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.

Sensations of dizziness or fainting (pre-syncope or syncope) on standing up from a lying or a seated position are usually associated with impaired blood pressure regulation leading to inadequate perfusion of the brain. The purpose of this project was to develop a simple method to provide scientists and doctors a convenient way to monitor cardiovascular control during orthostatic stress with the non-invasive FinometerTM device. This apparatus provides a continuous estimate of arterial blood pressure (BP) contour from the finger and computes brachial blood pressure contours (systolic (SBP) and diastolic (DBP) blood pressure), heart rate (HR), stroke volume and cardiac output (Q) from the Modelflow equation. In this thesis, a method was implemented to obtain an estimate of central venous pressure (CVP) to provide greater insight into cardiovascular control. The accuracy and potential errors resulting from measurement of finger arterial pressure were also evaluated. The thesis first examined whether key variables essential to monitor cardiovascular control can be reliably measured by the FinometerTM in comparison to independent methods. HR was accurate and precise at rest and during stress (difference between methods: 0.05± 0.18 beats/min). According to standards established by the American Association for the Advancement of Medical Instrumentation (AAMI); at rest, DBP was accurate but not precise (1.6± 8.8 mmHg) and SBP was not accurate but precise (14.2± 8.0 mmHg). These errors could be due to an improper use of our reference method. The post-test correction for individual characteristics proposed by the FinometerTM developers did improve overall Q estimation (0.255± 0.441 L/min (6.9%) instead of 0.797± 0.441 L/min (22.4%)) when compared with Doppler ultrasound but did not account for the increasing error with a greater orthostatic stress induced by lower body negative pressure. Using finger BP instead of aortic BP to calculate Q did not explain this error as revealed by a new approach that compared the simultaneous pulse contours from different methods. Indeed, there was no significant difference between the error of the estimation of Q from the finger arterial pulse compared to the estimation of Q from the independent measurement by tonometry on the brachial artery at rest (-1.13± 14.67%) and at the maximum orthostatic stress used (-0.61± 9.33%) (p>0.05). Using brachial BP to calculate Q did not improve the result found with finger BP. The first hypothesis of this thesis that CVP could be estimated from outputs of the FinometerTM compared to direct venous pressure measurement was supported for the individual (0.2± 1.7 mmHg) and test specific (0.1± 1.2 mmHg) equations. The general equations derived from group data were accurate but not precise enough (0.4± 2.8 mmHg) to be used in clinical and research setting. The success of the individual equations suggests that it might be possible to derive a personal equation that will be useful over a long period for similar tests by using a catheter only once. The second and third hypotheses related to the cause of discrepancy between Q from FinometerTM and Q from Doppler, were not supported by the data. However, a new contour analysis method introduced here in a graphical format might provide an opportunity for systematic analyses of the deviation between methods. It could reveal sources of error allowing future improvements in the accuracy and precision of Q from FinometerTM during orthostatic or physical stress.

Sensations of dizziness or fainting (pre-syncope or syncope) on standing up from a lying or a seated position are usually associated with impaired blood pressure regulation leading to inadequate perfusion of the brain. The purpose of this project was to develop a simple method to provide scientists and doctors a convenient way to monitor cardiovascular control during orthostatic stress with the non-invasive FinometerTM device. This apparatus provides a continuous estimate of arterial blood pressure (BP) contour from the finger and computes brachial blood pressure contours (systolic (SBP) and diastolic (DBP) blood pressure), heart rate (HR), stroke volume and cardiac output (Q) from the Modelflow equation. In this thesis, a method was implemented to obtain an estimate of central venous pressure (CVP) to provide greater insight into cardiovascular control. The accuracy and potential errors resulting from measurement of finger arterial pressure were also evaluated. The thesis first examined whether key variables essential to monitor cardiovascular control can be reliably measured by the FinometerTM in comparison to independent methods. HR was accurate and precise at rest and during stress (difference between methods: 0.05± 0.18 beats/min). According to standards established by the American Association for the Advancement of Medical Instrumentation (AAMI); at rest, DBP was accurate but not precise (1.6± 8.8 mmHg) and SBP was not accurate but precise (14.2± 8.0 mmHg). These errors could be due to an improper use of our reference method. The post-test correction for individual characteristics proposed by the FinometerTM developers did improve overall Q estimation (0.255± 0.441 L/min (6.9%) instead of 0.797± 0.441 L/min (22.4%)) when compared with Doppler ultrasound but did not account for the increasing error with a greater orthostatic stress induced by lower body negative pressure. Using finger BP instead of aortic BP to calculate Q did not explain this error as revealed by a new approach that compared the simultaneous pulse contours from different methods. Indeed, there was no significant difference between the error of the estimation of Q from the finger arterial pulse compared to the estimation of Q from the independent measurement by tonometry on the brachial artery at rest (-1.13± 14.67%) and at the maximum orthostatic stress used (-0.61± 9.33%) (p>0.05). Using brachial BP to calculate Q did not improve the result found with finger BP. The first hypothesis of this thesis that CVP could be estimated from outputs of the FinometerTM compared to direct venous pressure measurement was supported for the individual (0.2± 1.7 mmHg) and test specific (0.1± 1.2 mmHg) equations. The general equations derived from group data were accurate but not precise enough (0.4± 2.8 mmHg) to be used in clinical and research setting. The success of the individual equations suggests that it might be possible to derive a personal equation that will be useful over a long period for similar tests by using a catheter only once. The second and third hypotheses related to the cause of discrepancy between Q from FinometerTM and Q from Doppler, were not supported by the data. However, a new contour analysis method introduced here in a graphical format might provide an opportunity for systematic analyses of the deviation between methods. It could reveal sources of error allowing future improvements in the accuracy and precision of Q from FinometerTM during orthostatic or physical stress.

Despite years of research, the role that hypovolemia plays in orthostatic intolerance after head down bed rest (BR) and spaceflight remains unclear. Additionally, the efficacy of oral saline countermeasures, employed in an attempt to restore plasma volume (PV) after BR is questionable. Several previous studies have suggested that a new homeostatic set point is achieved in space or during BR, making attempts to restore PV temporary at best. We tested the hypotheses that one day of BR would induce a transient increase in PV followed by hypovolemia and new hormonal balance; that a salt tablet and water fluid loading (FL) countermeasure would be ineffective in restoring PV; and also that the FL would not attenuate the exaggerated hormonal responses to orthostatic stress that are expected after 28hr of BR. Plasma volume, serum sodium and osmolarity, and plasma ANP, AVP, renin, angiotensin II, aldosterone, and catecholamines were measured in nine male subjects undergoing 5 different protocols (28hr Bed Rest without Fluid Loading = 28NFL, 28hr Bed Rest with Fluid Loading = 28FL, 4hr Seated Control = 4NFLS, 4hr Seated Control with Fluid Loading = 4FLS, and 4hr Bed Rest = 4BR) in a randomized repeated measures design. The FL countermeasure was 15 ml/kg of body weight of water with 1g of NaCl per 125ml of water. Orthostatic testing by lower body negative pressure (LBNP) was performed before and after all protocols. In agreement with our first hypothesis, we observed transient reductions in renin, angiotensin II, and aldosterone, which after 25.5hr were restored to baseline, slightly augmented, and suppressed, respectively. Also after 25.5hr, PV was reduced in the 28hr BR protocols and was not restored in 28FL; however, the FL protocol increased PV during 4FLS. We additionally observed augmented renin and aldosterone responses, as well as generally elevated angiotensin II after 28NFL, but not after 28FL or any of the 4hr protocols. Furthermore, no changes in plasma norepinephrine responses to LBNP were documented from Pre-Post test in any protocol. Our results indicate that: 1) PV is reduced after short term BR and is not restored by an oral FL; 2) renin-angiotensin-aldosterone system (RAAS) responses to orthostatic stress are augmented after 28hr of BR and the amplified response can be abrogated by FL; and 3) plasma norepinephrine responses during orthostatic stress are not affected by BR or FL, suggesting that RAAS activity may be modulated by FL independently of sympathetic activity and PV during orthostasis after bed rest.

Despite years of research, the role that hypovolemia plays in orthostatic intolerance after head down bed rest (BR) and spaceflight remains unclear. Additionally, the efficacy of oral saline countermeasures, employed in an attempt to restore plasma volume (PV) after BR is questionable. Several previous studies have suggested that a new homeostatic set point is achieved in space or during BR, making attempts to restore PV temporary at best. We tested the hypotheses that one day of BR would induce a transient increase in PV followed by hypovolemia and new hormonal balance; that a salt tablet and water fluid loading (FL) countermeasure would be ineffective in restoring PV; and also that the FL would not attenuate the exaggerated hormonal responses to orthostatic stress that are expected after 28hr of BR. Plasma volume, serum sodium and osmolarity, and plasma ANP, AVP, renin, angiotensin II, aldosterone, and catecholamines were measured in nine male subjects undergoing 5 different protocols (28hr Bed Rest without Fluid Loading = 28NFL, 28hr Bed Rest with Fluid Loading = 28FL, 4hr Seated Control = 4NFLS, 4hr Seated Control with Fluid Loading = 4FLS, and 4hr Bed Rest = 4BR) in a randomized repeated measures design. The FL countermeasure was 15 ml/kg of body weight of water with 1g of NaCl per 125ml of water. Orthostatic testing by lower body negative pressure (LBNP) was performed before and after all protocols. In agreement with our first hypothesis, we observed transient reductions in renin, angiotensin II, and aldosterone, which after 25.5hr were restored to baseline, slightly augmented, and suppressed, respectively. Also after 25.5hr, PV was reduced in the 28hr BR protocols and was not restored in 28FL; however, the FL protocol increased PV during 4FLS. We additionally observed augmented renin and aldosterone responses, as well as generally elevated angiotensin II after 28NFL, but not after 28FL or any of the 4hr protocols. Furthermore, no changes in plasma norepinephrine responses to LBNP were documented from Pre-Post test in any protocol. Our results indicate that: 1) PV is reduced after short term BR and is not restored by an oral FL; 2) renin-angiotensin-aldosterone system (RAAS) responses to orthostatic stress are augmented after 28hr of BR and the amplified response can be abrogated by FL; and 3) plasma norepinephrine responses during orthostatic stress are not affected by BR or FL, suggesting that RAAS activity may be modulated by FL independently of sympathetic activity and PV during orthostasis after bed rest.

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.

Abstract available in the Faseb Journal

Reductions in baroreflex responsiveness have been thought to increase the prevalence of orthostatic hypotension in endurance trained athletes. To test this hypothesis, cardiovascular responses to orthostatic stress, cardiopulmonary and carotid baroreflex responsiveness, and the effect of cardiopulmonary receptor deactivation on carotid baroreflex responses were examined in 24 men categorized by maximal aerobic power (V02max) into one of three groups: high fit (HF, V0-2max=67.0±1.9 ml•kg^-1•min^-1), moderately fit (MF, V0-2max=50.9±1.4 ml•kg^-1•min^-1), and low fit (LF, V0-2max=38.9±1.5 ml•kg^-1•min^-1). Orthostatic stress was induced using lower body negative pressure (LBNP) at -5, -10, -15, -20, -35, and -50 torr. Cardiopulmonary baroreflex responsiveness was assessed as the slope of the relationship between forearm vascular resistance (FVR, strain gauge plethysmography) and central venous pressure (CVP, dependent arm technigue) during LBNP<-35 torr. Carotid baroreflex responsiveness was assessed as the change in heart rate (HR, electrocardiography) or mean arterial pressure (MAP, radial artery catheter) elicited by 600 msec pulses of neck pressure and neck suction (NP/NS) from +40 to -70 torr. Pressures were applied using a lead collar wrapped about the subjects' necks during held expiration. Stimulus response data were fit to a logistic model and the parameters describing the curve were compared using two-factor ANOVA. The reductions CVP, mean (MAP), systolic, and pulse pressures during LBNP were similar between groups (P<0.05). However, diastolic blood pressure increased during LBNP m all but the HF group. (P<0.05). The slope of the FVR/CVP relationship did not differ between groups, nor did the form of the carotid-cardiac baroreflex stimulus response curve change during LBNP. changes in HR elicited with NP/NS were not different between groups (£>0.05). The range of the MAP stimulus response curve, however, was significantly less in the HP group compared to either the MP or LF group (£<0.05). These data imply that carotid baroreflex control of HR is unaltered by endurance exercise training, but carotid baroreflex control of blood pressure is impaired significantly, predisposing athletes to faintness.