Arterial baroreflex control of sympathetic vasoconstrictor traffic and orthostatic intolerance after head-down bed rest

The purpose of the present study is to examine the changes in the arterial baroreflex control of muscle sympathetic nerve activity (MSNA) after head-down bed rest (HDBR), in relation to orthostatic hypotension after HDBR. Therefore, we performed 60 degrees head-up tilt (HUT) tests before and after 14 days of HDBR, with monitoring MSNA, heart rate and blood pressure. We calculated the gain of the arterial baroreflex control of MSNA, and compared the gains between the subjects who did (defined as the fainters) and those who did not (defined as the nonfainters) become presyncopal in HUT tests after HDBR.     

Increased vasoconstriction predisposes to hyperpnea and postural faint

Our prior studies indicated that postural fainting relates to splanchnic hypervolemia and thoracic hypovolemia during orthostasis. We hypothesized that thoracic hypovolemia causes excessive sympathetic activation, increased respiratory tidal volume, and fainting involving the pulmonary stretch reflex. We studied 18 patients 13-21 yr old, 11 who fainted within 10 min of upright tilt (fainters) and 7 healthy control subjects. We measured continuous blood pressure and heart rate, respiration by inductance plethysmography, end-tidal carbon dioxide (ET(CO(2))) by capnography, and regional blood flows and blood volumes using impedance plethysmography, and we calculated arterial resistance with patients supine and during 70 degrees upright tilt. Splanchnic resistance decreased until faint in fainters (44 +/- 8 to 21 +/- 2 mmHg.l(-1).min(-1)) but increased in control subjects (47 +/- 5 to 53 +/- 4 mmHg.l(-1).min(-1)). Percent change in splanchnic blood volume increased (7.5 +/- 1.0 vs. 3.0 +/- 11.5%, P < 0.05) after the onset of tilt. Upright tilt initially significantly increased thoracic, pelvic, and leg resistance in fainters, which subsequently decreased until faint. In fainters but not control subjects, normalized tidal volume (1 +/- 0.1 to 2.6 +/- 0.2, P < 0.05) and normalized minute ventilation increased throughout tilt (1 +/- 0.2 to 2.1 +/- 0.5, P < 0.05), whereas respiratory rate decreased (19 +/- 1 to 15 +/- 1 breaths/min, P < 0.05). Maximum tidal volume occurred just before fainting. The increase in minute ventilation was inversely proportionate to the decrease in ET(CO(2)). Our data suggest that excessive splanchnic pooling and thoracic hypovolemia result in increased peripheral resistance and hyperpnea in simple postural faint. Hyperpnea and pulmonary stretch may contribute to the sympathoinhibition that occurs at the time of faint.     

Respiration drives phase synchronization between blood pressure and RR interval following loss of cardiovagal baroreflex during vasovagal syncope

Loss of the cardiovagal baroreflex (CVB), thoracic hypovolemia, and hyperpnea contribute to the nonlinear time-dependent hemodynamic instability of vasovagal syncope. We used a nonlinear phase synchronization index (PhSI) to describe the extent of coupling between cardiorespiratory parameters, systolic blood pressure (SBP) or arterial pressure (AP), RR interval (RR), and ventilation, and a directional index (DI) measuring the direction of coupling. We also examined phase differences directly. We hypothesized that AP-RR interval PhSI would be normal during early upright tilt, indicating intact CVB, but would progressively decrease as faint approached and CVB failed. Continuous measurements of AP, RR interval, respiratory plethysomography, and end-tidal CO2 were recorded supine and during 70-degree head-up tilt in 15 control subjects and 15 fainters. Data were evaluated during five distinct times: baseline, early tilt, late tilt, faint, and recovery. During late tilt to faint, fainters exhibited a biphasic change in SBP-RR interval PhSI. Initially in fainters during late tilt, SBP-RR interval PhSI decreased (fainters, from 0.65±0.04 to 0.24±0.03 vs. control subjects, from 0.51±0.03 to 0.48±0.03; P<0.01) but then increased at the time of faint (fainters=0.80±0.03 vs. control subjects=0.42±0.04; P<0.001) coinciding with a change in phase difference from positive to negative. Starting in late tilt and continuing through faint, fainters exhibited increasing phase coupling between respiration and AP PhSI (fainters=0.54±0.06 vs. control subjects=0.27±0.03; P<0.001) and between respiration and RR interval (fainters=0.54±0.05 vs. control subjects=0.37±0.04; P<0.01). DI indicated respiratory driven AP (fainters=0.84±0.04 vs. control subjects=0.39±0.09; P<0.01) and RR interval (fainters=0.73±0.10 vs. control subjects=0.23±0.11; P<0.001) in fainters. The initial drop in the SBP-RR interval PhSI and directional change of phase difference at late tilt indicates loss of cardiovagal baroreflex. The subsequent increase in SBP-RR interval PhSI is due to a respiratory synchronization and drive on both AP and RR interval. Cardiovagal baroreflex is lost before syncope and supplanted by respiratory reflexes, producing hypotension and bradycardia.     

Blood pressure regulation in neurally intact human vs. acutely injured paraplegic and tetraplegic patients during passive tilt

We investigated autonomic control of cardiovascular function in able-bodied (AB), paraplegic (PARA), and tetraplegic (TETRA) subjects in response to head-up tilt following spinal cord injury. We evaluated spectral power of blood pressure (BP), baroreflex sensitivity (BRS), baroreflex effectiveness index (BEI), occurrence of systolic blood pressure (SBP) ramps, baroreflex sequences, and cross-correlation of SBP with heart rate (HR) in low (0.04-0.15 Hz)- and high (0.15-0.4 Hz)-frequency regions. During tilt, AB and PARA effectively regulated BP and HR, but TETRA did not. The numbers of SBP ramps and percentages of heartbeats involved in SBP ramps and baroreflex sequences increased in AB, were unchanged in PARA, and declined in TETRA. BRS was lowest in PARA and declined with tilt in all groups. BEI was greatest in AB and declined with tilt in all groups. Low-frequency power of BP and the peak of the SBP/HR cross-correlation magnitude were greatest in AB, increased during tilt in AB, remained unchanged in PARA, and declined in TETRA. The peak cross-correlation magnitude in HF decreased with tilt in all groups. Our data indicate that spinal cord injury results in decreased stimulation of arterial baroreceptors and less engagement of feedback control as demonstrated by lower 1) spectral power of BP, 2) number (and percentages) of SBP ramps and barosequences, 3) cross-correlation magnitude of SBP/HR, 4) BEI, and 5) changes in delay between SBP/HR. Diminished vasomotion and impaired baroreflex regulation may be major contributors to decreased orthostatic tolerance following injury.     

Baroreflex control of muscle sympathetic nerve activity in postural orthostatic tachycardia syndrome

Postural orthostatic tachycardia syndrome (POTS) is characterized by excessive tachycardia during orthostasis. To test the hypothesis that patients with POTS have decreased sympathetic neural responses to baroreflex stimuli, we measured heart rate (HR) and muscle sympathetic nerve activity (MSNA) responses to three baroreflex stimuli including vasoactive drug boluses (modified Oxford technique), Valsalva maneuver, and head-up tilt (HUT) in POTS patients and healthy control subjects. The MSNA response to the Valsalva maneuver was significantly greater in the POTS group (controls, 26 +/- 7 vs. POTS, 48 +/- 6% of baseline MSNA/mmHg; P = 0.03). POTS patients also had an exaggerated MSNA response to 30 degrees HUT (controls, 123 +/- 24 vs. POTS, 208 +/- 30% of baseline MSNA; P = 0.03) and tended to have an exaggerated response to 45 degrees HUT (controls, 137 +/- 27 vs. POTS, 248 +/- 58% of baseline MSNA; P = 0.10). Sympathetic baroreflex sensitivity calculated during administration of the vasoactive drug boluses also tended to be greater in the POTS patients; however, this did not reach statistical significance (P = 0.15). Baseline MSNA values during supine rest were not different between the groups (controls, 23 +/- 4 vs. POTS, 16 +/- 5 bursts/100 heartbeats; P = 0.30); however, resting HR was significantly higher in the POTS group (controls, 58 +/- 3 vs. POTS, 82 +/- 4 beats/min; P = 0.0001). Our results suggest that POTS patients have exaggerated MSNA responses to baroreflex challenges compared with healthy control subjects, although resting supine MSNA values did not differ between the groups.     

Blood pressure regulation in diabetic patients with and without peripheral neuropathy

Cardiac and vascular dysfunctions resulting from autonomic neuropathy (AN) are complications of diabetes, often undiagnosed. Our objectives were to: 1) determine sympathetic and parasympathetic components of compromised blood pressure (BP) regulation in patients with peripheral neuropathy and 2) rank noninvasive indexes for their sensitivity in diagnosing AN. We continuously measured electrocardiogram, arterial BP, and respiration during supine rest and 70° head-up tilt in 12 able-bodied subjects, 7 diabetics without, 7 diabetics with possible, and 8 diabetics with definite, sensory, and/or motor neuropathy (D2). During the first 3 min of tilt, systolic BP (SBP) of D2 decreased [-10.9 ± 4.5 (SE) mmHg] but increased in able-bodied (+4.8 ± 5.4 mmHg). Compared with able-bodied, D2 had smaller low-frequency (0.04-0.15 Hz) spectral power of diastolic BP, lower baroreflex effectiveness index (BEI), and more SBP ramps. Except for low-frequency power of SBP, D2 had greater SBP and smaller RR interval harmonic and nonharmonic components at rest across the 0.003- to 0.45-Hz region. In addition, our results support previous findings of smaller HF RR interval power, smaller numbers of baroreflex sequences, and lower baroreflex sensitivity in D2. We conclude that diabetic peripheral neuropathy is accompanied by diminished parasympathetic and sympathetic control of heart rate and peripheral vasomotion and diminished baroreflex regulation. A novel finding of this study lies in the sensitivity of BEI to detect AN, presumably because of its combination of parameters that measure reductions in both sympathetic control of vasomotion and parasympathetic control of heart rate.     

Baroreflex sensitivity, blood pressure buffering, and resonance: what are the links? Computer simulation of healthy subjects and heart failure patients.

The arterial baroreflex buffers slow (<0.05 Hz) blood pressure (BP) fluctuations, mainly by controlling peripheral resistance. Baroreflex sensitivity (BRS), an important characteristic of baroreflex control, is often noninvasively assessed by relating heart rate (HR) fluctuations to BP fluctuations; more specifically, spectral BRS assessment techniques focus on the BP-to-HR transfer function around 0.1 Hz. Skepticism about the relevance of BRS to characterize baroreflex-mediated BP buffering is based on two considerations: 1) baroreflex-modulated peripheral vasomotor function is not necessarily related to baroreflex-HR transfer; and 2) although BP fluctuations around 0.1 Hz (Mayer waves) might be related to baroreflex BP buffering, they are merely a not-intended side effect of a closed-loop control system. To further investigate the relationship between BRS and baroreflex-mediated BP buffering, we set up a computer model of baroreflex BP control to simulate normal subjects and heart failure patients. Output variables for various randomly chosen combinations of feedback gains in the baroreflex arms were BP resonance, BP-buffering capacity, and BRS. Our results show that BP buffering and BP resonance are related expressions of baroreflex BP control and depend strongly on the sympathetic gain to the peripheral resistance. BRS is almost uniquely determined by the vagal baroreflex gain to the sinus node. In conclusion, BP buffering and BRS are unrelated unless coupled gains in all baroreflex limbs are assumed. Hence, the clinical benefit of a high BRS is most likely to be attributed to vagal effects on the heart instead of to effective BP buffering.     

Does long-term experimental antiorthostasis lead to cardiovascular deconditioning in the rat?

Microgravity or simulated microgravity induces acute and chronic cardiovascular responses, whose mechanism is pivotal for understanding of physiological adaptation and pathophysiological consequences. We investigated hemodynamic responses of conscious Wistar rats to 45? head-down tilt (HDT) for 7 days. Arterial blood pressure (BP) was recorded by telemetry. Heart rate (HR), spectral properties and the spontaneous baroreflex sensitivity (sBRS) were calculated. Head-up tilt (HUT) was applied for 2 h before and after HDT to assess the degree of any possible cardiovascular deconditioning. Horizontal control BP and HR were 112.5+/-2.8 mmHg and 344.7+/-10 bpm, respectively. HDT elicited an elevation in BP and HR by 8.3 % and 8.8 %, respectively, in less than 1 h. These elevations in BP and HR were maintained for 2 and 3 days, respectively, and then normalized. Heart rate variability was unchanged, while sBRS was permanently reduced from the beginning of HDT (1.01+/-0.08 vs. 0.74+/-0.05 ms/mmHg). HUT tests before and after HDT resulted in BP elevations (6.9 vs. 11.6 %) and sBRS reduction (0.44 vs. 0.37 ms/mmHg), respectively. The pressor response during the post-HDT HUT test was accompanied by tachycardia (13.7 %). In conclusion, chronic HDT does not lead to symptoms of cardiovascular deconditioning. However the depressed sBRS and tachycardic response seen during the post-HDT HUT test may indicate disturbances in cardiovascular control.     

Baroreflex control of muscle sympathetic nerve activity after 120 days of 6 degrees head-down bed rest

To examine how long-lasting microgravity simulated by 6 degrees head-down bed rest (HDBR) induces changes in the baroreflex control of muscle sympathetic nerve activity (MSNA) at rest and changes in responses of MSNA to orthostasis, six healthy male volunteers (range 26-42 yr) participated in Valsalva maneuver and head-up tilt (HUT) tests before and after 120 days of HDBR. MSNA was measured directly using a microneurographic technique. After long-term HDBR, resting supine MSNA and heart rate were augmented. The baroreflex slopes for MSNA during Valsalva maneuver (in supine position) and during 60 degrees HUT test, determined by least-squares linear regression analysis, were significantly steeper after than before HDBR, whereas the baroreflex slopes for R-R interval were significantly flatter after HDBR. The increase in MSNA from supine to 60 degrees HUT was not different between before and after HDBR, but mean blood pressure decreased in 60 degrees HUT after HDBR. In conclusion, the baroreflex control of MSNA was augmented, whereas the same reflex control of R-R interval was attenuated after 120 days of HDBR.     

Age dependency of cardiovascular autonomic responses to head-up tilt in healthy subjects.

In elderly subjects, heart rate responses to postural change are attenuated, whereas their vascular responses are augmented. Altered strategy in maintaining blood pressure homeostasis during upright position may result from various cardiovascular changes, including age-related cardiovascular autonomic dysfunction. This exploratory study was conducted to evaluate impact of age on cardiovascular autonomic responses to head-up tilt (HUT) in healthy subjects covering a wide age range. The study population consisted of 63 healthy, normal-weight, nonsmoking subjects aged 23-77 yr. Five-minute electrocardiogram and finger blood pressure recordings were performed in the supine position and in the upright position 5 min after 70 degrees HUT. Stroke volume was assessed from noninvasive blood pressure signals by the arterial pulse contour method. Heart rate variability (HRV) and systolic blood pressure variability (SBPV) were analyzed by using spectral analysis, and baroreflex sensitivity (BRS) was assessed by using sequence and cross-spectral methods. Cardiovascular autonomic activation during HUT consisted of decreases in HRV and BRS and an increase in SBPV. These changes became attenuated with aging. Age correlated significantly with amplitude of HUT-stimulated response of the high-frequency component (r = -0.61, P < 0.001) and the ratio of low-frequency to high-frequency power of HRV (r = -0.31, P < 0.05) and indexes of BRS (local BRS: r = -0.62, P < 0.001; cross-spectral baroreflex sensitivity in the low-frequency range: r = -0.38, P < 0.01). Blood pressure in the upright position was maintained well irrespective of age. However, the HUT-induced increase in heart rate was more pronounced in the younger subjects, whereas the increase in peripheral resistance was predominantly observed in the older subjects. Thus it is likely that whereas the dynamic capacity of cardiac autonomic regulation decreases, vascular responses related to vasoactive mechanisms and vascular sympathetic regulation become augmented with increasing age.     

Heat acclimation increases skin vasodilation and sweating but not cardiac baroreflex responses in heat-stressed humans.

In the present study, to test the hypothesis that exercise-heat acclimation increases orthostatic tolerance via the improvement of cardiac baroreflex control in heated humans, we examined cardiac baroreflex and thermoregulatory responses, including cutaneous vasomotor and sudomotor responses, during whole body heating before and after a 6-day exercise-heat acclimation program [4 bouts of 20-min exercise at 50% peak rate of oxygen uptake separated by 10-min rest in the heat (36 degrees C; 50% relative humidity)]. Ten healthy young volunteers participated in the study. On the test days before and after the heat acclimation program, subjects underwent whole body heat stress produced by a hot water-perfused suit during supine rest for 45 min and 75 degrees head-up tilt (HUT) for 6 min. The sensitivity of the arterial baroreflex control of heart rate (HR) was calculated from the spontaneous changes in beat-to-beat arterial pressure and HR. The HUT induced a presyncopal sign in seven subjects in the preacclimation test and in six subjects in the postacclimation test, and the tilting time did not differ significantly between the pre- (241 +/- 33 s) and postacclimation (283 +/- 24 s) tests. Heat acclimation did not change the slope in the HR-esophageal temperature (Tes) relation and the cardiac baroreflex sensitivity during heating. Heat acclimation decreased (P < 0.05) the Tes thresholds for cutaneous vasodilation in the forearm and dorsal hand and for sweating in the forearm and chest. These findings suggest that short-term heat acclimation does not alter the spontaneous baroreflex control of HR during heat stress, although it induces adaptive change of the heat dissipation response in nonglabrous skin.     

Dynamic cerebral autoregulation is preserved in neurally mediated syncope.

To test whether cerebral autoregulation is impaired in patients with neurally mediated syncope (NMS), we evaluated 15 normal subjects and 37 patients with recurrent NMS. Blood pressure (BP), heart rate, and cerebral blood velocity (CBV) (transcranial Doppler) were recorded at rest and during 80 degrees head-up tilt (HUT). Static cerebral autoregulation as assessed from the change in cerebrovascular resistance during HUT was the same in NMS and controls. Properties of dynamic cerebral autoregulation were inferred from transfer gain, coherence, and phase of the relationship between BP and CBV estimated from filtered data segments (0.02-0.8 Hz). During the 3 min preceding syncope, dynamic cerebral autoregulation of subjects with NMS did not differ from that of controls nor did it change over the course of HUT in patients with NMS or in control subjects. Dynamic cerebral autoregulation was also unaffected by the degree of orthostatic intolerance as inferred from latency to onset of syncope. We conclude that cerebral autoregulation in patients with recurrent syncope does not differ from that of normal control subjects.     

Differential effects of lower body negative pressure and upright tilt on splanchnic blood volume

Upright posture and lower body negative pressure (LBNP) both induce reductions in central blood volume. However, regional circulatory responses to postural changes and LBNP may differ. Therefore, we studied regional blood flow and blood volume changes in 10 healthy subjects undergoing graded lower-body negative pressure (-10 to -50 mmHg) and 8 subjects undergoing incremental head-up tilt (HUT; 20 degrees , 40 degrees , and 70 degrees ) on separate days. We continuously measured blood pressure (BP), heart rate, and regional blood volumes and blood flows in the thoracic, splanchnic, pelvic, and leg segments by impedance plethysmography and calculated regional arterial resistances. Neither LBNP nor HUT altered systolic BP, whereas pulse pressure decreased significantly. Blood flow decreased in all segments, whereas peripheral resistances uniformly and significantly increased with both HUT and LBNP. Thoracic volume decreased while pelvic and leg volumes increased with HUT and LBNP. However, splanchnic volume changes were directionally opposite with stepwise decreases in splanchnic volume with LBNP and stepwise increases in splanchnic volume during HUT. Splanchnic emptying in LBNP models regional vascular changes during hemorrhage. Splanchnic filling may limit the ability of the splanchnic bed to respond to thoracic hypovolemia during upright posture.     

Control of cerebral blood velocity with furosemide-induced hypovolemia and upright tilt

The purpose of this study was to test the hypothesis that exacerbated reductions of cerebral blood velocity (CBV) during upright tilt with dehydration are associated with impaired cerebrovascular control. Nine healthy men were tilted head-up (HUT) to 70° for 10 min on two occasions separated by 7 days under euhydration (EUH) and dehydration (DEH; 40 mg of furosemide and water restriction) conditions. Beat-by-beat arterial pressures and CBV were measured during a 5-min supine baseline and during the first (T1) and last (T2) 5 min of HUT. Cerebral autoregulation and arterial baroreflex sensitivity were assessed in the frequency domain with cross-spectral techniques. DEH reduced plasma volume by 10% (P = 0.008) and supine mean CBV (CBV(mean)) by 11% (P = 0.002). Mean arterial pressure (MAP), stroke volume, and baroreflex sensitivity decreased during HUT (P ≤ 0.002), but absolute reductions were similar between hydration conditions, with the exception of stroke volume, which was lower at T1 during DEH than EUH (P = 0.04). CBV(mean) during DEH was lower (7 cm/s) over the course of the entire 10 min of HUT (P ≤ 0.004) than during EUH. Low-frequency oscillations (0.07-0.2 Hz) of MAP and CBV(mean) and MAP-CBV(mean) coherence were higher during DEH than EUH at T1 (P ≤ 0.02), but not at T2. Our results suggest that increased coherence between arterial pressure and CBV with the combination of DEH and HUT are indicative of altered cerebrovascular control. Increased CBV oscillations with DEH may reflect acute protective mechanisms to ensure adequate cerebral perfusion under conditions of reduced central blood volume.     

Does nitric oxide buffer arterial blood pressure variability in humans?

Animal studies suggest that nitric oxide (NO) plays an important role in buffering short-term arterial pressure variability, but data from humans addressing this hypothesis are scarce. We evaluated the effects of NO synthase (NOS) inhibition on arterial blood pressure (BP) variability in eight healthy subjects in the supine position and during 60 degrees head-up tilt (HUT). Systemic NOS was blocked by intravenous infusion of N(G)-monomethyl-L-arginine (L-NMMA). Electrocardiogram and beat-by-beat BP in the finger (Finapres) were recorded continuously for 6 min, and brachial cuff BP was recorded before and after L-NMMA in each body position. BP and R-R variability and their transfer functions were quantified by power spectral analysis in the low-frequency (LF; 0.05-0.15 Hz) and high-frequency (HF; 0.15-0.35 Hz) ranges. L-NMMA infusion increased supine BP (systolic, 109 +/- 4 vs. 122 +/- 3 mmHg, P = 0.03; diastolic, 68 +/- 2 vs. 78 +/- 3 mmHg, P = 0.002), but it did not affect supine R-R interval or BP variability. Before L-NMMA, HUT decreased HF R-R variability (P = 0.03), decreased transfer function gain (LF, 12 +/- 2 vs. 5 +/- 1 ms/mmHg, P = 0.007; HF, 18 +/- 3 vs. 3 +/- 1 ms/mmHg, P = 0.002), and increased LF BP variability (P < 0.0001). After L-NMMA, HUT resulted in similar changes in BP and R-R variability compared with tilt without L-NMMA. Increased supine BP after L-NMMA with no effect on BP variability during HUT suggests that tonic release of NO is important for systemic vascular tone and thus steady-state arterial pressure, but NO does not buffer dynamic BP oscillations in humans.     

Cardiovagal regulation during combined hypoxic and orthostatic stress: fainters vs. nonfainters.

We tested the hypothesis that individual differences in the effect of acute hypoxia on the cardiovagal arterial baroreflex would determine individual susceptibility to hypoxic syncope. In 16 healthy, nonsmoking, normotensive subjects (8 women, 8 men, age 20-33 yr), we assessed orthostatic tolerance with a 20-min 60 degrees head-upright tilt during both normoxia and hypoxia (breathing 12% O(2)). On a separate occasion, we assessed baroreflex control of heart rate (cardiovagal baroreflex gain) using the modified Oxford technique during both normoxia and hypoxia. When subjects were tilted under hypoxic conditions, 5 of the 16 developed presyncopal signs or symptoms, and the 20-min tilt had to be terminated. These "fainters" had comparable cardiovagal baroreflex gain to "nonfainters" under both normoxic and hypoxic conditions (normoxia, fainters: -1.2 +/- 0.2, nonfainters: -1.0 +/- 0.2 beats.min(-1).mmHg(-1), P = 0.252; hypoxia, fainters: -1.3 +/- 0.2, nonfainters: -1.0 +/- 0.1 beats.min(-1).mmHg(-1), P = 0.208). Furthermore, hypoxia did not alter cardiovagal baroreflex gain in either group (both P > 0.8). It appears from these observations that hypoxic syncope results from the superimposed vasodilator effects of hypoxia on the cardiovascular system and not from a hypoxia-induced maladjustment in baroreflex control of heart rate.     

Gender influence on vasoactive hormones at rest and during a 70 degrees head-up tilt in healthy humans.

To evaluate the influence of age and gender on the neuroendocrine control of blood pressure in normal subjects, a 13-min 70 degrees head-up tilt (HUT) was applied after 3 h of recumbency to 109 healthy men and women aged 23-50 yr (age group I) and 51-77 yr (age group II). We found that age and gender had a significant influence on plasma norepinephrine (PNE) concentration at baseline and in the upright position. PNE was significantly higher in older men compared with the younger men and women of both age groups, suggesting a divergent age-related activation of the sympathetic nervous system between genders at baseline as well as during a sustained orthostatic challenge. There was no significant influence of age or gender on plasma epinephrine at baseline or during HUT. Plasma renin activity was significantly higher at baseline as well as in the upright position during HUT in elderly men than in women. Age or gender had no influence on plasma vasopressin (PAVP), and, regardless of age, nonhypotensive HUT induced an extremely modest increase in PAVP. The syncopal subjects displayed a hormonal pattern associating increased PNE and a surge in plasma epinephrine and PAVP minutes before syncope during HUT. The orthostatic intolerance appears not to be a feature of healthy aging per se. In healthy subjects, both age and gender modulate markedly the cardiovascular and neuroendocrine responses to an orthostatic challenge and must be taken into consideration, particularly when catecholamine responses are studied.     

Time delay of vagally mediated cardiac baroreflex response varies with autonomic cardiovascular control.

To examine whether changes in autonomic activity have an effect on the latency of the vagally mediated cardiac baroreflex response in humans, we investigated the effects of neck suction fluctuating sinusoidally at 0.2 Hz on R-R intervals (known to be mediated mainly by vagal activity) in the supine position, during 15 degrees head-down tilt and 60 degrees head-up tilt, and during vagotonic (2 microg/kg) and vagolytic (10 microg/kg) doses of atropine while the subjects breathed at 0.25 Hz. The phase shift between fluctuations in neck chamber pressure and in R-R interval was calculated by complex transfer function analysis and was used as a measure of the time delay between carotid baroreceptor stimulation and cardiac effector response. Cardiac baroreflex responsiveness increased significantly during low-dose atropine and decreased during head-up tilt or 10 microg/kg atropine. With increasing tilt angle, the time delay between cyclic baroreceptor stimulation and oscillations in R-R interval increased from 0.32 +/- 0.27 s (head down), to 0.59 +/- 0.25 s (supine position, P < 0.05 vs. head down), and to 0.86 +/- 0.27 s (head up, P < 0.01 vs. supine). Low-dose atropine had a similar effect to head-down tilt on baroreflex latency, whereas 10 microg/kg atropine increased the time delay markedly to 1.24 +/- 0.30 s. Our results demonstrate that changes in autonomic activity, generated either by gravitational stimulus or by atropine, not only affect baroreflex responsiveness but also have a major influence on the latency of the vagally mediated carotid baroreceptor-heart rate reflex. The prolonged baroreflex latency during decreased parasympathetic function may contribute to an unstable regulation of heart rate in patients with cardiac disease.     

Effect of acute exposure to 3660 m altitude on orthostatic responses and tolerance.

Orthostatic reflexes were examined at 375 m and after 60 min of exposure in a hypobaric chamber at 3660 m using a 20-min 70 degrees head-up tilt (HUT) test. Mean arterial blood pressure, R wave-R wave interval (RRI), and mean cerebral blood flow velocity (MFV) were examined with coarse-graining spectral analysis. Of 14 subjects, 7 at 375 m and 12 at 3660 m were presyncopal. Immediately on arrival to high altitude, breathing frequency and MFV increased, and endtidal PCO2, RRI, RRI complexity, and the parasympathetic nervous system indicator decreased. MFV was similar in HUT at both altitudes. The sympathetic nervous system indicator increased with tilt at 3660 m, whereas parasympathetic nervous system indicator decreased with tilt at both altitudes. Multiple regression analysis of supine variables from either 375 or 3660 m and the time to presyncope at 3660 m indicated that, after 1 h of exposure, increased presyncope at altitude was the result of 1). ineffective peripheral vasoconstriction, despite increased cardiac sympathetic nervous system activity with HUT, and 2). insufficient cerebral perfusion owing to cerebral vasoconstriction as the result of hypoxic hyperventilation-induced hypocapnia.     

Ghrelin modulates baroreflex-regulation of sympathetic vasomotor tone in healthy humans

Ghrelin, a neuropeptide originally known for its growth hormone-releasing and orexigenic properties, exerts important pleiotropic effects on the cardiovascular system. Growing evidence suggests that these effects are mediated by the sympathetic nervous system. The present study aimed at elucidating the acute effect of ghrelin on sympathetic outflow to the muscle vascular bed (muscle sympathetic nerve activity, MSNA) and on baroreflex-mediated arterial blood pressure (BP) regulation in healthy humans. In a randomized double-blind cross-over design, 12 lean young men were treated with a single dose of either ghrelin 2 μg/kg iv or placebo (isotonic saline). MSNA, heart rate (HR), and BP were recorded continuously from 30 min before until 90 min after substance administration. Sensitivity of arterial baroreflex was repeatedly tested by injection of vasoactive substances based on the modified Oxford protocol. Early, i.e., during the initial 30 min after ghrelin injection, BP significantly decreased together with a transient increase of MSNA and HR. In the course of the experiment (>30 min), BP approached placebo level, while MSNA and HR were significantly lower compared with placebo. The sensitivity of vascular arterial baroreflex significantly increased at 30-60 min after intravenous ghrelin compared with placebo, while HR response to vasoactive drugs was unaltered. Our findings suggest two distinct phases of ghrelin action: In the immediate phase, BP is decreased presumably due to its vasodilating effects, which trigger baroreflex-mediated counter-regulation with increases of HR and MSNA. In the delayed phase, central nervous sympathetic activity is suppressed, accompanied by an increase of baroreflex sensitivity.