Ken-ichi Iwasaki

Autonomic Neural Control of Dynamic Cerebral Autoregulation in Humans

Background—The purpose of the present study was to determine the role of autonomic neural control of dynamic cerebral autoregulation in humans. Methods and Results—We measured arterial pressure and cerebral blood flow (CBF) velocity in 12 healthy subjects (aged 29±6 years) before and after ganglion blockade with trimethaphan. CBF velocity was measured in the middle cerebral artery using transcranial Doppler. The magnitude of spontaneous changes in mean blood pressure and CBF velocity were quantified by spectral analysis. The transfer function gain, phase, and coherence between these variables were estimated to quantify dynamic cerebral autoregulation. After ganglion blockade, systolic and pulse pressure decreased significantly by 13% and 26%, respectively. CBF velocity decreased by 6% (P <0.05). In the very low frequency range (0.02 to 0.07 Hz), mean blood pressure variability decreased significantly (by 82%), while CBF velocity variability persisted. Thus, transfer function gain increased by 81%. In addition, the phase lead of CBF velocity to arterial pressure diminished. These changes in transfer function gain and phase persisted despite restoration of arterial pressure by infusion of phenylephrine and normalization of mean blood pressure variability by oscillatory lower body negative pressure. Conclusions—These data suggest that dynamic cerebral autoregulation is altered by ganglion blockade. We speculate that autonomic neural control of the cerebral circulation is tonically active and likely plays a significant role in the regulation of beat-to-beat CBF in humans.

Human muscle sympathetic neural and haemodynamic responses to tilt following spaceflight

Orthostatic intolerance is common when astronauts return to Earth: after brief spaceflight, up to two‐thirds are unable to remain standing for 10 min. Previous research suggests that susceptible individuals are unable to increase their systemic vascular resistance and plasma noradrenaline concentrations above pre‐flight upright levels. In this study, we tested the hypothesis that adaptation to the microgravity of space impairs sympathetic neural responses to upright posture on Earth. We studied six astronauts ∼72 and 23 days before and on landing day after the 16 day Neurolab space shuttle mission. We measured heart rate, arterial pressure and cardiac output, and calculated stroke volume and total peripheral resistance, during supine rest and 10 min of 60 deg upright tilt. Muscle sympathetic nerve activity was recorded in five subjects, as a direct measure of sympathetic nervous system responses. As in previous studies, mean (±s.e.m.) stroke volume was lower (46 ± 5 vs. 76 ± 3 ml, P= 0.017) and heart rate was higher (93 ± 1 vs. 74 ± 4 beats min−1, P= 0.002) during tilt after spaceflight than before spaceflight. Total peripheral resistance during tilt post flight was higher in some, but not all astronauts (1674 ± 256 vs. 1372 ± 62 dynes s cm−5, P= 0.32). No crew member exhibited orthostatic hypotension or presyncopal symptoms during the 10 min of postflight tilting. Muscle sympathetic nerve activity was higher post flight in all subjects, in supine (27 ± 4 vs. 17 ± 2 bursts min−1, P= 0.04) and tilted (46 ± 4 vs. 38 ± 3 bursts min−1, P= 0.01) positions. A strong (r2= 0.91–1.00) linear correlation between left ventricular stroke volume and muscle sympathetic nerve activity suggested that sympathetic responses were appropriate for the haemodynamic challenge of upright tilt and were unaffected by spaceflight. We conclude that after 16 days of spaceflight, muscle sympathetic nerve responses to upright tilt are normal.

Lithocholic acid derivatives act as selective vitamin D receptor modulators without inducing hypercalcemia

1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3], a vitamin D receptor (VDR) ligand, regulates calcium homeostasis and also exhibits noncalcemic actions on immunity and cell differentiation. In addition to disorders of bone and calcium metabolism, VDR ligands are potential therapeutic agents in the treatment of immune disorders, microbial infections, and malignancies. Hypercalcemia, the major adverse effect of vitamin D3 derivatives, limits their clinical application. The secondary bile acid lithocholic acid (LCA) is an additional physiological ligand for VDR, and its synthetic derivative, LCA acetate, is a potent VDR agonist. In this study, we found that an additional derivative, LCA propionate, is a more selective VDR activator than LCA acetate. LCA acetate and LCA propionate induced the expression of the calcium channel transient receptor potential vanilloid type 6 (TRPV6) as effectively as that of 1α,25-dihydroxyvitamin D3 24-hydroxylase (CYP24A1), whereas 1,25(OH)2D3 was more effective on TRPV6 than on CYP24A1 in intestinal cells. In vivo experiments showed that LCA acetate and LCA propionate effectively induced tissue VDR activation without causing hypercalcemia. These bile acid derivatives have the ability to function as selective VDR modulators.

Mechanism of blood pressure and R-R variability: insights from ganglion blockade in humans

Spontaneous blood pressure (BP) and R‐R variability are used frequently as ‘windows’ into cardiovascular control mechanisms. However, the origin of these rhythmic fluctuations is not completely understood. In this study, with ganglion blockade, we evaluated the role of autonomic neural activity versus other ‘non‐neural’ factors in the origin of BP and R‐R variability in humans. Beat‐to‐beat BP, R‐R interval and respiratory excursions were recorded in ten healthy subjects (aged 30 ± 6 years) before and after ganglion blockade with trimethaphan. The spectral power of these variables was calculated in the very low (0.0078‐0.05 Hz), low (0.05‐0.15 Hz) and high (0.15‐0.35 Hz) frequency ranges. The relationship between systolic BP and R‐R variability was examined by cross‐spectral analysis. After blockade, R‐R variability was virtually abolished at all frequencies; however, respiration and high frequency BP variability remained unchanged. Very low and low frequency BP variability was reduced substantially by 84 and 69 %, respectively, but still persisted. Transfer function gain between systolic BP and R‐R interval variability decreased by 92 and 88 % at low and high frequencies, respectively, while the phase changed from negative to positive values at the high frequencies. These data suggest that under supine resting conditions with spontaneous breathing: (1) R‐R variability at all measured frequencies is predominantly controlled by autonomic neural activity; (2) BP variability at high frequencies (> 0.15 Hz) is mediated largely, if not exclusively, by mechanical effects of respiration on intrathoracic pressure and/or cardiac filling; (3) BP variability at very low and low frequencies (< 0.15 Hz) is probably mediated by both sympathetic nerve activity and intrinsic vasomotor rhythmicity; and (4) the dynamic relationship between BP and R‐R variability as quantified by transfer function analysis is determined predominantly by autonomic neural activity rather than other, non‐neural factors.

Cardiovascular and sympathetic neural responses to handgrip and cold pressor stimuli in humans before, during and after spaceflight

Astronauts returning to Earth have reduced orthostatic tolerance and exercise capacity. Alterations in autonomic nervous system and neuromuscular function after spaceflight might contribute to this problem. In this study, we tested the hypothesis that exposure to microgravity impairs autonomic neural control of sympathetic outflow in response to peripheral afferent stimulation produced by handgrip and a cold pressor test in humans. We studied five astronauts ≈72 and 23 days before, and on landing day after the 16 day Neurolab (STS‐90) space shuttle mission, and four of the astronauts during flight (day 12 or 13). Heart rate, arterial pressure and peroneal muscle sympathetic nerve activity (MSNA) were recorded before and during static handgrip sustained to fatigue at 40 % of maximum voluntary contraction, followed by 2 min of circulatory arrest pre‐, in‐ and post‐flight. The cold pressor test was applied only before (five astronauts) and during flight (day 12 or 13, four astronauts). Mean (±s.e.m.) baseline heart rates and arterial pressures were similar among pre‐, in‐ and post‐flight measurements. At the same relative fatiguing force, the peak systolic pressure and mean arterial pressure during static handgrip were not different before, during and after spaceflight. The peak diastolic pressure tended to be higher post‐ than pre‐flight (112 ± 6 vs. 99 ± 5 mmHg, P= 0.088). Contraction‐induced rises in heart rate were similar pre‐, in‐ and post‐flight. MSNA was higher post‐flight in all subjects before static handgrip (26 ± 4 post‐ vs. 15 ± 4 bursts min−1 pre‐flight, P= 0.017). Contraction‐evoked peak MSNA responses were not different before, during, and after spaceflight (41 ± 4, 38 ± 5 and 46 ± 6 bursts min−1, all P > 0.05). MSNA during post‐handgrip circulatory arrest was higher post‐ than pre‐ or in‐flight (41 ± 1 vs. 33 ± 3 and 30 ± 5 bursts min−1, P= 0.038 and 0.036). Similarly, responses of MSNA and blood pressure to the cold pressor test were well maintained in‐flight. We conclude that modulation of muscle sympathetic neural outflow by muscle metaboreceptors and skin nociceptors is preserved during short duration spaceflight.

Human cerebral autoregulation before, during and after spaceflight

Exposure to microgravity alters the distribution of body fluids and the degree of distension of cranial blood vessels, and these changes in turn may provoke structural remodelling and altered cerebral autoregulation. Impaired cerebral autoregulation has been documented following weightlessness simulated by head‐down bed rest in humans, and is proposed as a mechanism responsible for postspaceflight orthostatic intolerance. In this study, we tested the hypothesis that spaceflight impairs cerebral autoregulation. We studied six astronauts ∼72 and 23 days before, after 1 and 2 weeks in space (n= 4), on landing day, and 1 day after the 16 day Neurolab space shuttle mission. Beat‐by‐beat changes of photoplethysmographic mean arterial pressure and transcranial Doppler middle cerebral artery blood flow velocity were measured during 5 min of spontaneous breathing, 30 mmHg lower body suction to simulate standing in space, and 10 min of 60 deg passive upright tilt on Earth. Dynamic cerebral autoregulation was quantified by analysis of the transfer function between spontaneous changes of mean arterial pressure and cerebral artery blood flow velocity, in the very low‐ (0.02–0.07 Hz), low‐ (0.07–0.20 Hz) and high‐frequency (0.20–0.35 Hz) ranges. Resting middle cerebral artery blood flow velocity did not change significantly from preflight values during or after spaceflight. Reductions of cerebral blood flow velocity during lower body suction were significant before spaceflight (P < 0.05, repeated measures ANOVA), but not during or after spaceflight. Absolute and percentage reductions of mean (±s.e.m.) cerebral blood flow velocity after 10 min upright tilt were smaller after than before spaceflight (absolute, −4 ± 3 cm s−1 after versus−14 ± 3 cm s−1 before, P= 0.001; and percentage, −8.0 ± 4.8% after versus−24.8 ± 4.4% before, P < 0.05), consistent with improved rather than impaired cerebral blood flow regulation. Low‐frequency gain decreased significantly (P < 0.05) by 26, 23 and 27% after 1 and 2 weeks in space and on landing day, respectively, compared with preflight values, which is also consistent with improved autoregulation. We conclude that human cerebral autoregulation is preserved, and possibly even improved, by short‐duration spaceflight.

Changes in bone turnover markers during 14-day 6° head-down bed rest

Osteoporosis caused by exposure to microgravity represents a serious clinical concern, but the mechanisms have yet to be fully elucidated. The present research aimed to elucidate the effects of microgravity environments on bone turnover, with a specific focus on changes in bone resorption markers such as type I collagen cross-linked N-telopeptides (NTx) and deoxypyridinoline (Dpyr), for which scant data are available regarding detailed time course. Methods using 6° head-down bed rest were utilized to simulate a microgravity environment. Eleven adult male volunteers underwent 6° head-down bed rest for 14 days; measurements were made of serum and urine Ca concentrations, in addition to osteocalcin (OC), bone alkaline phosphatase (ALP), NTx, and Dpyr as bone turnover markers. By the end of bed rest, concentrations of bone ALP had significantly increased, but OC displayed a tendency toward decrease. Concentrations of Dpyr significantly increased from day 6, remaining elevated until the end of bed rest. Concentrations of NTx significantly increased on day 13 and at the end of bed rest. Serum and urinary concentrations of Ca increased significantly at the end of bed rest. Bone ALP represents a relatively early marker of osteoblast differentiation at the matrix maturation phase and OC is a late marker in osteoblast differentiation at the calcification phase. The present results therefore suggest an absolute increase in bone resorption and normal or reduced bone formation, together causing prominent uncoupling and rapid bone loss after simulated microgravity. Moreover, the present results suggest that bone resorption is enhanced at an early stage of exposure to microgravity environments.

Usefulness of daily +2Gz load as a countermeasure against physiological problems during weightlessness.

UNLABELLED Adaptation to head-down-tilt bed rest as a simulated microgravity leads to an abnormality of reflex control of circulation, hypovolemia and reduction of exercise capacity. We hypothesized that this cardiovascular deconditioning and reduction of exercise capacity could be prevented by a daily 1 hr centrifugation at +2Gz. To test this hypothesis, twenty healthy male subjects underwent 4 day of 6 degrees head-down-tilt bed rest. Ten of them were exposed to a +2Gz load for up to 30 min twice per day (the Gz group). The remaining 10 were not exposed to a Gz load (the no-Gz group). We estimated autonomic cardiovascular control by power spectral analysis of blood pressure and R-R interval variability, and baroreflex regulation by the transfer function analysis and the sequence method, before and after bed rest. Further, we measured hematocrit as an index of changes in plasma volume and maximal oxygen consumption as an index of exercise capacity, before and after bed rest. RESULT In the no-Gz group, heart rate increased after bed rest. The high frequency power of R-R interval variability as an index of cardiac parasympathetic nervous activity, baroreflex gains estimated by transfer function analysis and the sequence method as index of the integrated arterial-cardiac baroreflex function decreased significantly. Associated with these changes, the ratio of low to high frequency power of R-R as an indicator of cardiac sympathovagal balance tended to increase after bed rest in the no-Gz group. However, those showed no significant changes after bed rest in the Gz group. Hematocrit increased after bed rest in the no-Gz group. It also tended to increase in the Gz group, however it did not achieve statistical significance. Maximal oxygen consumption decreased significantly to similar extent in both the groups. CONCLUSION This result suggested that 1) a daily 1hr +2Gz load produced by a centrifuge might eliminate the changes in autonomic cardiovascular control during simulated weightlessness; 2) furthermore, it might partly reverse hypovolemia induced by bed rest; 3) however, it could not prevent the decreases in exercise capacity.

Acute Exposure to Normobaric Mild Hypoxia Alters Dynamic Relationships between Blood Pressure and Cerebral Blood Flow at Very Low Frequency

Acute hypoxia directly causes cerebral arteriole vasodilation and also stimulates peripheral chemoreceptors to change autonomic neural activity. These changes may alter cerebral vascular modulation. We therefore hypothesized that dynamic cerebral autoregulation would be altered during acute exposure to hypoxia. Fifteen healthy men were examined under normoxic (21%) and hypoxic conditions. Oxygen concentrations were decreased in stepwise fashion to 19%, 17%, and 15%, for 10 mins at each level. Mean blood pressure (MBP) in the radial artery was measured via tonometry, and cerebral blood flow velocity (CBFV) in the middle cerebral artery was measured by transcranial Doppler ultrasonography. Dynamic cerebral autoregulation was assessed by spectral and transfer function analysis of beat-by-beat changes in MBP and CBFV. Arterial oxygen saturation decreased significantly during hypoxia, while end-tidal CO2 and respiratory rate were unchanged, as was steady-state CBFV. With 15% O2, very-low-frequency power of MBP and CBFV variability increased significantly by 185% and 282%, respectively. Moreover, transfer function coherence (21% O2, 0.46 ± 0.04; 15% O2, 0.64 ± 0.04; P = 0.028) and gain (21% O2, 0.61 ± 0.05 cm/secs/mm Hg; 15% O2, 0.86 ± 0.08 cm/secs/mm Hg; P = 0.035) in the very-low-frequency range increased significantly by 53% and 48% with 15% O2, respectively. However, these indices were unchanged in low- and high-frequency ranges. Acute hypoxia thus increases arterial pressure oscillations and dependence of cerebral blood flow (CBF) fluctuations on blood pressure oscillations, resulting in apparent increases in CBF fluctuations in the very-low-frequency range. Hypoxia may thus impair dynamic cerebral autoregulation in this range. However, these changes were significant only with hypoxia at 15% O2, suggesting a possible threshold for such changes.

Central Hypervolemia with Hemodilution Impairs Dynamic Cerebral Autoregulation

BACKGROUND:Frequent changes in the perioperative central blood volume could affect cerebral autoregulation through alterations in sympathetic nerve activity, cardiac output, blood viscosity, and cerebral vasomotor tone. However, the effect of dynamic cerebral autoregulation has not been studied during acute wide-ranging changes in central blood volume, especially with respect to central hypervolemia with hemodilution. METHODS:We evaluated dynamic cerebral autoregulation during central hypovolemia and central hypervolemia with hemodilution using spectral and transfer function analysis between mean arterial blood pressure (MBP) and cerebral blood flow (CBF) velocity variability in 12 individuals. Rapid changes in central blood volume were achieved using two levels of lower body negative pressure (−15 and −30 mm Hg) and two discrete infusions of normal saline (15 mL/kg and total 30 mL/kg). We then estimated changes in central blood volume as central venous pressure (CVP) and/or cardiac output using impedance cardiography. RESULTS:Steady-state CBF velocity and cardiac output decreased at −30 mm Hg lower body negative pressure (changes of CVP approximately −4 mm Hg) or were increased by each saline infusion (changes of CVP 4–6 mm Hg), without a significant change in MBP. However, transfer function gain (magnitude of transfer) between MBP and CBF velocity variability significantly increased only after saline infusion, suggesting an increased magnitude of transfer from MBP oscillations to CBF fluctuations during central hypervolemia with hemodilution. CONCLUSION:Our results suggest that, although steady-state CBF velocity changes under both central hypervolemia and hypovolemia, only hypervolemic hemodilution impairs dynamic cerebral autoregulation.