (HR) is crucial during bleeding and hemorrhagic shock (HS) to compensate for hypotension and hypoxia. Previous works have observed that at the point of hemodynamic decompensation a marked suppression of BP and HR variability occurs, leading to irreversible shock. We hypothesized that recovery of the autonomic control may be decisive for effective resuscitation, along with restoration of mean BP. We computed cardiovascular indexes of baroreflex sensitivity and BP and HR variability by analyzing hemodynamic recordings collected from five pigs during a protocol of severe hemorrhage and resuscitation; three pigs were sham-treated controls. Moreover, we assessed the effects of severe hemorrhage on heart functionality by integrating the hemodynamic findings with measures of plasma high-sensitivity cardiac troponin T and metabolite concentrations in left ventricular (LV) tissue. Resuscitation was performed with fluids and norepinephrine and then by reinfusion of shed blood. After first resuscitation, mean BP reached the target value, but cardiovascular indexes were not fully restored, hinting at a partial recovery of the autonomic mechanisms. Moreover, cardiac troponins were still elevated, suggesting a persistent myocardial sufferance. After blood reinfusion all the indexes returned to baseline. In the harvested heart, LV metabolic profile confirmed the acute stress condition sensed by the cardiomyocytes. Variability indexes and baroreflex trends can be valuable tools to evaluate the severity of HS, and they may represent a more useful end point for resuscitation in combination with standard measures such as mean values and biological measures.NEW & NOTEWORTHY Autonomic control of blood pressure was highly impaired during hemorrhagic shock, and it was not completely recovered after resuscitation despite global restoration of mean pressures. Moreover, a persistent myocardial sufferance emerged from measured cardiac troponin T and metabolite concentrations of left ventricular tissue. We highlight the importance of combining global mean values and biological markers with measures of variability and autonomic control for a better characterization of the effectiveness of the resuscitation strategy.

Comparison of Autonomic Control of Blood Pressure During Standing and Artificial Gravity Induced via Short-Arm Human Centrifuge.

Autonomic control of blood pressure is essential toward maintenance of cerebral perfusion during standing, failure of which could lead to fainting. Long-term exposure to microgravity deteriorates autonomic control of blood pressure. Consequently, astronauts experience orthostatic intolerance on their return to gravitational environment. Ground-based studies suggest sporadic training in artificial hypergravity can mitigate spaceflight deconditioning. In this regard, short-arm human centrifuge (SAHC), capable of creating artificial hypergravity of different g-loads, provides an auspicious training tool. Here, we compare autonomic control of blood pressure during centrifugation creating 1-g and 2-g at feet with standing in natural gravity. Continuous blood pressure was acquired simultaneously from 13 healthy participants during supine baseline, standing, supine recovery, centrifugation of 1-g, and 2-g, from which heart rate (RR) and systolic blood pressure (SBP) were derived. The autonomic blood pressure regulation was assessed via spectral analysis of RR and SBP, spontaneous baroreflex sensitivity, and non-linear heart rate and blood pressure causality (RR↔SBP). While majority of these blood pressure regulatory indices were significantly different (p < 0.05) during standing and 2-g centrifugation compared to baseline, no change (p > 0.05) was observed in the same indices during 2-g centrifugation compared to standing. The findings of the study highlight the capability of artificial gravity (2-g at feet) created via SAHC toward evoking blood pressure regulatory controls analogous to standing, therefore, a potential utility toward mitigating deleterious effects of microgravity on cardiovascular performance and minimizing post-flight orthostatic intolerance in astronauts.

Sex-specific factors regulating pressure and flow.

What is the topic of this review? There are sex- and sex-hormone-specific differences in autonomic control of blood pressure, central haemodynamics and cerebral blood flow. What advances does it highlight? Sex differences in autonomic control of blood pressure may underlie other sex-specific characteristics associated with cerebral blood flow, which can, in turn, affect tissue function. Over the last decade, there have been many published reports on sex differences in blood pressure regulation between young men and young women. The autonomic nervous system is a primary contributor to both acute and long-term blood pressure regulation. Sex differences in blood pressure regulation are likely to have effects that extend beyond mean arterial pressure and that can affect blood flow and tissue function. This short review includes recent literature from our laboratory focusing on autonomic control of the circulation, specifically age- and sex-hormone-related differences in central haemodynamics and cerebral blood flow, and discusses potential clinical implications.

Abstract P204: Gender-specific Relationships Between Plasma Levels of Endocannabinoids and Vagal and Sympathetic Control of Heart Rate in Normotensive Obese Older Adults

Previous studies in obese individuals indicate higher circulating endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) than in lean counterparts. However, the association between plasma endocannabinoids and autonomic control of blood pressure and heart rate has not been assessed in obesity. In a sample of normotensive, obese older adults we analyzed plasma content of the endocannabinoids AEA and total AG using mass spectrometry and examined correlations with various indices of spontaneous sympathovagal activity. Spontaneous baroreflex sensitivity (BRS) for heart rate control was calculated by spectral analysis of arterial pressure (AP) time (Sequence [Seq] Up, Seq Down and Seq All) and frequency (low-frequency [LF] and high-frequency [HF] α) domains from continuous resting AP recordings. In addition, time domain analysis was used to calculate heart rate variability (HRV) and blood pressure variability, indices of cardiac vagal tone and vascular sympathetic tone, respectively. The sample included 8 males and 17 females with a mean age of 68.4 ± 0.6 years, a mean body mass index of 35.0 ± 0.8 kg/m 2 , and mean AP of 101.0 ± 2.2 mmHg. Across the complete sample, we report a significant inverse correlation between plasma AG content and HFα, an index of the vagally-mediated parasympathetic spontaneous BRS ( r = -0.50, P &lt; 0.05). We further report a significant inverse correlation between plasma AG and the vagal spontaneous BRS (Seq Up) in males ( r = -0.87, P &lt; 0.01) but not in females. However, in females but not males we found significant positive relationships between AEA and LFα, an index of sympathetic spontaneous BRS ( r = 0.49, P &lt; 0.05), and AEA and HRV ( r = 0.50, P &lt; 0.05). These results are consistent with a role for the endocannabinoid system to modulate autonomic control of the circulation in populations at risk for hypertension and cardiovascular disease, and suggest gender differences that have yet to be elucidated.

Abstract P127: Chromogranin A Pathway: From Pathogenic Molecule to Renal Disease

Introduction: Chromogranin A (CHGA) is released into circulation with catecholamine from secretory granules of chromaffin cells and post-ganglionic sympathetic neurons. Several CHGA gene polymorphisms contributing to traits of autonomic blood pressure control, hypertension and hypertensive nephropathy have been identified. Plasma CHGA is elevated in hypertension and renal failure. This study seeks to understand the role of CHGA in the progression of CKD/ ESRD. Hypothesis: Kidney injury results in elevated expression of CHGA which in turn affects biochemical and physiological traits that determine progression and development of CKD/ESRD. Methods: The remnant kidney model was used to investigate the influence of CHGA on kidney function in response to injury. Distinction in response to kidney injury in wild-type (WT) and Chga-/- (KO) mice was evaluated by measuring glomerular function, fibrosis and microarray analysis. Mesangial cells were treated with CHGA to delineate pathway leading to inflammation and fibrosis. Results: Nephrectomy (Npx) exacerbated azotemia in WT mice compared to their KO counterparts. WT-Npx mice displayed far excess fibrosis as equated with KO-Npx. Gene expression profiling revealed greater mitochondrial dysfunction due to Npx in WT mice. Mesangial cells in culture treated with CHGA, triggered NO release, by a signaling mechanism involving SR-A. CHGA treatment augmented NO production by a 2-step mechanism involving upregulation of iNOS and the arginine transporter Slc7a7. CHGA-treated vs. untreated cells exhibited differential involvement of cytokine, chemokine, complement, acute phase pro-inflammatory markers and apoptotic pathway genes. Plasma creatinine and CHGA was measured in a twin population (N=740) and an inverse correlation between GFR and CHGA was observed. Therefore, in both mice and humans an inverse correlation suggested decrease in glomerular function with increasing plasma CHGA concentration. Conclusions: Kidney injury leads to elevated levels of CHGA which serves as an insult to the mesangial cells resulting in reduction of mitochondrial efficiency, concerted transcription of genes involved in NO production, inflammation and fibrosis, progression of CKD and development of ESRD.

Premature vascular deterioration in young patients affected by Wilson’s disease: a pilot study

Introduction: Wilson’s disease (WD) is a genetically inherited pathology which leads to an excessive deposition of copper in the human tissues, most of all in those of liver and brain. Even the cardiovascular system may be involved, although heart and vessels in those suffering from WD were fleetingly studied. This research aimed at evaluating the autonomic control of blood pressure (BP) and the endothelial function in a sample of young WD subjects. Methods: Eleven WD individuals were recruited in the study (54% females; mean age and age at diagnosis: 16.3 ± 5.0 and 8.3 ± 4.0 years, respectively). BP was measured at the right arm (supine and upright after 3 minutes of standing) and ankle-brachial index (ABI) was evaluated as well. WD findings were compared with those of healthy peers (controls). Results: In those with WD, systolic BP in the upright position raised when compared to the value in the supine position (128 ± 2 vs 112 ± 3 mmHg, p < 0.002), while declined in the controls. ABI was significantly lower in WD group (0.9 ± 0.2 vs 1.1 ± 0.1 in the control group, p < 0.05) and an inverse correlation was found between the disease duration and ABI as well (r = -0.66, p < 0.03). Conclusions: These preliminary results suggest an early vascular de­terioration in WD patients, notwithstanding their very young age and concomitant copper-chelating treatment. Although the heart and vessels are not the main target of WD, the detection of this unique population, potentially predisposed to cardiovascular accidents, suggests to enhance strategies of primary prevention.

Neural control of blood pressure in women: differences according to age.

The blood pressure "error signal" represents the difference between an individual's mean diastolic blood pressure and the diastolic blood pressure at which 50% of cardiac cycles are associated with a muscle sympathetic nerve activity burst (the "T50"). In this study we evaluated whether T50 and the error signal related to the extent of change in blood pressure during autonomic blockade in young and older women, to study potential differences in sympathetic neural mechanisms regulating blood pressure before and after menopause. We measured muscle sympathetic nerve activity and blood pressure in 12 premenopausal (25±1years) and 12 postmenopausal women (61±2years) before and during complete autonomic blockade with trimethaphan camsylate. At baseline, young women had a negative error signal (-8±1 versus 2±1mmHg, p<0.001; respectively) and lower muscle sympathetic nerve activity (15±1 versus 33±3bursts/min, p<0.001; respectively) than older women. The change in diastolic blood pressure after autonomic blockade was associated with baseline T50 in older women (r=-0.725, p=0.008) but not in young women (r=-0.337, p=0.29). Women with the most negative error signal had the lowest muscle sympathetic nerve activity in both groups (young: r=0.886, p<0.001; older: r=0.870, p<0.001). Our results suggest that there are differences in baroreflex control of muscle sympathetic nerve activity between young and older women, using the T50 and error signal analysis. This approach provides further information on autonomic control of blood pressure in women.

Cardiovascular Response Patterns to Sympathetic Stimulation by Central Hypovolemia.

In healthy subjects, variation in cardiovascular responses to sympathetic stimulation evoked by submaximal lower body negative pressure (LBNP) is considerable. This study addressed the question whether inter-subject variation in cardiovascular responses coincides with consistent and reproducible responses in an individual subject. In 10 healthy subjects (5 female, median age 22 years), continuous hemodynamic parameters (finger plethysmography; Nexfin, Edwards Lifesciences), and time-domain baroreflex sensitivity (BRS) were quantified during three consecutive 5-min runs of LBNP at −50 mmHg. The protocol was repeated after 1 week to establish intra-subject reproducibility. In response to LBNP, 5 subjects (3 females) showed a prominent increase in heart rate (HR; 54 ± 14%, p = 0.001) with no change in total peripheral resistance (TPR; p = 0.25) whereas the other 5 subjects (2 females) demonstrated a significant rise in TPR (7 ± 3%, p = 0.017) with a moderate increase in HR (21 ± 9%, p = 0.004). These different reflex responses coincided with differences in resting BRS (22 ± 8 vs. 11 ± 3 ms/mmHg, p = 0.049) and resting HR (57 ± 8 vs. 71 ± 12 bpm, p = 0.047) and were highly reproducible over time. In conclusion, we found distinct cardiovascular response patterns to sympathetic stimulation by LBNP in young healthy individuals. These patterns of preferential autonomic blood pressure control appeared related to resting cardiac BRS and HR and were consistent over time.