This thesis comprises of four experiments from which related but independent analyses were undertaken. The interventions employed were designed to investigate the effect of cardiovascular adaptation, both in the short and long term on the cardiovascular responses to orthostatic stress. The first study, described in Chapter 3, tested the hypothesis that the cardiovascular system (CVS) could adapt to repeated orthostatic challenges in a single session. 14 subjects were exposed to ten +75° head-up tilts (HUT) over 70 mins. Each tilt involved a 5 min supine period (SUPINE) followed by 2 min HUT (TILT). Various indices of cardiovascular function were determined non-invasively. Cardiovascular responses to HUT10 for the final 30s of SUPINE and the first 30s of TILT were compared with those of HUT1. Integrated cardiac baroreflex sensitivity (BRS) was assessed using the Valsalva Manoeuvre (VM). Results showed MAP and DBP increased in both SUPINE (MAP p=0.009, DBP p=0.002) and TILT (MAP p=0.003, DBP p=0.009) for HUT10 compared with HUT1. TPR increased during TILT only (p=0.001) during HUT10 compared with HUT1. CO and SV were decreased during SUPINE at HUT10 relative to HUT1, however, there were no differences in TILT at HUT10 for either CO or SV. There was no change in the response of BRS, HR or SBP from HUT1 to HUT10. This study indicated that 10 repetitive HUTs can elicit changes in the cardiovascular responses to orthostasis, reflected by an increased TPR. The second study, described in Chapter 4, investigated the effect of the repeated HUT protocol outlined above on the cardiovascular responses to the squat-stand test (SST). 16 subjects were randomly allocated into either a tilting group that underwent ten +75° HUTs in 70 min (TILTING) or a control group that underwent 70 min of rest (CONTROL). Before and after the 70 min of either HUT or rest, subjects performed a SST (SST1 and SST2 respectively). The same cardiovascular parameters as those used in Chapter 3 were determined during both SSTs. The final 30s of SQUAT and the first 30s of STAND (divided into three 10-sec blocks termed STAND10, STAND20 and STAND30) were compared between SST1 and SST2, results were as follows. TILTING: during the SQUAT phase of SST2, SBP, MAP, DBP and TPR were significantly elevated (p less than 0.05) and HR was significantly decreased (p=0.032) compared with SST1; at STAND10, DBP and MAP were significantly increased (p less than 0.05); at STAND20, SBP was increased (p=0.03); and, at STAND30, DBP, SBP and MAP (p less than 0.05) were increased. There were no differences observed between SST1 and SST2 in the CONTROL group. Results indicated that ten consecutive +75° HUTs can improve the CVS responses to the SST. This is predominantly due to an increase in DBP, indicative of a change in vascular resistance. The third study, outlined in Chapter 5, investigated the effect of lower limb unilateral and bilateral resistance exercise on the blood pressure (BP) and HR responses in young males. 12 normotensive, sedentary young males were divided into 2 groups; one group exercised unilaterally and the other bilaterally. Thirty seconds of resting data were collected before subjects performed 4 SETs of 10-12 reps on a seated leg press. SET 1 was performed at 50% of 10-12RM, SET 2 was performed at 75% and SET 3 and SET 4 were performed at 10- 12RM. Bilateral resistance exercise elicited greater increases in SBP than unilateral exercise at SETs 2, 3 and 4 (p less than 0.05). DBP was only greater with bilateral exercise relative to unilateral exercise at SET 2 (p=0.036). There were no differences between the groups for the HR response. This study demonstrated that the BP response to bilateral lower limb resistance exercise was significantly greater than that of unilateral exercise in young sedentary males. This information could be beneficial to many populations for whom lower BP responses to exercise would be an advantage. Following on from this, to investigate long term improvements in cardiovascular responses to orthostasis the study outlined in Chapter 6, investigated the effect of acute (10 weeks) and chronic (more than 4 years) resistance training (RT) on the cardiovascular responses to both HUT and SST. 22 young males were allocated into three groups. The UNILATERAL (N=7) and the BILATERAL (N=7) groups performed baseline testing followed by 10 weeks of lower limb RT (performed unilaterally or bilaterally), followed by repeats of the tests performed at baseline. The CONTROL group (N=8) followed the same protocol except they were asked to perform no resistance training during the 10 weeks between testing sessions. An additional 7 subjects were allocated to a CHRONIC group consisting of individuals who had been training for more than 4 years. These subjects only performed the baseline testing. Baseline testing consisted of a number of cardiovascular tests, ultrasound for vein diameter, BRS via VM, and tests for calf ejection fraction and venous elasticity. Results demonstrated that neither unilateral nor bilateral RT caused an alteration in the cardiovascular response to the HUT or SST. There were no changes in any cardiovascular variable in response to acute RT relative to the control group. The CHRONIC group had a decreased cardiovascular response to both orthostatic challenges, with a decrease in SV in response to HUT being greater in the chronic group relative to the other groups (p less than 0.05) and the TPR response to SST being significantly less than the control group (p less than 0.05). The CHRONIC group also had a smaller elastic modulus for the right leg in comparison to the other groups (p less than 0.05). Results indicate that heavy resistance exercise may cause a decreased cardiovascular response to orthostatic stress and that these decreases may be controlled by a decreased venous elasticity. Collectively, these results demonstrate that the CVS is highly adaptable to repeated orthostatic stress and the dominant underlying feature of this protective adaptation is increased vascular resistance. Following the repeated HUT the CVS is in a more protected state and has become better able to defend itself against the adverse consequences of rapidly applied hydrostatic force. However lower limb RT performed bilaterally (with large increases in BP) or unilaterally (with lower increases in BP) does not improve CVS response to orthostatic stress, in fact chronic RT (more than 4 yrs) appears to impair the CVS response to orthostasis, potentially due to decreased venous elasticity.

Abstract Healthy subjects show wide interindividual variation in their heart rate behavior, but the factors affecting heart rate dynamics are not well known. This research was undertaken to evaluate heart rate variability (HRV) and baroreflex sensitivity (BRS) in a large random sample of subjects without evidence of heart disease, and to estimate the relation of heart rate behavior to age, sex and cardiovascular risk factors. Short-term HRV was analyzed from 15-minute periods of standardized recording in supine and upright positions using time and frequency domain measures, and BRS was calculated using the Valsalva maneuver in an original randomly selected population of 600 hypertensive and 600 control middle-aged subjects. In addition, HRV was analyzed from the same segments using new measures based on fractals and complexity (chaos theory) of R - R interval dynamics in the same random population, and from 24-hour period in 114 healthy subjects aged from 1 to 82 years. Large interindividual variation was observed in the measures of HRV and BRS in middle-aged subjects; coefficient of variation (CV) of the standard deviation of R - R intervals (SDNN) 39% (54 ± 21 ms) and CV of BRS 49% (9.9 ± 4.9 ms/mmHg). In healthy middle-aged men, SDNN was weakly related to age (r = -0.19, p < 0.01), HDL cholesterol (0.19, p < 0.01), serum insulin (-0.23, p < 0.001) and triglyceride (-0.25, p < 0.001) levels. In women, SDNN was only related to insulin levels (r = -0.23, p < 0.001). BRS was related to systolic blood pressure (r = -0.31 and -0.30, in men and women respectively, p < 0.001 for both) and blood glucose (r = -0.25, p < 0.01) and serum insulin levels (r = -0.34, p < 0.001) in women. Lesser intersubject variation was observed in the non-linear measures of HRV; CV 14% of short-term scaling exponent (a1), a measure of fractal-like correlation properties of HRV, (1.21 ± 0.17) and CV 12% of approximate entropy, a measure of complexity, (1.13 ± 0.14). Neither a1 or ApEn was related to any risk factors. Women had lower overall short-term HRV (p < 0.01) and BRS (p < 0.001), but a higher spectral high-frequency component of HRV, higher ApEn and lower a1 (p < 0.001 for all) compared to men. The impairment in overall HRV was confined to the hypertensive subjects with metabolic features of the insulin resistance syndrome (IRS, n = 69), but the BRS and spectral high-frequency component were also impaired in hypertensive subjects without IRS compared to normotensive subjects. The 24-hour cardiac interbeat interval dynamics changed markedly from childhood to old age. Children showed similar complexity and fractal correlation properties of R - R intervals as young adults. Healthy aging resulted in R - R interval dynamics with higher regularity and predictability and altered fractal scaling. The traditional measures of HRV and BRS are weakly related to many cardiovascular risk factors in subjects without heart disease, but the interindividual variation of HRV and BRS is only partly explained by these factors, suggesting a genetic background of the intersubject variation in cardiovascular autonomic regulation. The new dynamical measures of HRV show less interindividual variation than the conventional measures of HRV in healthy subjects and are not related to cardiovascular risk variables, suggesting that these dynamical measures quantify the "intrinsic" capacity of a healthy cardiovascular control system without the significant influence of life-style, metabolic or demographic variables. However, there are sex and age-related differences also in the fractal and complexity measures of heart rate behavior.

Human cardiovascular adaptations to microgravity include decreased plasma volume, exercise capacity, baroreflex function as well as decreased orthostatic tolerance upon return to a gravity environment. Several countermeasures have been proposed and tested, although currently none have been developed to prevent post-spaceflight orthostatic intolerance (OI). Artificial gravity (AG) generated by short-radius centrifugation (SRC) has been proposed as a countermeasure to OI as well as other cardiovascular alterations. Methods: Fifteen men and fourteen women underwent three weeks of daily (5 days a week) exposure to intermittent (1.0 to 2.5 Gz) artificial gravity on a 1.9m human powered centrifuge (HPC) at the NASA Ames Research Center. Half the subjects exercised (active) to power the HPC while half rode passively (passive). A combination head-up tilt (HUT) and lower body negative pressure (LBNP) test was used to determine orthostatic tolerance before and after training. Oscillatory LBNP (OLBNP) was used at seven frequencies (0.01 to 0.15 Hz) for two minutes each to assess the dynamic responses of the cardiovascular system to orthostatic stress, before and after AG training. Results: Training improved overall tolerance in the group of subjects by 13% (pandlt;0.05); men were more tolerant than were women (pandlt;0.05); and active subjects were more improved than passive subjects (pandlt;0.05). Mechanisms of improvement appear to be through decreased total peripheral resistance (TPR) and increased stroke volume after training, and increased responsiveness of TPR to fluid shifts (faster changes in TPR to changes in calfcircumference [CC] and OLBNP after training). There was no change in spontaneous baroreflex sensitivity (BRS, calculated by sequence method) or number of sequences per number of heart beats (NNS), although BRS analysis did indicate that stimulation to the cardiac baroreceptors during 1.0 Gz and 2.5 Gz centrifugation was no different than supine control and 70?? HUT, respectively. Taken together, these results suggest that AG training improved tolerance through training of local mechanisms in the peripheral vasculature, or extrinsic control of peripheral vascular resistance, rather than through changes of autonomic control of heart rate.

The influence of levels of hostility on the lateralized tasks of verbal and nonverbal fluency, and the concurrent cerebral regulation of autonomic nervous system functioning was examined. Forty-eight right-handed males were recruited for participation with half classified as low-hostile and the other half as high-hostile. Previous research has shown that high-hostile males, at rest, have greater right hemisphere arousal relative to low-hostile males. It was predicted that this heightened, at rest, arousal would lead to reduced capacity to perform right hemisphere lateralized proximal tasks simultaneously. Two commonly used neuropsychological tests sensitive to left and right anterior cerebral systems are the Controlled Oral Word Association Test and the Ruff Figural Fluency Test (RFFT) respectively. Nonverbal fluency, verbal fluency, and perseverative errors were assessed using these measures. Cardiovascular measures of systolic and diastolic blood pressure, and heart rate were assessed using oscillometric technique with a digital blood pressure meter. A dual-task methodology was used to evaluate these anterior and posterior cerebral systems simultaneously. Since cardiovascular regulation and nonverbal fluency are both right-frontal tasks, it was predicted that high hostile men would evidence increased interference on cardiovascular regulation concurrent with the nonverbal fluency task in comparison with low hostile men. It was also predicted that high-hostile males would display more perseverative errors than low- hostile males on the nonverbal fluency task as a function of regulatory interference. The results supported a capacity-limited prediction in high-hostile males. High-hostile males evidenced significantly heightened systolic blood pressure responses during the nonverbal fluency task in comparison with low hostile males. Further, high-hostile males displayed more perseverative errors in nonverbal fluency than did the low-hostile males. No differences were found in the overall fluency scores (verbal or nonverbal). These results partially support the expectation that differences exist between high and low hostile males for right frontal functioning. Moreover, these differences manifest in multiple domains of associated right frontal functioning. These findings extend the evidence for the proposed anterior-posterior inhibition model of hostility. / Master of Science

Orthostatic intolerance (OI), i.e., the inability to maintain stable arterial pressure during upright posture, is a major problem for astronauts after spaceflight. Therefore, one important goal of spaceflight-related research is the development of countermeasures to prevent post flight OI. Given the rarity and expense of spaceflight, countermeasure development requires ground-based simulations of partial gravity to induce appropriate orthostatic effects on the human body, and to test the efficacy of potential countermeasures. To test the efficacy of upright lower body positive pressure (LBPP) as a model for simulating cardiovascular responses to lunar and Martian gravities on Earth, cardiovascular responses to upright LBPP were compared with those of head-up tilt (HUT), a well-accepted simulation of partial gravity, in both ambulatory and cardiovascularly deconditioned subjects. Results indicate that upright LBPP and HUT induced similar changes in cardiovascular regulation, supporting the use of upright LBPP as a potential model for simulating cardiovascular responses to standing and moving in lunar and Martian gravities. To test the efficacy of a short exposure to artificial gravity (AG) as a countermeasure to spaceflight-induced OI, orthostatic tolerance limits (OTL) and cardiovascular responses to orthostatic stress were tested in cardiovascularly deconditioned subjects, using combined 70º head-up tilt and progressively increased lower body negative pressure, once following 90 minutes AG exposure and once following 90 minutes of -6º head-down bed rest (HDBR). Results indicate that a short AG exposure increased OTL of cardiovascularly deconditioned subjects, with increased baroreflex and sympathetic responsiveness, compared to those measured after HDBR exposure. To gain more insight into mechanisms of causal connectivity in cardiovascular and cardiorespiratory oscillations during orthostatic challenge in both ambulatory and cardiovascularly deconditioned subjects, couplings among R-R intervals (RRI), systolic blood pressure (SBP) and respiratory oscillations in response to graded HUT and dehydration were studied using a phase synchronization approach. Results indicate that increasing orthostatic stress disassociated interactions among RRI, SBP and respiration, and that dehydration exacerbated the disconnection. The loss of causality from SBP to RRI following dehydration suggests that dehydration also reduced involvement of baroreflex regulation, which may contribute to the increased occurrence of OI.

Modest recovery of somatic function after incomplete spinal cord injury (SCI) has been widely demonstrated. Recently we have shown that spontaneous recovery of baroreflex regulation of sympathetic activity also occurs in rats. Dietary restriction in the form of every other day fasting (EODF) has been shown to have beneficial effects on the recovery of motor function after SCI in rats. The goal of this study was to determine if EODF augments the improvement of baroreflex regulation of sympathetic activity after chronic left thoracic (T8) surgical spinal hemisection. To determine this, we performed baroreflex tests on ad-lib fed or EODF rats 1 week or 7 weeks after left T8 spinal hemisection. One week after T8 left hemisection baroreflex testing revealed that gain of baroreflex responsiveness, as well as the ability to increase renal sympathetic nerve activity (RSNA) at low arterial pressure, was significantly impaired in the ad-lib fed but not the EODF rats compared with sham lesioned control rats. However, baroreflex tests performed 7 weeks after T8 left hemisection revealed the inability of both ad-lib and EODF rats to decrease RSNA at elevated arterial pressures. While there is evidence to suggest that EODF has beneficial effects on the recovery of motor function in rats, EODF did not significantly improve the recovery of baroreflex regulation of sympathetic activity.

Substance P (SP) is associated with metabo- and mechanoreceptor afferent fibers ('ergoreceptors') in skeletal muscle as well as the afferent fibers from carotid sinus baroreceptors. Afferent activity from each of these are at least partially integrated in the nucleus tractus solitarius (NTS). The purpose of this study was to determine whether SP was released from the NTS during acute reflex-induced changes in blood pressure caused by stimulating these receptors. Both the muscle pressor response and the baroreflex were studied in adult cats anaesthetized with α-chloralose. SP antibody-coated microprobes were used to measure the possible release of SP from the NTS. The muscle pressor response caused a release of immunoreactive SP-like substances (irSP) from the rostral medial NTS, as well as the dorsal motor nucleus (DMV) and lateral tegmental field (FTL). This release was not dependent on intact afferent input from the carotid sinus nerve, but was a function of activation of muscle ergoreceptors, since no irSP was released in response to stimulation of the motor nerves after the muscle was paralyzed. There was no detectable release of irSP from the mNTS during carotid artery occlusions (baroreceptor unloading). Baroreceptor activation, induced by the i.v. injection of the vasoconstrictor, phenylephrine, did not cause the release of irSP from the mNTS above resting baseline levels. These data suggest that SP is involved with the mediation of the afferent signal from muscle ergoreceptor fibers in the medial NTS. SP is not involved with the mediation of baroreceptor afferent signaling in the medial NTS. The release of SP in response to ergoreceptors activation may function to excite an inhibitory pathway which inhibits baroreflex signals that would tend to reduce the blood pressure and heart rate during the muscle pressor response.

One hundred twenty-six right-handed undergraduate men and women underwent physiological measurements of SBP, DBP, and HR before and after verbal and figural fluency tasks, used as stressors. Dynamic and functional cerebral regulation of cardiovascular reactivity was assessed, specifically, the role that the frontal lobes have in regulating SBP, DBP, and HR in men and women. Sex differences in the functional cerebral regulation of these cardiovascular factors were predicted. Hostility was assessed in these participants, using the Cook-Medley Hostility Inventory (6 total groups of 21 participants each: high-, mid-, and low-hostile participants were identified). Sex and group (hostility) differences were predicted, as well as task (fluency type) differences. Comparisons were also made from a time estimation task (30 and 180 seconds), and the effect that women's menstrual cycle had on fluency. The MCSDS and the STAI were administered. The principal findings of the current investigation were that the verbal fluency task raised SBP across sex and group, that both stressors raised SBP or DBP in different patterns (no sex differences were found), while stressors interacted with both sex and group. High-hostile men performed better on the first trial of the verbal fluency test compared to low-hostile men, while high-hostile women performed worse on the first trial of the verbal fluency test, compared to low-hostile women. Men perseverated more on each trial of the verbal fluency test, while women perseverated less across trials. High-hostile men's time perception seems to be more rapid than low-hostile men, while for women it is the opposite. Women reported significantly more stress from the figural fluency task than men. Women in the luteal phase of menstruation did better on the verbal fluency test than women in the follicular phase of menstruation, and hostility and menstrual phase interact with verbal fluency. This study encourages the consideration of neuropsychological sex differences in order to better understand cardiovascular regulation mechanisms and disease, leading to the development of improved prevention and behavioral management programs. Findings supporting this idea may bring about a new research focus, as some forms of cardiovascular disease may be more appropriately investigated as arising from neuropsychological problems. / Ph. D.

One countermeasure to cardiovascular spaceflight deconditioning being tested is the application of intermittent artificial gravity provided by centripetal acceleration of a human via centrifuge. However, artificial gravity protocols have not been optimized for the cardiovascular system, or any other physiological system for that matter. Before artificial gravity protocols can be optimized for the cardiovascular system, cardiovascular responses to the variables of artificial gravity need to be quantified. The research presented in this document is intended to determine how the artificial gravity variables, radius (gravity gradient) and lower limb exercise, affect cardiovascular responses during centrifugation. Net fluid (blood) shifts between body segments (thorax, abdomen, upper leg, lower leg) will be analyzed to assess the cardiovascular responses to these variables of artificial gravity, as well as to begin to understand potential mechanism(s) underlying the beneficial orthostatic tolerance response resulting from artificial gravity training. Methods: Twelve healthy males experienced the following centrifuge protocols. Protocol A: After 10 minutes of supine control, the subjects were exposed to rotational 1 Gz at radius of rotation 8.36 ft (2.54 m) for 2 minutes followed by 20 minutes alternating between 1 and 1.25 Gz. Protocol B: Same as A, but lower limb exercise (70% V02max) preceded ramps to 1.25 Gz. Protocol C: Same as A but radius of rotation 27.36 ft (8.33 m). Results: While long radius without exercise presented an increased challenge for the cardiovascular system compared to short radius without exercise, it is likely at the expense of more blood “pooling” in the abdominal region. Whereas short radius with exercise provided a significant response compared to short radius without exercise. More fluid loss occurred from the thorax and with the increased fluid loss from the thorax blood did not “pool” in the abdominal region but instead was essentially “mobilized” to the upper and lower leg. The exercise fluid shift profile presented in this document is applicable to not only artificial gravity protocol design but also proposes a mechanistic reason as to why certain artificial gravity protocols are more effective than others in increasing orthostatic tolerance.

京都大学 / 新制・課程博士 / 博士(工学) / 甲第25273号 / 工博第5232号 / 新制||工||1997(附属図書館) / 京都大学大学院工学研究科建築学専攻 / (主査)教授 小椋 大輔, 教授 原田 和典, 教授 石田 泰一郎 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM