Cardiovagal Baroreflex Research Articles

Neuro-humoral control during orthostasis in health and disease.

Different from many other species, human beings spend nearly two-thirds of the day in an upright posture. Due to gravity, about 700 to 900 ml of blood shift into the lower body during quiet standing. As a result, central blood volume decreases and this leads to a series of neural-humoral adjustments that aim to maintain the mean arterial pressure during orthostasis. Both the sympathetic nervous system and the renin-angiotensin-aldosterone system contribute importantly to the arterial pressure maintenance in upright humans. There is a growing interest in the blood pressure regulation during orthostasis in healthy individuals and patient populations. This e-book provides some updates on sympathetic neural control and renal-adrenal function in health and disease. Sympathetic neural activity regulates blood pressure mainly through the baroreflex-mediated vasoconstriction during orthostasis. The baroreflex is a closed-loop feedback system, but requires open-loop experiments to identify its characteristics, which is impossible in human research. Kamiya et al. demonstrated that system identification based analysis and numerical simulation using baroreflex subsystem characteristics identified in animal models may contribute to our understanding of human sympathetic physiology under orthostasis (Kamiya et al., 2014). Neural and renal-adrenal control of blood pressure can be affected by not only age but also race and physical fitness. For example, it was found that young normotensive Caucasian women may rely on sympathetic neural activity more so than African-American women who had a tendency to rely on the renal-adrenal system to regulate blood pressure during orthostatic challenges (Jarvis et al., 2014). Conversely, Sugawara et al. reported that endurance-trained men had increased orthostatic tachycardia and enhanced cardiovagal baroreflex sensitivity, which may favorably mitigate accumulated risks for post-exercise orthostatic intolerance (Sugawara et al., 2014). Failure of the sympathetic nervous system during orthostasis may result in syncope (Iwase et al., 2014). However, orthostatic tolerance does not seem to be related to resting sympathetic neural activity or sympathetic baroreflex sensitivity (Hinojosa-Laborde et al., 2014). Studies in healthy young individuals indicate that in addition to sympathetic vasoconstriction, the heart rate response may also contribute importantly to orthostatic tolerance (Convertino, 2014). On the other hand, it is argued that cardiac effector mechanisms appear not to be important for the adjustment of arterial pressure to the upright posture in humans (Wieling et al., 2014). Indeed, investigations into the role of the sympathetic nervous system in orthostatic intolerance have yielded mixed results. The review article by Lambert and Lambert (2014) outlines the current knowledge of the function of the sympathetic nervous system in vasovagal syncope and the Postural Orthostatic Tachycardia Syndrome (POTS, also called Chronic Orthostatic Intolerance). There are multiple pathophysiological mechanisms that underlie POTS; some POTS patients have evidence of elevated sympathoneural tone, others have a hypovolemic state, and many patients have a perturbed renin-angiotensin-aldosterone system profile (Mar and Raj, 2014). Patients with POTS have acute changes in cognitive performance in response to orthostatic challenges, and these patients also have an increased prevalence of depression and higher levels of anxiety (Anderson et al., 2014). Impaired cerebral autoregulation may underlie upright cognitive dysfunction in POTS (Medow et al., 2014). Finally, patients with autonomic failure often have orthostatic hypotension and (pre)syncopal symptoms. Arnold et al. showed that ergotamine combined with caffeine could be used as an alternate treatment in carefully selected patients without comorbid coronary artery disease (Arnold et al., 2014). Taken together, this e-book highlights only a small portion of the recent advances in neural-humoral control during orthostasis in humans. More research is needed to better understand the role of the sympathetic nervous system and the renin-angiotensin-aldosterone system in the regulation of blood pressure in health and disease.

Peripheral heart action (PHA) training as a valid substitute to high intensity interval training to improve resting cardiovascular changes and autonomic adaptation.

The present study evaluated the effects of peripheral heart action training compared with high intensity interval training on changes in autonomic regulation and physical fitness. Eighteen young adults (9 women, 9 men) (age 24 ± 3 years, BMI of 22.67 kg/m(2), V'O2max 32.89 ml/kg/min) were randomly assigned to either a high intensity interval training group (n = 8) or a peripheral heart action training (PHA) group (n = 10). Before and after training, maximal whole-body muscular strength, time series of beat-to-beat intervals for heart rate variability, and baroreflex sensitivity were recorded. Arterial baroreflex sensitivity and heart rate variability were estimated on both time and frequency domains. Physical fitness level was evaluated with maximum oxygen consumption test. The effects of PHA whole-body resistance training increased muscular strength and maximum oxygen consumption, with an effect on vagal-cardiac control and cardiovagal baroreflex sensitivity. After 30 training sessions performed in 3 months, PHA resistance exercise promoted cardiovascular adaptations, with a decrease in the power spectral component of vascular sympathetic activity and an increase in the vagal modulation. Low-frequency oscillation estimated from systolic blood pressure variability seems to be a suitable index of the sympathetic modulation of vasomotor activity. This investigation also want to emphasize the beneficial effects of this particular resistance exercise training, considering also that the increase in muscular strength is inversely associated with all-cause mortality and the prevalence of metabolic syndrome, independent of cardiorespiratory fitness levels.

Endogenous leptin contributes to baroreflex suppression within the solitary tract nucleus of aged rats.

The decline in cardiovagal baroreflex function that occurs with aging is accompanied by an increase in circulating leptin levels. Our previous studies showed that exogenous leptin impairs the baroreflex sensitivity for control of heart rate in younger rats, but the contribution of this hormone to baroreflex dysfunction during aging is unknown. Thus we assessed the effect of bilateral leptin microinjection (500 fmol/60 nl) within the solitary tract nucleus (NTS) on the baroreflex sensitivity in older (66 ± 2 wk of age) urethane/chloralose anesthetized Sprague-Dawley rats with elevated circulating leptin levels. In contrast to the 63% reduction observed in younger rats, leptin did not alter the baroreflex sensitivity for bradycardia evoked by phenylephrine in older rats (0.76 ± 0.19 baseline vs. 0.71 ± 0.15 ms/mmHg after leptin; P = 0.806). We hypothesized that this loss of sensitivity reflected endogenous suppression of the baroreflex by elevated leptin, rather than cardiovascular resistance to the peptide. Indeed, NTS administration of a leptin receptor antagonist (75 pmol/120 nl) improved the baroreflex sensitivity for bradycardia in older rats (0.73 ± 0.13 baseline vs. 1.19 ± 0.26 at 10 min vs. 1.87 ± 0.32 at 60 min vs. 1.22 ± 0.54 ms/mmHg at 120 min; P = 0.002), with no effect in younger rats. There was no effect of the leptin antagonist on the baroreflex sensitivity for tachycardia, responses to cardiac vagal chemosensitive fiber activation, or resting hemodynamics in older rats. These findings suggest that the actions of endogenous leptin within the NTS, either produced locally or derived from the circulation, contribute to baroreflex suppression during aging.

Greater autonomic modulation during post-exercise hypotension following high-intensity interval exercise in endurance-trained men and women

An acute reduction in blood pressure observed after a single bout of exercise is termed post-exercise hypotension (PEH). In contrast to moderate intensity aerobic exercise, little is known about the PEH response following high-intensity interval exercise. The present purpose is to assess how sex and training status impact PEH following high-intensity interval exercise. Cardiac volumes and function via echocardiography were measured in 40 normotensive, endurance-trained (ET) and normally active (NA) men and women (Age ± SD = 30.5 ± 5.7) following high-intensity interval cycle exercise. Continuous measurements of ECG and beat-by-beat blood pressure were collected before and 30 min post-exercise for determination of cardiovagal baroreflex function (BRS and αLF), spectral analysis of heart rate and systolic blood pressure (SBP LF). Post-exercise systolic BP was significantly reduced from baseline, occurring to a greater degree in ET compared with NA (-12.9 vs. -5.3 mmHg, P = 0.008), while mean arterial pressure was similarly reduced in all groups (-4.6 mmHg, P = 0.003). Despite reduced SVI and TPRI, CI was increased post-exercise (P < 0.01). ET experienced a greater decrease in αLF (P = 0.037) and increase in SBP LF (P = 0.017) than NA. Lean body mass was a significant predictor of change in SBP LF (Std. β = 0.735, P = 0.008). These results characterize greater depressions in cardiovagal baroreflex function, and increased sympathetic activity, following vigorous exercise in endurance-trained individuals compared with normally active participants. This heightened sympathovagal balance after high-intensity exercise may be a compensatory mechanism in response to greater peripheral blood flow demands following vigorous exercise.

Influence of regular exercise training on post-exercise hemodynamic regulation to orthostatic challenge.

To prevent orthostatic hypotension, arterial blood pressure (BP) is neurally and hormonally regulated via increases in heart rate (HR) and peripheral vascular tone. After dynamic exercise, however, the latter arm is blunted because of the increased vasodilators in exercised muscles. Orthostatic tachycardia is likely a more important compensatory mechanism for post-exercise orthostatic intolerance in individuals who have higher leg vasodilator capacity, such as endurance-trained athletes. To test the hypothesis that regular endurance training was associated with the greater augmentation of tachycardia response to post-exercise orthostasis, we compared hemodynamic responses to 5-min 60° head-up tilt (HUT) before and after 60 min of cycling at 70% of HR reserve in the endurance-trained (n = 8) and sedentary men (n = 9). Calf peak vascular conductance was 62% greater in the endurance-trained than the sedentary (P < 0.001). After the exercise, the HUT-induced reduction of SV was significantly augmented in the endurance-trained (from −27.7 ± 6.9 to −33.7 ± 7.7 ml, P = 0.03) but not in their sedentary peers. Nevertheless, MAP was well maintained during post-exercise HUT even in the endurance-trained (from 81 ± 10 to 80 ± 8 mmHg). Tachycardia responses during sustained orthostasis were significantly increased in the sedentary (1.3-fold vs. pre-exercise) and more in the endurance-trained (2.0-fold). The augmented response of HUT-induced tachycardia was greater in the endurance-trained than the sedentary (P = 0.04). Additionally, cardiovagal baroreflex sensitivity (BRS), evaluated by the HR response to the hypotensive perturbation, was improved after the exercise in the endurance-trained (from −0.56 ± 0.32 to −1.03 ± 0.26 bpm/mmHg, P = 0.007) but not in the sedentary. These results suggest that in the endurance-trained men the increased orthostatic tachycardia and augmented cardiovagal BRS may favorably mitigate accumulated risks for orthostatic intolerance in the early phase of post-exercise.

Increased Central Arterial Stiffness Explains Baroreflex Dysfunction in Spinal Cord Injury

After cervical spinal cord injury (SCI), orthostatic hypotension and intolerance commonly ensue. The cardiovagal baroreflex plays an important role in the acute regulation of blood pressure (BP) and is associated with the onset of presyncope. The cardiovagal baroreflex is dysfunctional after SCI; however, this may be influenced by either increased stiffening of the arteries containing the stretch-receptors (which has been shown in SCI) or a more downstream neural mechanism (i.e., solitary nucleus, sinoatrial node). Identifying where along this pathway baroreflex dysfunction occurs may highlight a potential therapeutic target. This study examined the relationship between spontaneous cardiovagal baroreflex sensitivity (BRS) and common carotid artery (CCA) stiffness in those with high level SCI before and after midodrine (alpha1-agonist) administration, as well as in able-bodied controls, to evaluate: (1) the role arterial stiffening plays mediating baroreflex function after SCI and (2) the effect of normalizing BP on these parameters. Three to five min recordings of beat-by-beat BP and heart rate, as well as 30 sec duration recordings of CCA diameter were used for analysis. All participants were tested supine and during upright-tilt. Arterial stiffness (β-stiffness index) was elevated in those with SCI when upright (+12%; p<0.05). Further, β-stiffness index was negatively related to reduced BRS in those with SCI when upright (R2=0.55; p<0.05), but not in able-bodied persons. Normalizing BP did not improve BRS or CCA stiffness. This study clearly shows that reduced BRS is closely related to increased arterial stiffness in the population with SCI.

Neurovascular control following small muscle mass exercise in humans (1170.10)

Sympathetic vascular transduction is blunted and the arterial baroreflex curve is reset to a lower operating pressure after dynamic large muscle mass exercise in humans. It is unknown whether these neural adaptations contribute to sustained post‐exercise vasodilation in small muscle mass exercise. The purpose of this study was to determine if cardiovagal, vascular, and integrated baroreflex sensitivity as well as sympathetic neurovascular transduction were altered following dynamic knee extension (DKE) exercise. It was hypothesized that sympathetic vascular transduction would be reduced after DKE, the arterial baroreflex would be reset to a lower operating point, and baroreflex sensitivity would be enhanced. Eleven healthy, college‐aged subjects completed one‐leg DKE exercise for one hour at 60% of peak power. Neurovascular transduction was estimated by measuring the percent change in femoral vascular conductance due to external neck pressure. There was no effect of exercise on transduction (P = 0.46) and no difference in integrated baroreflex sensitivity across time (P = 0.77). Cardiovagal baroreflex sensitivity increased 25% relative to baseline and had not recovered at 60 minutes post‐exercise (P = 0.02). Vascular baroreflex sensitivity was reduced in both the exercised (P = 0.05) and rested leg (P = 0.09). There is likely no effect of small muscle mass exercise on postexercise sympathetic transduction, the carotid baroreflex, or integrated baroreflex sensitivity. Cardiovagal baroreflex sensitivity was augmented and vascular baroreflex sensitivity was reduced after exercise and this has not been previously shown after small muscle mass exercise.Grant Funding Source: NIH R01 HL115027

Cardiovagal baroreflex sensitivity is improved in children with high blood pressure after a psychosocial intervention (852.1)

The aim of this study was to assess the effectiveness of a Leisure and Well‐Being Model (LWM) psychosocial intervention on blood pressure (BP) regulation in children. Children with consistent BP 蠅 95th percentile and &lt;90th percentile were grouped into high (HBP) and normal blood pressure (NBP) groups, respectively. Anthropometric data were collected along with five minutes of supine beat‐by‐beat BP and R–R interval. High frequency (HF; 0.15‐0.5 Hz) and low frequency (LF; 0.05‐0.15 Hz) power spectral indices were computed and transfer function analysis for the LF region was used to calculate baroreflex sensitivity (BRS). Pre and post‐test measures were taken one year apart. Results from 60 children (43 NBP, 17 HBP) indicated a three‐way interaction between intervention, BP status (NBP or HBP) and time (year 1 to year 2) independent of BMI (p=0.036). HBP participants receiving the intervention demonstrated an improvement in BRS from year 1 (11.4 ± 5.4 ms/mmHg) to year 2 (17.4 ± 8.5 ms/mmHg) compared to the HBP participants that did not receive the intervention (15.3 ± 8.5 ms/mmHg to 13.4 ± 6.5 ms/mmHg). These findings demonstrate that a LWM psychosocial intervention had a positive impact on BP regulation in children with elevated BP. These findings provide evidence of the importance of psychosocial determinants on autonomic regulation of BP in children.Grant Funding Source: Heart and Stroke Foundation of Ontario

Assessing the impact of pubertal maturity and sex on cardiovagal baroreflex sensitivity in children and adolescents (852.3)

Puberty is associated with important hormonal and metabolic changes associated with growth and maturation. The impact of puberty on blood pressure (BP) regulation is relatively unexplored. The purpose of this study was to assess whether pubertal maturity has an effect on cardiovagal baroreflex sensitivity (BRS) in children and adolescents. The study was cross‐sectional and included 77 participants (44 boys and 33 girls) aged 8‐18 years old. Participants were organized into four pubertal groups based on Tanner criteria; pre‐pubertal (Tanner stage 1, n=16), early pubertal (Tanner stage 2, n=11), peri‐pubertal (Tanner 3 &amp; 4, n=34), and post‐pubertal (Tanner 5 &amp; 6, n=16). Body composition (lean mass and percent body fat), body mass index (BMI) and demographic variables were collected. Beat‐by‐beat BP and R‐R interval (RRI) were collected in supine rest. BRS was assessed by transfer function analysis in the low frequency (LF) range (0.05 – 0.15Hz). The results of the study demonstrated a group by sex interaction (p=0.012) with BRS increasing in girls (21.2 7.6 to 26.8 8.0 ms/mmHg) and decreasing in boys (21.6 7.2 to 12.7 7.4 ms/mmHg) from pre‐ to post‐puberty. These findings were independent of body composition changes associated with puberty. In conclusion, this study demonstrates that pubertal maturity affects BRS differentially in boys than girls and may be due to hormonal changes that occur with puberty.

Calcitonin gene-related peptide (CGRP) in autonomic cardiovascular regulation and vascular structure

Calcitonin gene-related peptide (CGRP) is reported to play important roles in cardiovascular regulation in human and animal models. In spite of this, its role remains controversial. We aim to clarify this by studying the autonomic cardiovascular function and vascular structure in CGRP knockout (CGRP−/−) mice. Blood pressure (BP) and heart rate (HR) were assessed by telemeters. Urine (24-hour) and blood were collected for catecholamines measurements. Baroreflex sensitivity was assessed using phenylephrine and sodium nitroprusside administered in an acute study. Daytime mean arterial pressure (MAP; 12-hour period) was significantly higher in the CGRP−/− mice than in the wild type (WT) mice (114.5 vs 104.5 mm Hg; P = .04). Norepinephrine was elevated in plasma and 24-hour urine in the knockouts (Urine, 956 vs 618 pg/mL; P = .004; Plasma, 2505 vs 1168 pg/mL; P = .04). Paradoxically, cardiovagal baroreflex sensitivity was higher in CGRP−/− mice (3.2 vs 1.4 ms/mm Hg; P = .03). To increase insight, we studied aortic stiffness in CGRP−/− mice and found it increased compared with age-matched WT mice, as evidenced by the depression of the compliance curve (P < .05). CGRP−/− mice have higher BP due to elevated sympathetic signals and abnormalities in blood vessel structure. Moreover, our data also showed that CGRP plays an important role in the regulation of the cardio-vagal tone.

Cardiovascular reactivity to stressors: Effect of time of day?

Reduced cardiovagal baroreflex sensitivity and a peak in the incidence of cardiovascular events in the hours immediately after waking from nocturnal sleep suggest that cardiovascular control is impaired in the morning compared with other times of day. Previous research indicates that diurnal variation exists in acute blood pressure (BP) responses to exercise. However, the effect of time of day on activities such as cognitive tasks and “passive coping” physical tasks has yet to be established. Therefore, the primary aim of this study was to explore cardiovascular responses to physical and mental stressors at two times of day that have previously been associated with differing levels of cardiovascular control. In addition, the effect of the chronotype was examined to identify possible interactions between morningness/eveningness, time of day and responses to stressors. Fourteen healthy, young subjects completed a morning (08:30 h) and an afternoon (13:30 h) trial on separate days. Subjects performed a mental arithmetic task and a cold pressor test while beat-to-beat measurements of BP and heart rate were recorded continuously. Reactivity was determined using mean change scores in systolic BP, diastolic BP, mean arterial pressure, heart rate and rate-pressure product (RPP) from a period of rest recorded immediately prior to the task. There was no significant difference in cardiovascular reactivity between the morning and afternoon (p > 0.05). The time course of the responses and subsequent recovery were also consistent between the two times of day (p > 0.05). There was a significant interaction between time of day and chronotype, although this was apparent only for heart rate and RPP reactivity (p < 0.05); subjects tending towards “morningness” exhibited greater heart rate and RPP reactivity in the afternoon, and subjects tending towards “eveningness” exhibited greater heart rate and RPP reactivity in the morning. No interactions were observed between time of day and chronotype for BP reactivity (p > 0.05). Despite effects of time of day on heart rate that are dependent upon chronotype, this study suggests that BP control during mental and passive physical stress is not altered between the morning and afternoon.

Abstract 304: The Role of Calcitonin Gene Related Peptide (CGRP) in Cardiovascular Regulation and Blood Vessel Structure

Calcitonin gene related peptide (CGRP) is known to be a potent microvascular dilator and hypotensive agent. This peptide and its receptors are distributed widely in both central and peripheral nervous systems. CGRP-containing neural fibers are closely associated with blood vessels in the arterial circulation where its release leads to vascular dilation. However, its role in cardiovascular regulation remains controversial. We studied the hemodynamic and autonomic function, as well as blood vessel structure in CGRP knockout (KO) mice. Blood pressure (BP), heart rate (HR) and activity level were assessed at least one week after mice were implanted with telemeters. Ten CGRP KO and ten wild type (WT) mice (4-5 month old) were used in this study. After the recording period, 24-hr urine and blood were collected for assessment of catecholamines and their metabolites. To study the baroreflex sensitivity, phenylephrine and sodium nitroprusside were administered in an acute study with seven mice from each group. We found no significant difference in 24-hr mean arterial pressure (MAP) (105.0 ± 1.8mmHg, vs. 112.1 ± 3.1mmHg, p= 0.05) between the two groups. There was also no difference in HR (KO: 566.4 ± 12.1; WT: 581.9 ± 8.5, p = 0.31). Norepinephrine was greatly elevated in both plasma and 24-hr urine in KO mice (in urine: KO: 956 ± 91 pg/ml, WT: 618 ± 46pg/ml, p = 0.004; in plasma: KO: 2505 ± 596pg/ml, n=6, WT: 1168 ± 98 pg/ml, p = 0.04). Paradoxically, cardiovagal baroreflex sensitivity was higher in the KO mice (KO: 3.2 ± 0.7 ms/mmHg, n=7, WT: 1.4 ± 0.3 ms/mmHg, n=7, p=0.03). Thoracic aortas were collected from both groups to measure vessel stiffness. The diameter at 125 mmHg of the aorta was significantly smaller in CGRP KO mice than in WT (321±30μm, vs. 422±82μm, p&lt;0.01). Therefore, we hypothesize that although CGRP may have a limited contribution to physiological cardiovascular regulation, it may play a significant role in modulating the vagal tone and the structure properties of blood vessels.

Abstract 157: MAP Kinase Phosphatase-1 Inhibitor Injection into the Solitary Tract Nucleus Impairs Cardiovagal Baroreflex Function in Transgenic ASrAOGEN Rats

Hypotensive transgenic ASrAOGEN rats (AS) with low brain angiotensinogen resulting from glial overexpression of an antisense oligonucleotide to angiotensinogen, have enhanced baroreflex sensitivity (BRS) relative to hypertensive transgenic (mRen2)27 rats (mRen) that overexpress the murine Ren2 gene or normotensive Sprague Dawley rats (SD). The AS rats exhibit elevated protein expression and activity (less phosphorylated-ERK) of the MAP Kinase Phosphatase-1 [MKP-1], a negative regulator of MAP Kinase signaling in the brain dorsal medulla compared with either mRen or SD rats at 26 wks of age. To determine if MKP-1 plays a role in maintenance of BRS, we gave acute bilateral microinjections of an irreversible MKP-1 inhibitor {2,3-bis-[(2-Hydroxyethyl)thiol]-1,4-naphthoquinone, NSC 95397; 200 nM/120 nL} into the solitary tract nucleus (NTS), an important site in the dorsal medulla for modulation of BRS in urethane/chloralose anesthetized AS, mRen and SD rats at 21 wks of age. The MKP-1 inhibitor impaired the BRS for bradycardia in response to increases in pressure by 48 % at 10 min (1.01 ± 0.16 baseline vs. 0.49 ± 0.1 msec/mm Hg at 10 min), 56 % at 60 min and 64 % at 120 min in the AS rats (p = 0.02, n = 8), but not in the mRen or SD rats. In addition, NSC 95397 reduced resting pressure (91 ± 3 at baseline vs. 79 ± 3 at 60 min vs. 80 ± 3 mm Hg at 120 min) in the SD rats, with a similar trend in the other strains, without effects on resting heart rate in any strain. Thus, up-regulated expression of MKP-1 contributes to the higher resting BRS function in AS rats. AS animals are spared age-related declines in BRS and they maintain higher expression of MKP-1 protein in the dorsal medulla vs. either mRen or SD rats (AS: 1.6 ± 0.2, mRen: 0.8 ± 0.1, SD: 1 ± 0.1 arbitary units; p = 0.01, n = 6 per group) at 66 wks of age. Thus, higher MKP-1 may be involved the preservation of BRS in older AS rats, suggesting the phosphatase be a novel therapeutic target to improve BRS function in aging and hypertension.

Baroreflex sensitivity analysis: spontaneous methodology vs. Valsalva’s maneuver

Spontaneous analysis techniques and Valsalva's maneuver (VM) are often used as a non-pharamcological approach to assess both sympathetic (sBRS) and cardiovagal (cBRS) baroreflex sensitivity. Despite their wide utilization, no studies have assessed the intra-individual reliability between these analysis techniques. Accordingly, we hypothesized that spontaneous BRS would be positively correlated to VM BRS. Heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) were measured in 26 healthy subjects (age, 22 ± 1 year; 14 men and 12 women) during 10 min supine rest and 3 VM at 40 mmHg expiratory pressure (15 s, 1 min recoveries). For spontaneous BRS, relations between diastolic BP and MSNA were used to determine sBRS, while relations between systolic BP and R-R interval were used to determine cBRS. During VM, sBRS was the ratio of MSNA and the maximum diastolic BP reduction during early phase II, and cBRS was derived from linear relations between systolic BP and R-R interval during early phase II (i.e., hypotensive stimulus) and phase IV (i.e., hypertensive stimulus). Spontaneous sBRS was significantly correlated to VM sBRS (r = 0.516, p = 0.036). In contrast, spontaneous cBRS from up-up sequence was not correlated to VM phase IV cBRS (r = 0.274, p = 0.109). Similarly, spontaneous cBRS from down-down sequence was not correlated to VM phase II cBRS (r = 0.199, p = 0.207). In conclusion, our findings demonstrate positive association between spontaneous sBRS and VM sBRS, but there is no correlation between spontaneous and VM cBRS.

Oral supplementation with the rutin improves cardiovagal baroreflex sensitivity and vascular reactivity in hypertensive rats

The hypothesis that oral supplementation with the flavonoid rutin improves baroreflex sensitivity and vascular reactivity in hypertensive (2-kidney-1-clip (2K1C)) rats was tested. Sixty-four rats were divided in 4 groups: sham + saline; sham + rutin; 2K1C + saline, and 2K1C + rutin. Six weeks after 2K1C surgery, the animals were treated with saline or rutin (40 mg·kg(-1)·day(-1)) by gavage for 7 days. Baroreflex sensitivity test using phenylephrine (8 μg·kg(-1), iv) and sodium nitroprusside (25 μg·kg(-1), iv), vascular reactivity, and thiobarbituric acid reactive substances assay were performed. Baroreflex sensitivity in hypertensive rats was impaired and compared with sham (-2.77 ± 0.15 vs. -1.53 ± 0.27 beats·min(-1)·mm Hg(-1); n = 8; p < 0.05). Oral supplementation with rutin restored baroreflex sensitivity in 2K1C rats (-2.40 ± 0.24 vs. -2.77 ± 0.15 beats·min(-1)·mm Hg(-1); n = 8; p > 0.05). Besides, hypertensive rats have greater contraction to phenylephrine (129.49% ± 4.46% vs. 99.50% ± 11.36%; n = 8; p < 0.05), which was restored by rutin (99.10% ± 1.77% vs. 99.50% ± 11.36%; n = 8; p > 0.05). Furthermore, vasorelaxation to acetylcholine was diminished in hypertensive rats (96.42% ± 2.80% vs. 119.35% ± 5.60%; n = 8; p < 0.05), which was also restored by rutin (117.55% ± 6.94% vs. 119.35% ± 5.60%; n = 8; p > 0.05). Finally, oxidative stress was greater in hypertensive rats (1.54 ± 0.12 vs. 0.53 ± 0.12 nmol MDA·mL(-1); n = 8; p < 0.05) and rutin supplementation significantly decreased oxidative stress in those animals (0.70 ± 0.13 vs. 1.54 ± 0.12 nmol MDA·mL(-1); n = 8; p < 0.05). We concluded that oral supplementation with rutin restores impaired baroreflex sensitivity and vascular reactivity in hypertensive rats by decreasing oxidative stress.

Blood pressure regulation in women – differences emerge when challenged by orthostasis

Blood pressure regulation in women – differences emerge when challenged by orthostasis

Spontaneous fluctuation indices of the cardiovagal baroreflex accurately measure the baroreflex sensitivity at the operating point during upright tilt

Spontaneous fluctuation indices of cardiovagal baroreflex have been suggested to be inaccurate measures of baroreflex function during orthostatic stress compared with alternate open-loop methods (e.g. neck pressure/suction, modified Oxford method). We therefore tested the hypothesis that spontaneous fluctuation measurements accurately reflect local baroreflex gain (slope) at the operating point measured by the modified Oxford method, and that apparent differences between these two techniques during orthostasis can be explained by a resetting of the baroreflex function curve. We computed the sigmoidal baroreflex function curves supine and during 70° tilt in 12 young, healthy individuals. With the use of the modified Oxford method, slopes (gains) of supine and upright curves were computed at their maxima (Gmax) and operating points. These were compared with measurements of spontaneous indices in both positions. Supine spontaneous analyses of operating point slope were similar to calculated Gmax of the modified Oxford curve. In contrast, upright operating point was distant from the centering point of the reset curve and fell on the nonlinear portion of the curve. Whereas spontaneous fluctuation measurements were commensurate with the calculated slope of the upright modified Oxford curve at the operating point, they were significantly lower than Gmax. In conclusion, spontaneous measurements of cardiovagal baroreflex function accurately estimate the slope near operating points in both supine and upright position.

Sympathetic and cardiovagal baroreflex sensitivity in humans: Comparison of Valsalva's maneuver and spontaneous methodologies

Valsalva's maneuver (VM) and spontaneous techniques have been used to assess sympathetic (sBRS) and cardiovagal (cBRS) baroreflex sensitivity, but the intra‐individual reliability between these methodologies has not been examined. We hypothesized that spontaneous BRS would be positively correlated to VM BRS. Heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) were measured in 28 healthy subjects (age, 23±1 yr; 14 men, 14 women) during 10min supine rest and 3 VM at 40mmHg expiratory pressure (15s, 1min recovery). For spontaneous BRS, relations between diastolic BP and MSNA were used to determine sBRS, while relations between systolic BP and RR interval were used to determine cBRS. During VM, sBRS was the ratio of MSNA and the maximum diastolic BP reduction during early phase II, and cBRS was derived from linear relations between systolic BP and RR interval during early phase II (i.e. hypotensive stimulus) and phase IV (i.e. hypertensive stimulus). Spontaneous sBRS was significantly correlated to VM sBRS (r=0.516, p=0.036). Spontaneous cBRS (up‐up sequence) was correlated to VM phase IV cBRS (r=0.356, p=0.048). In contrast, spontaneous cBRS (down‐down sequence) was not correlated to VM phase II cBRS (r=0.128, p=0.295). In conclusion, our findings demonstrate low ‐to‐ moderate associations between spontaneous and VM estimates of sBRS and cBRS. Supported by NIH (HL‐ 098676).

Reduction in central mitochondrial ROS improves cardiovagal baroreflex function independent of blood pressure in (mRen2)27 rats

Mitochondria‐derived reactive oxygen species (ROS) are potential therapeutic targets in hypertension. Transgenic (mRen2)27 rats overexpressing the murine Ren2 gene are hypertensive with impaired baroreflex sensitivity (BRS) for control of heart rate (HR). These animals also show elevated mitochondrial ROS in brain dorsal medulla, an important site for modulation of BRS. To determine whether central mitochondrial ROS influences mean arterial pressure (MAP) and BRS, the mitochondria‐targeted ROS scavenger Mito‐TEMPO (MT; 0.15 mg/day for 4 weeks) or artificial cerebrospinal fluid (aCSF) were infused ICV in 18 week old male (mRen2)27 rats. MT treatment failed to lower MAP but reduced HR [400 ± 23 vs. aCSF: 450 ± 7 bpm; p = 0.03; n = 4–7]. Lowering of HR was associated with increased vagal components of the spontaneous BRS [Sequence UP: 0.2 ± 0.2 vs. aCSF: −0.2 ± 0.1 ms/mm Hg; p = 0.03] and HR variability [SDRR: 7.6 ± 2 vs. aCSF: 3.3 ± 0.6 ms; p = 0.02]. Overall sympathovagal balance was reduced [LFRRI/HFRRI: −0.1 ± 0.1 vs. aCSF: 0.3 ± 0.1, p = 0.03]. Central scavenging of mitochondrial ROS improved BRS independent of MAP alterations in the (mRen2)27 rats. Since impaired BRS significantly associates with cardiovascular pathologies, both targeting of mitochondrial ROS and lowering of MAP may provide optimal therapeutic benefit.

SYMPATHOVAGAL IMBALANCE IN TAKOTSUBO CARDIOMYOPATHY

Takotsubo cardiomyopathy is an acute reversible cardiac dysfunction syndrome associated with high circulating catecholamine levels. Our objective was to investigate whether abnormal cardiovascular control might play a role in the pathophysiology.We studied autonomic cardiovascular reflexes in 10 women who had takotsubo (33±7 months after being hospitalized) and 10 age/BMI matched healthy women.In the women with takotsubo, indices of vagal modulation of heart rate induced by respiration were uniformly reduced (expiratory:inspiratory ratio: p&lt;0.01, pnn50%: p&lt;0.02, rMSSD: p&lt;0.03). Cognitive (stroop test: p&lt;0.03) and emotional arousal (event recall: p&lt;0.05) produced exaggerated pressor responses, without detectable ECG changes. Pressor responses to hemodynamic stimuli were also amplified (Valsalva SBP overshoot: p&lt;0.05). Takotsubo women had increased BP variability in the short‐term (St. Dev. SBP: p&lt;0.01). Ambulatory recordings captured an exaggerated morning surge in SBP after awakening from sleep (p&lt;0.05). Cardiovagal baroreflex gain was significantly lower in the takotsubo women (sequence analysis: p&lt;0.01, regression method: p&lt;0.001, transfer function gain: p&lt;0.001).Women with takotsubo have heightened sympathetic responsiveness, labile BP and reduced vagal modulation of the heart. This shift in sympathovagal balance could play a role in the pathophysiology.