Baroreflex Buffering Research Articles

Complete autonomic blockade reveals nitric oxide contribution to blood pressure regulation in obese Black women

PurposeHypertension is one of the major causes of cardiovascular morbidity and mortality in the USA and disproportionately affects Black women. Endothelial-derived nitric oxide (eNO) substantially regulates blood pressure in humans, and impaired NO-mediated vasodilation has been reported in the Black population. Previous studies using an NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA) did not fully determine the NO contribution to blood pressure because of baroreflex buffering. Therefore, in the present study we used trimethaphan, a ganglionic blocker, to inhibit baroreflex buffering and study NO modulation of blood pressure in Black women during L-NMMA infusion.MethodsL-NMMA at doses of 250 μg/kg per minute was infused in combination with trimethaphan at doses of 4 mg/min to eliminate baroreflex mechanisms. Heart rate (HR) was obtained with continuous electrocardiogram monitoring, and continuous blood pressure was measured with the volume clamp method. The increase in systolic blood pressure (SBP) during both infusions was used to estimate the contribution of NO to blood pressure.ResultsTen Black (age range 30–50 years, body mass index [BMI] 30–45 kg/m2), and nine White women (age range 30–50 years, body mass index 30–45 kg/m2) were enrolled in this study. During autonomic blockade, there was no difference in the decrease in SBP between Black and White women (− 20 ± 16.45 vs. − 24 ± 15.49 mm Hg, respectively; P = 0.659). When autonomic blockade was combined with L-NMMA, Black women had a significant increase in SBP compared to White women (54 ± 13.62 vs. 39 ± 09.64 mm Hg, respectively; P = 0.022, respectively).ConclusionAutonomic blood pressure regulation was similar between Black and White women. However, NO contribution to blood pressure was significantly greater in Black women compared to White women.RegistrationClinicalTrials.gov: NCT01122407.

The Arterial Baroreflex Buffers Muscle Metaboreflex-Induced Coronary Vasoconstriction

The ability to increase cardiac output and thereby skeletal muscle blood flow during dynamic exercise is paramount to maintaining exercise workload. Increases in cardiac output are driven via increases in heart rate, ventricular function, and central blood volume mobilization which raises arterial blood pressure, in part, due to activation of the muscle metaboreflex. The increase in cardiac sympathetic tone also activates coronary vascular alpha-adrenergic receptors which restrains increases in coronary blood flow which limits increases in ventricular function. During submaximal dynamic exercise, the muscle metaboreflex acts primarily to raise cardiac output with little net peripheral vasoconstriction. However, after sinoaortic baroreceptor denervation (SAD), the muscle metaboreflex causes increases in both cardiac output and total peripheral resistance indicating that the baroreflex buffers the muscle metaboreflex mainly via restraint of peripheral vasoconstriction. To what degree the arterial baroreflex restrains muscle metaboreflex-induced coronary vasoconstriction is unknown. Therefore, we utilized our chronically instrumented canine model to evaluate if SAD would significantly impact muscle metaboreflex-induced coronary vasoconstriction. Canines were chronically instrumented to measure cardiac output, left circumflex coronary artery blood flow, hindlimb blood flow and arterial blood pressure. During steady-state mild treadmill exercise (3.2 kph, 0% grade) the muscle metaboreflex was activated via partial inflation of vascular occluders placed distal to the hindlimb blood flow probe. Metaboreflex activation caused substantial increases in cardiac output, heart rate, cardiac power, coronary blood flow, and arterial blood pressure. Assessment of coronary vasodilation was performed via linear regression of the relationship between coronary vascular conductance (CVC; coronary blood flow/mean arterial pressure) vs. cardiac power (CP, an index of O2 demand). Experiments were performed at least 2 weeks after chronic bilateral SAD. Muscle metaboreflex activation after SAD caused a significantly greater pressor response driven by increases in both cardiac output and total peripheral resistance. Furthermore, after SAD the slope of the CVC-CP relationship was significantly lower during muscle metaboreflex activation (0.072 ml/min/mmHg/Watt, control vs 0.033 ml/min/mmHg/Watt, SAD; p<0.05) We conclude that the arterial baroreflex buffers the muscle metaboreflex and restrains the reflex coronary vasoconstriction. This baroreflex-induced restraint of metaboreflex mediated coronary vasoconstriction potentially limits metaboreflex-induced reductions myocardial oxygen delivery. Augmented coronary vasoconstriction with metaboreflex activation after SAD likely contributes to the smaller role of cardiac output in mediating the rise in arterial blood pressure after SAD, and provides further evidence that baroreflex buffering of metaboreflex responses improves cardiac function. Thus, reduced baroreflex function in heart failure may contribute to the accentuated metaboreflex coronary vasoconstriction which impairs ventricular performance during exercise in heart failure. This work was supported by the National Heart, Lung and, Blood Institute grants HL-055473, HL-126706. 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.

Abstract P413: Association Between Supine Hypertension And Autonomic Impairment In Patients With Autonomic Failure

Autonomic failure is characterized by an inability to regulate blood pressure (BP). The dominant clinical manifestation of these patients is orthostatic hypotension (OH). However, at least half of them also have supine hypertension, which can arise de novo or due to worsening of preexisting essential hypertension. We hypothesized that, regardless of the cause of hypertension, the loss of baroreflex buffering capacity in these patients contributes to the severity of their hypertension. Thus, we tested whether supine hypertension reflects the severity of autonomic impairment (i.e., reduced BP buffering capacity) in a retrospective cohort of 307 patients (66±1 yr, 183 males, BMI 26.1±0.3) with a diagnosis of neurogenic OH due to multiple system atrophy (MSA, n=95) or peripheral autonomic failure (pAF, n=212). Autonomic impairment was assessed by standard autonomic testing (posture test, Valsalva maneuver [VM], and sinus arrhythmia [SA] ratio) performed off pressor and antihypertensive medications. The association between supine systolic BP (SBP; median [interquartile range, IQR], 146 [130-168] mmHg) and autonomic testing was assessed using multiple regression analyses. After adjusting for age, sex, BMI, and type of autonomic failure (MSA vs. pAF), we found that supine SBP was positively related to age (β=0.33; P=0.034), the severity of OH (the drop in SBP on standing; β= -0.48, P<0.001), and indices of severity of autonomic impairment, including the lack of adequate compensatory increase in heart rate in the setting of OH (ΔHR/ΔSBP, β=-15.43, P=0.044), and lack of recovery of SBP during late phase 2 of the Valsalva maneuver (β=-0.31; P<0.001; model R 2 =0.55, P<0.001). VM and SA ratios were not related to supine hypertension. In conclusion, we postulate that the magnitude of supine hypertension correlates with the severity of autonomic impairment and that both OH and supine hypertension reflect the inability of autonomic failure to regulate blood pressure.

Arterial Baroreceptor Denervation Enhances Muscle Metaboreflex Induced Increases in Effective Arterial Elastance Without Worsening Stoke Work During Dynamic Exercise in Heart Failure

Optimal energy transfer from the left ventricle to the systemic circulation is paramount to the maintenance of workload performance during exercise. This interaction between the heart and circulation is quantified by the ventricular‐vascular coupling relationship which is the ratio of direct assessments of arterial and ventricular elastance. During exercise, increases in both arterial and ventricular elastance occur as a result of sympatho‐excitatory efferent responses brought about by activation of metabosensitive skeletal muscle afferents ‐ termed the muscle metaboreflex. In heart failure, ventricular elastance is reduced and arterial elastance is increased causing ventricular‐vascular uncoupling at rest and further sympatho‐activation elicited by the muscle metaboreflex worsens this relationship through profound systemic vasoconstriction. Recent studies have concluded that the arterial baroreflex substantially buffers vasoconstriction within peripheral vascular beds. In heart failure, the arterial baroreflex buffering capacity is significantly reduced and muscle metaboreflex induced vasoconstriction is enhanced. To what extent this shift in metaboreflex control of peripheral sympathetic tone affects ventricular‐vascular coupling is unknown. We examined the effect of sino‐aortic baroreceptor denervation (SAD) on the ventricular‐vascular relationship at rest and during moderate dynamic exercise (6.4 km/h 10% grade) in chronically instrument conscious canines before and after the induction of heart failure to determine whether loss of baroreflex buffering engendered further uncoupling of the ventricular‐vascular relationship in heart failure. Increases in effective arterial elastance (Ea), were significantly enhanced during muscle metaboreflex activation after SAD (0.5 ± 0.1 mmHg/ml to 2.0 ± 0.4 mmHg/mL). Furthermore, SAD elicited a significant increase in the ability to improve stroke work during muscle metaboreflex activation (2.7 ± 0.1 L*mmHg to 3.5 ± 0.1 L*mmHg) suggesting that even without the arterial baroreflex muscle metaboreflex activation in healthy subjects maintains ventricular‐vascular coupling. In heart failure, SAD elicited a 2‐fold increase in Ea during muscle metaboreflex activation (0.9 ± 0.2 mmHg/ml to 1.8 ± 0.2 mmHg/ml). Stroke work did not improve during muscle metaboreflex activation in heart failure with SAD. Thus, enhanced increases in Ea are likely not matched by ventricular elastance thereby exacerbating the already uncoupled ventricular‐vascular relationship. We conclude that the arterial baroreflex actively restrains increases in Ea and stroke work during muscle metaboreflex activation and SAD does not appear to significantly impact the ventricular‐vascular relationship in healthy subjects. In heart failure, the arterial baroreflex retains some degree of restraint over metaboreflex induced increases in Ea and thus is likely a mechanism which prevents worsening of the already impaired energy transfer from the left ventricle to the systemic circulation.

Reliability of measuring resting spontaneous cardiac baroreflex sensitivity using short sampling durations in healthy humans: Impact of central blood volume mobilization

IntroductionCalculation of spontaneous cardiac baroreflex sensitivity (cBRS) is used commonly to quantify arterial baroreflex buffering of beat‐to‐beat changes in blood pressure (BP). Studies report large interindividual variability in resting cBRS, which may be exacerbated by the supine posture and the use of shorter sampling duration (1‐3 min). However, this has yet to be reported in humans. Therefore, the purpose of the present study was to examine the impact of sampling duration on the intratest reliability of resting cBRS in healthy subjects. To accomplish this, we sought to compare resting cBRS derived from a standard 10‐min epoch (control) with values sampled over 7, 5, 3, and 1 min epoch durations. In addition, we examined the impact of central blood volume (CBV) mobilization on intratest reliability of resting cBRS.MethodsIn 30 healthy subjects (28 men; 22±3yrs) beat‐to‐beat measurements of BP and heart rate were recorded for 10‐min during both sitting and supine position. The cBRS was derived by sequence technique. Randomly selected epochs of 1‐min, 3‐min, 5‐min and 7‐min were then compared to the 10‐min control. To calculate the relative and absolute reliability we analyzed the technical error of the measurement (TEM), the intraclass correlation coefficients (ICC), Bland‐Altman analysis and coefficient of variations (CV). To test the impact of CBV mobilization on resting cBRS, ten subjects were also randomized to a non‐hypotensive lower body negative pressure (LBNP) trial at ‐20mmHg.ResultscBRS was lower in the sitting position than in the supine position (P<0.01). All cBRS values were similar between each sampling duration compared to the 10‐min control (P>0.12). The ICC obtained for cBRS ranged from very good to excellent in the supine position, whereas in the sitting position values demonstrated excellent between‐sampling duration reliability. The absolute and relative TEM increased with a shorter sampling duration (Table 1). In the LBNP trial, no significant differences in cBRS were observed within sampling durations in the LBNP trial (P=0.27). No significant differences in cBRS were observed between supine LBNP, sitting and supine positions (P=0.17). During LBNP trial, TEM increased with shorter sampling durations [10 vs. 7‐min: 0.7 ms/mmHg (4%), 10 vs. 5‐min: 1.4 ms/mmHg (8%), 10 vs. 3‐min: 1.9 ms/mmHg (11%), 10 vs. 1‐min: 3.1 ms/mmHg (17%), which was similar to the sitting position when compared to the supine posture.ConclusionOur findings show that 1) reliability decreased progressively using the 3‐ and 1‐min sampling durations; 2) the sitting position provides more reliable measures than all epoch durations measured in the supine position and; 3) the increases in the limits of agreement with shorter durations were attenuated by supine LBNP, suggesting that a cardiopulmonary baroreflex mechanism may play a role in the level of variability in resting cBRS.

Arterial Baroreflex Inhibits Muscle Metaboreflex Induced Increases in Effective Arterial Elastance: Implications for Ventricular-Vascular Coupling.

The ventricular-vascular relationship assesses the efficacy of energy transferred from the left ventricle to the systemic circulation and is quantified as the ratio of effective arterial elastance to maximal left ventricular elastance. This relationship is maintained during exercise via reflex increases in cardiovascular performance raising both arterial and ventricular elastance in parallel. These changes are, in part, due to reflexes engendered by activation of metabosensitive skeletal muscle afferents—termed the muscle metaboreflex. However, in heart failure, ventricular-vascular uncoupling is apparent and muscle metaboreflex activation worsens this relationship through enhanced systemic vasoconstriction markedly increasing effective arterial elastance which is unaccompanied by substantial increases in ventricular function. This enhanced arterial vasoconstriction is, in part, due to significant reductions in cardiac performance induced by heart failure causing over—stimulation of the metaboreflex due to under perfusion of active skeletal muscle, but also as a result of reduced baroreflex buffering of the muscle metaboreflex-induced peripheral sympatho-activation. To what extent the arterial baroreflex modifies the metaboreflex-induced changes in effective arterial elastance is unknown. We investigated in chronically instrumented conscious canines if removal of baroreflex input via sino-aortic baroreceptor denervation (SAD) would significantly enhance effective arterial elastance in normal animals and whether this would be amplified after induction of heart failure. We observed that effective arterial elastance (Ea), was significantly increased during muscle metaboreflex activation after SAD (0.4 ± 0.1 mmHg/mL to 1.4 ± 0.3 mmHg/mL). In heart failure, metaboreflex activation caused exaggerated increases in Ea and in this setting, SAD significantly increased the rise in Ea elicited by muscle metaboreflex activation (1.3 ± 0.3 mmHg/mL to 2.3 ± 0.3 mmHg/mL). Thus, we conclude that the arterial baroreflex does buffer muscle metaboreflex induced increases in Ea and this buffering likely has effects on the ventricular-vascular coupling.

Stress and the baroreflex.

The stress response to emotions elicits the release of glucocorticoids from the adrenal cortex, epinephrine from the adrenal medulla, and norepinephrine from the sympathetic nerves. The baroreflex adapts to buffer these responses to ensure that perfusion to the organs meets the demands while maintaining blood pressure within a within a narrow range. While stressor-evoked autonomic cardiovascular responses may be adaptive for the short-term, the recurrent exaggerated cardiovascular stress reactions can be maladaptive in the long-term. Prolonged stress or loss of the baroreflex's buffering capacity can predispose episodes of heightened sympathetic activity during stress leading to hypertension, tachycardia, and ventricular wall motion abnormalities. This review discusses 1) how the baroreflex responds to acute and chronic stressors, 2) how lesions in the neuronal pathways of the baroreflex alter the ability to respond or counteract the stress response, and 3) the techniques to assess baroreflex sensitivity and stress responses. Evidence suggests that loss of baroreflex sensitivity may predispose heightened autonomic responses to stress and at least in part explain the association between stress, mortality and cardiovascular diseases.

Blood Pressure Variability and Baroreflex Sensitivity in Premature Newborns-An Effect of Postconceptional and Gestational Age.

Introduction: Cardiovascular system is the vitally important system in the dynamical adaptation process of the newborns to the extrauterine environment. To reliably detect immaturity in the given organ system, it is crucial to study the development of the organ functions in relation to maturation process.Objectives: The objective was to determine the changes in the spontaneous short-term blood pressure variability (BPV) and baroreflex sensitivity (BRS) reflecting various aspects of cardiovascular control during the process of maturation in preterm babies and to separate effects of gestational age and postnatal age.Methods: Thirty-three prematurely born infants without any signs of cardio-respiratory disorders (gestational age: 31.8, range: 27–36 weeks; birth weight: 1,704, range: 820–2,730 grams) were enrolled. Continuous peripheral blood pressure signal was obtained by non-invasive volume-clamp photoplethysmography method during supine rest. The recordings of 250 continuous beat-to-beat blood pressure values were processed by spectral analysis of BPV (assessed measures: total power, low frequency and high frequency powers of systolic BPV) and BRS calculation. For each infant we also assessed systolic, diastolic and mean blood pressures, heart rate and respiratory rate.Results: With the postconceptional age, BPV measures decreased (for total power: Spearman correlation coefficient rs = −0.345, P = 0.049; for low frequency power: rs = −0.365, P = 0.037; for high frequency power rs = −0.349; P = 0.046); and BRS increased significantly (rs = 0.448, P = 0.009). The further analysis demonstrated that these effects were more attributable to gestational age than to postnatal age. BRS correlated negatively with BPV magnitude (rs = −0.479 to −0.592, P = 0.001–0.005). Mean blood pressure and diastolic blood pressure increased during maturation (rs = 0.517 and 0.537, P = 0.002 and 0.001, respectively) while heart rate and respiratory rate decreased (rs = −0.366 and −0.516, P = 0.036 and 0.002, respectively).Conclusion: We conclude that maturation process is accompanied by an increased involvement of baroreflex buffering of spontaneous short-term blood pressure oscillations. Gestational age plays a dominant role not only in BPV changes but also in BRS, mean blood pressure, diastolic blood pressure and heart rate changes.

Pharmacologic treatment of orthostatic hypotension.

Neurogenic orthostatic hypotension (OH) is a disabling disorder caused by impairment of the normal autonomic compensatory mechanisms that maintain upright blood pressure. Nonpharmacologic treatment is always the first step in the management of this condition, but a considerable number of patients will require pharmacologic therapies. Denervation hypersensitivity and impairment of baroreflex buffering makes these patients sensitive to small doses of pressor agents. Understanding the underlying pathophysiology can help in selecting between treatment options. In general, patients with low "sympathetic reserve", i.e., those with peripheral noradrenergic degeneration (pure autonomic failure, Parkinson's disease) and low plasma norepinephrine, tend to respond better to "norepinephrine replacers" (midodrine and droxidopa). On the other hand, patients with relatively preserved "sympathetic reserve", i.e., those with impaired central autonomic pathways but spared peripheral noradrenergic fibers (multiple system atrophy) and normal or slightly reduced plasma norepinephrine, tend to respond better to "norepinephrine enhancers" (pyridostigmine, atomoxetine, and yohimbine). There is, however, a spectrum of responses within these extremes, and treatment should be individualized. Other nonspecific treatments include fludrocortisone and octreotide. The presence of associated clinical conditions, such as supine hypertension, heart failure, postprandial hypotension, PD, MSA, and diabetes need to be considered in the pharmacologic management of these patients.

Testing individual baroreflex responses to hypoxia-induced peripheral chemoreflex stimulation

IntroductionBaroreflexes and peripheral chemoreflexes control efferent autonomic activity making these reflexes treatment targets for arterial hypertension. The literature on their interaction is controversial, with suggestions that their individual and collective influence on blood pressure and heart rate regulation is variable. Therefore, we applied a study design that allows the elucidation of individual baroreflex–chemoreflex interactions.MethodsWe studied nine healthy young men who breathed either normal air (normoxia) or an air–nitrogen–carbon dioxide mixture with decreased oxygen content (hypoxia) for 90 min, with randomization to condition, followed by a 30-min recovery period and then exposure to the other condition for 90 min. Multiple intravenous phenylephrine bolus doses were applied per condition to determine phenylephrine pressor sensitivity as an estimate of baroreflex blood pressure buffering and cardiovagal baroreflex sensitivity (BRS).ResultsHypoxia reduced arterial oxygen saturation from 98.1 ± 0.4 to 81.0 ± 0.4% (p < 0.001), raised heart rate from 62.9 ± 2.1 to 76.0 ± 3.6 bpm (p < 0.001), but did not change systolic blood pressure (p = 0.182). Of the nine subjects, six had significantly lower BRS in hypoxia (p < 0.05), two showed a significantly decreased pressor response, and three showed a significantly increased pressor response to phenylephrine in hypoxia, likely through reduced baroreflex buffering (p < 0.05). On average, hypoxia decreased BRS by 6.4 ± 0.9 ms/mmHg (19.9 ± 2.0 vs. 14.12 ± 1.6 ms/mmHg; p < 0.001) but did not change the phenylephrine pressor response (p = 0.878).ConclusionWe applied an approach to assess individual baroreflex–chemoreflex interactions in human subjects. A subgroup exhibited significant impairments in baroreflex blood pressure buffering and BRS with peripheral chemoreflex activation. The methodology may have utility in elucidating individual pathophysiology and in targeting treatments modulating baroreflex or chemoreflex function.

Sympathetic baroreflex sensitivity is inversely related to vascular transduction in men but not women.

Sympathetic baroreflex sensitivity (BRS) is a measure of how effectively the baroreflex buffers beat-to-beat changes in blood pressure through the modulation of muscle sympathetic nerve activity (MSNA). However, current methods of assessment do not take into account the transduction of sympathetic nerve activity at the level of the vasculature, which is known to vary between individuals. In this study we tested the hypothesis that there is an inverse relationship between sympathetic BRS and vascular transduction. In 38 (18 men) healthy adults, continuous measurements of blood pressure, MSNA and superficial femoral artery diameter and blood flow (Doppler ultrasound) were recorded during 10 min of rest. Spontaneous sympathetic BRS was quantified as the relationship between diastolic pressure and MSNA burst incidence. Vascular transduction was quantified by plotting the changes in leg vascular conductance for 10 cardiac cycles following each burst of MSNA, and taking the nadir. In men, sympathetic BRS was inversely related to vascular transduction (r = -0.49; P = 0.04). However, this relationship was not present in women (r = -0.17; P = 0.47). To conclude, an interaction exists between sympathetic BRS and vascular transduction in healthy men, such that men with high sympathetic BRS have low vascular transduction and vice versa. This may be to ensure that blood pressure is regulated effectively, although further research is needed to explore what mechanisms are involved and examine why this relationship was not apparent in women.NEW & NOTEWORTHY Evidence suggests that compensatory interactions exist between factors involved in cardiovascular control. This study was the first to demonstrate an inverse relationship between sympathetic BRS and beat-to-beat vascular transduction. Those with low sympathetic BRS had high vascular transduction and vice versa. However, this interaction was present in young men but not women.

Attenuation of Spontaneous Baroreceptor Sensitivity after Concussion

Cardiovascular autonomic nervous system (CV-ANS) function is negatively impacted after concussion. The arterial baroreflex buffers pressor and depressor challenges through efferent modulation of cardiac chronotropism and inotropism, and peripheral vascular tone. Baroreceptor sensitivity (BRS) reflects the capacity of the CV-ANS to accommodate dynamic metabolic demands in the periphery. The impact of concussion on BRS has yet to be defined. Cardiovascular autonomic nervous system assessment (e.g., electrocardiogram and beat-to-beat systolic blood pressure [SBP]) was performed the seated upright position at rest within 48 h (V1) of concussion and 1 wk later (V2) in 10 intercollegiate male athletes with concussion and 10 noninjured male athletes. Changes in HR, SBP, high- and low-frequency HR variabilities (HF-HRV and LF-HRV, respectively), LF-SBP variability and BRS for increasing (BRSn-Up) and decreasing (BRSn-Dn) SBP excursions, and overall BRS (BRSn-Avg) were assessed for differences at V1 and V2. The concussion (age, 20 ± 1 yr; height, 1.79 ± 0.14 m; weight, 83 ± 10 kg) and control (age, 20 ± 1 yr; height, 1.78 ± 0.10 m; weight, 79 ± 13 kg) groups were matched for demographics. Concussed athletes had a significantly reduced BRSn-Up, BRSn-Dn, and BRSn-Avg compared with controls at V1 or V2; these changes occurred without differences in conventional markers of CV-ANS function (e.g., HF-HRV, LF-HRV, LF-SBP), HR, or SBP at either visit. Reduced BRS is a postconcussive consequence of CV-ANS dysfunction during the first postinjury week. Because SBP was similar between groups, it may be speculated that reduced BRS was not afferent in origin, but represents a postinjury consequence of the central nervous system after injury.

The Stability and Repeatability of Spontaneous Sympathetic Baroreflex Sensitivity in Healthy Young Individuals.

Spontaneous sympathetic baroreflex sensitivity (BRS) is a valuable tool for assessing how well the baroreflex buffers beat-to-beat changes in blood pressure. However, there has yet to be a study involving appropriate statistical tests to examine the stability of sympathetic BRS within an experimental session and the repeatability between separate sessions. The aim of this study was to use intra-class correlations, ordinary least products regression, and Bland–Altman analyses to examine the stability and repeatability of spontaneous sympathetic BRS assessment. In addition, the influence of recording duration on values of BRS was assessed. In eighty-four healthy young individuals (49 males, 35 females), continuous measurements of blood pressure, heart rate and muscle sympathetic nerve activity (MSNA) were recorded for 10 min. In a subgroup of 13 participants (11 male, 2 female) the measurements were repeated on a separate day. Sympathetic BRS was quantified using MSNA burst incidence (BRSinc) and total MSNA (BRStotal) for the first 5-min period, the second 5-min period, and a 2-min segment taken from the second 5-min period. Intra-class correlation coefficients indicated moderate stability in sympathetic BRSinc and BRStotal between the first and second 5-min periods in males (BRSinc r = 0.63, BRStotal r = 0.78) and females (BRSinc r = 0.61, BRStotal r = 0.47) with no proportional bias, but with fixed bias for BRSinc in females. When comparing the first 5-min with the 2-min period (n = 76), the intra-class correlation coefficient indicated poor to moderate repeatability in sympathetic BRSinc and BRStotal for males (BRSinc r = -0.01, BRStotal r = 0.70) and females (BRSinc r = 0.46, BRStotal r = 0.39). However, Bland–Altman analysis revealed a fixed bias for BRStotal in males and proportional bias for BRStotal in females, with lower BRS values for 5-min recordings. In the subgroup, intra-class correlations indicated moderate repeatability for measures of BRSinc (9 male, 2 female, r = 0.63) and BRStotal (6 male, 2 female, r = 0.68) assessed using 5-min periods recorded on separate days. However, Bland–Altman analysis indicated proportional bias for BRSinc and fixed bias for BRStotal. In conclusion, measures of spontaneous sympathetic BRS are moderately stable and repeatable within and between testing sessions in healthy young adults, provided that the same length of recording is used when making comparisons.

Relationship Between Sympathetic Baroreflex Sensitivity And Vascular Transduction

Sympathetic baroreflex sensitivity (BRS) is a tool used to quantify how effectively the baroreflex buffers beat‐to‐beat changes in blood pressure. However, current methods of assessment do not take into account vascular transduction, i.e. the response of the peripheral vasculature to vasoconstrictor drive. The aim of the study was to investigate the relationship between sympathetic BRS and vascular transduction. Muscle sympathetic nerve activity (MSNA, microneurography), blood pressure, heart rate and superficial femoral artery blood flow (Doppler ultrasound) were recorded at rest for 5 min in 28 healthy adults (18–31yrs, 13 males, 15 females). Sympathetic BRS was quantified by plotting MSNA burst incidence against mean diastolic pressure using 3 mmHg bins. For vascular transduction, the % change in leg vascular conductance was determined for 15 cardiac cycles following each MSNA burst and the nadir of the response was calculated. Linear regression analysis was used to examine the relationship between sympathetic BRS and vascular transduction in males and females separately. Sympathetic BRS was not significantly different between males (−2.9± 1.8) and females (−3.2 ± 1.6 %bursts/mmHg, p=0.68). However, vascular transduction was significantly lower in males (−5.5 ± 4.1) compared with females (9.1 ± 4.7 %change in ml/min/mmHg, p=0.04). In males there was a significant inverse relationship between sympathetic BRS and vascular transduction (r=0.78, p=0.002), but in females there was no significant relationship (r=0.34, p=0.21). The results suggest that in males those with high sympathetic BRS have low vascular transduction, and vice versa. This may represent a compensatory effect to ensure that blood pressure is regulated effectively. However, this relationship between sympathetic BRS and vascular transduction was not apparent in young females.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Abstract P392: Autonomic Reflexes Mask the Hemodynamic Effects of Continuous Positive Airway Pressure

Continuous positive airway pressure (CPAP) improves cardiac function and blood pressure (BP) in patients with sleep-breathing disorders by reducing increased sympathetic tone. The direct hemodynamic effects of increased intrathoracic pressure with CPAP, however, are not known and are likely masked by baroreflex buffering. To determine the acute hemodynamic effects of CPAP in the absence of autonomic modulation, we applied 5 levels of CPAP (0, 4, 8, 12 and 16 cm H 2 O, each for 2 min) to 7 healthy normotensive (NTN, 33±3 years, BMI 29±3, 4 females) and 12 hypertensive subjects (HTN, 50±2 years, BMI 30±2, 8 females) before and during autonomic withdrawal with the ganglionic blocker trimethaphan. Hemodynamic parameters were measured at the end of each CPAP level. At baseline, CPAP had no effect on systolic BP (SBP), heart rate (HR), cardiac output (CO), stroke volume (SV) or systemic vascular resistance (SVR) in either group. During the autonomic blockade, CPAP significantly decreased SBP in both groups (Figure). The maximal BP drop was twice as much in HTN than NTN (-17±2 vs. -8±2 mmHg at 16 cm H 2 O; P&lt;0.02) but the final SBP was the same in both groups (85±3 mmHg). In HTN, CO and SV decreased -25±4% and -24±4% at 16 cm H 2 O, respectively; whereas in NTN, the decreases were -20±5% and -24±4%. Neither SVR nor HR changed significantly with CPAP in either group. We conclude that, in the absence of autonomic modulation, CPAP acutely decreases SBP significantly, due to decreases in CO and SV likely reflecting a decrease in venous return and increase in venous capacitance. The effect on BP was greater in HTN suggesting that a sympathetically mediated reduction in capacitance may contribute to the hypertension.

Abstract P133: Angiotensin-(1-7) Does Not Acutely Lower Blood Pressure in Patients With Essential Hypertension

Angiotensin (Ang)-(1-7) is a beneficial renin-angiotensin hormone that produces vasodilation to lower blood pressure (BP) in animal models of hypertension. There are limited clinical studies, however, and it is unclear if Ang-(1-7) contributes to BP regulation in human hypertension. We propose the difficulties in showing cardiovascular effects in previous clinical studies relates to the buffering capacity of the arterial baroreflex. In this study, we tested the hypothesis that Ang-(1-7) would produce negligible effects on BP with intact baroreceptors, and that the cardiovascular effects of this hormone would be unmasked following elimination of baroreflex buffering. To test this, we examined the effects of acute intravenous Ang-(1-7) infusion (ascending doses from 0.5 to 20 ng/kg/min) on supine BP in subjects with essential hypertension under intact conditions and following acute autonomic withdrawal with the ganglionic blocker trimethaphan in a randomized, open-label, crossover study. BP was restored to baseline levels following autonomic blockade with individually titrated phenylephrine doses. Seven subjects with essential hypertension completed this study (6 male; 48±4 years of age; 29±2 body mass index). All subjects were withdrawn from antihypertensive medications for at least two weeks, and were placed on a fixed sodium diet (150 mEq/day) for three days, prior to each study day. When comparing change from baseline to maximum dose, Ang-(1-7) did not alter systemic hemodynamics under intact conditions (systolic BP: 3±4 mmHg; diastolic BP: 3±1 mmHg; heart rate (0±1 bpm). In contrast to our hypothesis, Ang-(1-7) did not elicit a BP-lowering effect under autonomic blockade (systolic BP: 10±8 mmHg, p=0.299 vs. intact; diastolic BP: 7±3 mmHg, p=0.512; heart rate: -2±1 bpm, p=0.166). Plasma Ang-(1-7) was measured in 4 subjects and showed an approximate 3-fold increase with infusions [0.8±0.7 baseline vs. 2.1±1.2 ng/mL after Ang-(1-7)]. These findings suggest that infusion of Ang-(1-7) to levels within a physiologic range does not acutely induce vasodilation to lower blood pressure in essential hypertension. We cannot exclude that Ang-(1-7) lowers BP by sympathetic inhibition, since those pathways were excluded by our study design.

Management of Supine Hypertension Complicating Neurogenic Orthostatic Hypotension.

Neurogenic orthostatic hypotension (NOH) can be present in a number of disorders, including synucleinopathies, autoimmune disorders, and various genetic disorders. All are characterized by defective norepinephrine release from sympathetic terminals upon standing, resulting in impaired vasoconstriction. NOH is defined as a drop in systolic blood pressure ≥20 mmHg or diastolic blood pressure ≥10 mmHg, or both, within 3 minutes of standing or head up-tilt at a minimum of 60°. However, approximately 50% of patients have associated supine hypertension, which greatly complicates treatment. Supine hypertension not only is a common side effect of many anti-hypotensive agents but is also present in untreated patients, suggesting it is, in part, innate to the pathophysiology of autonomic dysfunction. Pathological mechanisms differ depending on the underlying autonomic disorder. In central neurodegenerative disorders, residual post-ganglionic sympathetic activity is likely the primary mechanism, whereas plasma angiotensin, aldosterone, and inappropriate mineralocorticoid receptor activity may contribute in peripheral autonomic lesions. Baroreflex failure/loss of baroreflex buffering is common to both. More work is required. Clinically, there is much dispute regarding the treatment of supine hypertension when there is a risk of exacerbating orthostatic hypotension. However, given the similar levels of end-organ damage (i.e., heart attack and stroke) seen with transient hypertension, it seems clear that treatment is important. Current therapies for both NOH and supine hypertension include a combination of pharmacological and conservative measures. However, in addition to the current standard of care, protocols may consider 24-h blood pressure monitoring and potential future examination of the peripheral post-ganglionic sympathetic nerves in order to apply individualized adjunct therapies. Finally, no anti-hypertensive agents are currently approved for use in this patient population, and development of novel therapies should focus on short-acting agents, selective to the supine position, that act primarily at night when hypertension is most severe/prolonged.

The Pharmacology of Autonomic Failure: From Hypotension to Hypertension.

Primary neurodegenerative autonomic disorders are characterized clinically by loss of autonomic regulation of blood pressure. The clinical picture is dominated by orthostatic hypotension, but supine hypertension is also a significant problem. Autonomic failure can result from impairment of central autonomic pathways (multiple system atrophy) or neurodegeneration of peripheral postganglionic autonomic fibers (pure autonomic failure, Parkinson's disease). Pharmacologic probes such as the ganglionic blocker trimethaphan can help us in the understanding of the underlying pathophysiology and diagnosis of these disorders. Conversely, understanding the pathophysiology is crucial in the development of effective pharmacotherapy for these patients. Autonomic failure patients provide us with an unfortunate but unique research model characterized by loss of baroreflex buffering. This greatly magnifies the effect of stimuli that would not be apparent in normal subjects. An example of this is the discovery of the osmopressor reflex: ingestion of water increases blood pressure by 30-40 mm Hg in autonomic failure patients. Animal studies indicate that the trigger of this reflex is related to hypo-osmolality in the portal circulation involving transient receptor potential vanilloid 4 receptors. Studies in autonomic failure patients have also revealed that angiotensin II can be generated through noncanonical pathways independent of plasma renin activity to contribute to hypertension. Similarly, the mineralocorticoid receptor antagonist eplerenone produces acute hypotensive effects, highlighting the presence of non-nuclear mineralocorticoid receptor pathways. These are examples of careful clinical research that integrates pathophysiology and pharmacology to advance our knowledge of human disease.

Nonlinear identification of the total baroreflex arc: chronic hypertension model.

The total baroreflex arc is the open-loop system relating carotid sinus pressure (CSP) to arterial pressure (AP). Its linear dynamic functioning has been shown to be preserved in spontaneously hypertensive rats (SHR). However, the system is known to exhibit nonlinear dynamic behaviors. The aim of this study was to establish nonlinear dynamic models of the total arc (and its subsystems) in hypertensive rats and to compare these models with previously published models for normotensive rats. Hypertensive rats were studied under anesthesia. The vagal and aortic depressor nerves were sectioned. The carotid sinus regions were isolated and attached to a servo-controlled piston pump. AP and sympathetic nerve activity were measured while CSP was controlled via the pump using Gaussian white noise stimulation. Second-order, nonlinear dynamics models were developed by application of nonparametric system identification to a portion of the measurements. The models of the total arc predicted AP 21-43% better (P < 0.005) than conventional linear dynamic models in response to a new portion of the CSP measurement. The linear and nonlinear terms of these validated models were compared with the corresponding terms of an analogous model for normotensive rats. The nonlinear gains for the hypertensive rats were significantly larger than those for the normotensive rats [-0.38 ± 0.04 (unitless) vs. -0.22 ± 0.03, P < 0.01], whereas the linear gains were similar. Hence, nonlinear dynamic functioning of the sympathetically mediated total arc may enhance baroreflex buffering of AP increases more in SHR than normotensive rats.

Pressor threshold of muscle metaboreflex is modulated during unloading of carotid baroreceptors in humans

Static and dynamic exercise are accompanied by increases in arterial blood pressure, heart rate and sympathetic nerve activity. It is thought that the activation of the muscle metaboreflex is one of major mechanisms for evoking the pressor responses during heavy intensity exercise [1]. It has been shown that the arterial baroreflex buffers the muscle metaboreflex-mediated pressor responses [2]. However, it is unknown whether the carotid baroreflex modifies muscle metaboreflex function in humans. Therefore, the purpose of this study was to investigate the effects of unloading of carotid baroreceptors on threshold and gain of the muscle metaboreflex in humans.