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The current thesis examined whether sex-differences in local and whole-body heat loss are evident after accounting for confounding differences in physical characteristics and rate of metabolic heat production. Three experimental studies were performed: the first examined whole-body heat loss in males and females matched for body mass and surface area during exercise at a fixed rate of metabolic heat production; the second examined local and whole-body heat loss responses between sexes during exercise at increasing requirements for heat loss; the third examined sex-differences in local sweating and cutaneous vasodilation to given doses of pharmacological agonists, as well as during passive heating. The first study demonstrates that females exhibit a lower whole-body sudomotor thermosensitivity (553 ± 77 vs. 795 ± 85 W•°C-1, p=0.05) during exercise performed at a fixed rate of metabolic heat production. The second study shows that whole-body sudomotor thermosensitivity is similar between sexes at a requirement for heat loss of 250 W•m-2 (496 ± 139 vs. 483 ± 185 W•m-2•°C-1, p=0.91) and 300 W•m-2 (283 ± 70 vs. 211 ± 66 W•m-2•°C-1, p=0.17), only becoming greater in males at a requirement for heat loss of 350 W•m-2 (197 ± 61 vs. 82 ± 27 W•m-2•°C-1, p=0.007). In the third study, a lower sweat rate to the highest concentration of acetylcholine (0.27 ± 0.08 vs. 0.48 ± 0.13 mg•min-1•cm-2, p=0.02) and methylcholine (0.41 ± 0.09 vs. 0.57 ± 0.11 mg•min-1•cm-2, p=0.04) employed was evidenced in females, with no differences in cholinergic sensitivity. Taken together, the results of the current thesis show that sex itself can modulate sudomotor activity, specifically the thermosensitivity of the response, during both exercise and passive heat stress. Furthermore, the results of the third study point towards a peripheral modulation of the sweat gland as a mechanism responsible for the lower sudomotor thermosensitivity in females.

Heat stress-induced hyperthermia and exercise-induced hypohydration are associated with marked alterations in limb and systemic haemodynamics in humans. However, the mechanisms underlying these alterations their effects on muscle blood flow are not well understood. The present thesis examined whether whole body and local heat stresses increased limb skin and muscle blood flow (Study 1) and whether hypohydration and hyperthermia compromised leg muscle, skin and systemic haemodynamics (Study 2). The effects of heat stress and combined hypohydration and hyperthermia were examined at rest and during mild small muscle mass exercise in humans. The results from Study 1 suggested that heat stress was accompanied by vasodilation in both skeletal muscle and skin vasculatures. Therefore in line with concomitant elevations in blood flow, skeletal muscle and skin vasodilation contribute to increases in leg blood flow and vascular conductance with whole body heat stress. Furthermore, increases in leg muscle and skin blood flow with isolated elevations in leg tissue temperature accounted for at least one half of the total increase in leg blood flow with whole body heat stress. Enhanced leg blood flow owed to a net vasodilation as explained by an elevation in vasodilator activity that exceeded increases in vasoconstrictor activity. This phenomenon was closely related to increases in muscle temperature and intravascular adenosine triphosphate (ATP). The results from Study 2 demonstrated that mild and moderate hypohydration and hyperthermia do not compromise leg muscle and skin blood flow or cardiac output at rest or during mild exercise in humans. Furthermore, acute rehydration did not alter leg muscle and skin blood flow or cardiac output compared to hypohydration and hyperthermia despite large alterations in blood volume and haematological variables and the restoration of core temperature. Taken together, the findings of this thesis indicate that: 1) heat stress induces vasodilation in both skeletal muscle and cutaneous vasculature, 2) elevations in muscle temperature and intravascular ATP play a role in heat stress- and exercise-induced hyperaemia, and 3) moderate hypohydrationinduced hypovolemia and haemoconcentration and rehydration-induced hypervolaemia and haemodilution do not alter leg blood flow or cardiac output at rest and during low intensity exercise in humans when a large cardiovascular reserve is available.

The ability of the brain to keep a stable and adequate cerebral blood flow (CBF) independently of fluctuations in systemic blood pressure is referred to as cerebral pressure autoregulation (CPA). When the brain is injured by trauma or hemorrhage, this ability may be impaired, leaving the brain vulnerable to events of high or low blood pressure. The aims of this thesis were to study CPA in patients with severe traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH), the relation between CPA and other physiological parameters, and the influence of CPA on outcome. Four retrospective studies are included in the thesis. All patients were treated at the neurointensive care unit, Uppsala University hospital. In paper I, 58 TBI patients were studied. In patients with impaired CPA, cerebral perfusion pressure between 50-60 mm Hg was associated with favorable outcome while CPP > 70 and >80 mm Hg was associated with unfavorable outcome. In patients with intact CPA there was no association between CPP and outcome. In paper II, 107 TBI patients were studied. High CPP was associated with unfavorable outcome in patients with focal injuries. In patients with diffuse injury and impaired CPA, CPP > 70 mm Hg was associated with favorable outcome. In paper III, 47 SAH patients were studied. CBF was measured bedside with Xenon-enhance CT (Xe-CT). Patients with impaired CPA had lower CBF, both in the early (day 0-3) and late (day 4-14) acute phase of the disease. In paper IV, 64 SAH patients were studied. Optimal CPP (CPPopt) was calculated automatically as the level of CPP where CPA works best for the patient, i.e., where PRx is lowest. Patients with actual CPP below their calculated optimum had higher amounts of low-flow regions (CBF < 10 ml/100g/min). The findings in this thesis emphasize the importance of taking CPA into account in the management of TBI and SAH patients, and suggest that treatment should be individualized depending on status of autoregulation. PRx and CPPopt may be used bedside to guide management according to status of autoregulation. In the future CPA-guided management should be tested in prospective studies

Eclampsia is a hypertensive disorder of pregnancy and a leading cause of maternal death. The primary explanation for eclampsia is that it represents a form of hypertensive encephalopathy (HTE) with neurological symptoms including headaches, nausea, vomiting, visual disturbances, and seizures. The etiology of HTE involves an acute increase in arterial blood pressure that exceeds the autoregulatory capacity of the brain leading to forced dilatation of cerebral vessels, decreased cerebrovascular resistance, hyperperfusion, blood-brain barrier (BBB) disruption, and vasogenic cerebral edema formation. Due to the central role of the cerebral circulation in mediating these symptoms, a better understanding of how pregnancy affects the cerebral circulation is important to the treatment and prevention of eclampsia. A central goal of this dissertation was to determine pregnancy’s effect on cerebral blood flow (CBF) autoregulation, edema formation, and BBB permeability during acute hypertension. Women with eclampsia often seize at lower blood pressures than HTE patients. We hypothesized that pregnancy may predispose the brain to eclampsia by lowering the pressure of autoregulatory breakthrough and enhancing cerebral edema formation. Using an in vivo model of HTE, we found that the pressure of autoregulatory breakthrough was not different between nonpregnant (NP) and late-pregnant (LP) rats; however, cerebral edema formation was significantly increased only in LP animals. Nitric oxide synthase inhibition significantly increased the upper limit of autoregulation in both NP and LP animals and attenuated cerebral edema formation in LP animals. BBB permeability during acute hypertension was not different between these groups. Magnesium sulfate (MgSO4) is widely used to treat eclampsia despite an unclear mechanism of action. A second goal of this dissertation was to determine the cerebrovascular effects of MgSO4 during pregnancy. Specifically, we investigated the effect of MgSO4 on in vitro resistance artery vasodilation and in vivo BBB permeability during acute hypertension. We hypothesized that dilation to MgSO4 would be greater in mesenteric than cerebral vessels. MgSO4 elicited concentration-dependent vasodilation in all arteries, as determined by measuring lumen diameter of isolated and pressurized arteries, however, mesenteric arteries were considerably more sensitive than cerebral arteries. In addition, there was no effect of pregnancy on MgSO4 sensitivity in mesenteric arteries, whereas pregnancy decreased sensitivity to MgSO4 in cerebral arteries. We further hypothesized that MgSO4 would decrease BBB disruption during acute hypertension, thereby protecting the brain in eclampsia. Using an in vivo model of HTE, we showed that MgSO4 treatment decreased BBB permeability during acute hypertension in LP rats, with the greatest effect observed in the posterior cerebrum. In conclusion, this dissertation determined CBF autoregulation and cerebral edema formation during pregnancy, and also the effect of MgSO4 on cerebral resistance artery vasodilation and BBB permeability during acute hypertension in LP rats. Although pregnancy did not influence autoregulatory breakthrough, cerebral edema formation was enhanced in LP animals and this may potentiate neurological symptoms in eclampsia. In addition, MgSO4-induced cerebral vasodilation is likely not a primary mechanism of eclampsia treatment, rather MgSO4 may limit edema formation by attenuating BBB permeability during hypertension.

One of the earliest sub-clinical stages associated with atherosclerosis is endothelial dysfunction (ED), which has been shown to predict future cardiovascular events. Chronic exercise is thought to improve endothelium-dependent vasodilation; however, few studies have evaluated the effects of acute exercise on vascular function (VF). Moreover, studies evaluating ED following an exercise training program lack a standardized time frame in which to measure VF. Although most studies require subjects to abstain from exercise for 24 hours prior to any VF measure, no study to date has assessed VF longer than 24 hours after the cessation of exercise. Additionally, no studies have compared VF responses in obese and non-obese individuals following acute exercise. Purpose: Therefore, the purpose of this study was to evaluate VF, as determined by the assessment of forearm blood flow (FBF) and vascular reactivity (VR) before and up to 48 hours after a single bout of maximal exercise in obese and non-obese males. Methods: Twelve obese (37.0 ± 1.1 kg/m2) and twelve non-obese (21.9 ± 0.3 kg/m2) males volunteered to participate. FBF was assessed before and during reactive hyperemia (RH). FBF measures were obtained prior to (PRE-E), immediately after (POST-E), and at 1 (POST-1), 2 (POST-2), 24 (POST-24), and 48 (POST-48) hours after exercise. Total excess flow, calculated as the difference between baseline FBF and FBF during RH, was used as an indicator of VR. Blood samples were also obtained at each time point to evaluate the response of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), which are potential modifiers of VF. Results: Baseline FBF and FBF during RH were significantly (P < 0.05) increased in both groups POST-E before returning to baseline values by POST-1. VR was enhanced in both groups POST-E, although the magnitude of change was greater in non-obese males. VR was significantly (P < 0.05) increased in non-obese males POST-E and was not significantly (P < 0.05) reduced until POST-48. Concentrations of IL-6 and TNF-α were unchanged in response to exercise in non-obese and obese males. Conclusions: An acute bout of maximal exercise significantly increased forearm endothelium-dependent vasodilation in non-obese and obese males. Additionally, an increased reactive vasodilation was observed only in non-obese males following exercise. These results also suggest that in non-obese males, measurements used to verify improvements in VF following exercise training should be employed after a minimum of 48 hours following physical activity.

Master of Science / Department of Kinesiology / David C. Poole / Introduction: Dietary nitrate(NO[subscript]3[superscript]-) supplementation, via its reduction to nitrite (NO [subscript] 2 [superscript]-) and subsequent conversion to nitric oxide (NO) and other reactive nitrogen intermediates, reduces blood pressure and the O[subscript]2 cost of submaximal exercise in humans. Despite these observations, the effects of dietary NO [subscript]3 [superscript]- supplementation on skeletal muscle vascular control during locomotory exercise remain unknown. We tested the hypotheses that dietary NO [subscript]3 [superscript]- supplementation via beetroot juice (BR) would reduce mean arterial pressure (MAP) and increase hindlimb muscle blood flow in the exercising rat. Methods: Male Sprague-Dawley rats (3-6 months) were administered either NO [subscript]3 [superscript]- (via beetroot juice; 1 mmol · kg[superscript]-[superscript]1 · day[superscript]-[superscript]1, BR n=8) or untreated (control, n=11) tap water for 5 days. MAP and hindlimb skeletal muscle blood flow and vascular conductance (radiolabeled microsphere infusions) were measured during submaximal treadmill running (20 m · min[superscript]-[superscript]1, 5% grade). Results: BR resulted in significantly lower exercising MAP (control: 137 ± 3, BR: 127 ± 4 mmHg, P<0.05) and blood [lactate] (control: 2.6 ± 0.3, BR: 1.9 ± 0.2 mM, P<0.05) compared to control. Total exercising hindlimb skeletal muscle blood flow (control: 108 ± 8, BR: 150 ± 11 ml · min[superscript]-[superscript]1 · 100 g[superscript]-[superscript]1, P<0.05) and vascular conductance (control: 0.78 ± 0.05, BR: 1.16 ± 0.10 ml · min[superscript]-[superscript]1 · 100 g[superscript]-[superscript]1 · mmHg[superscript]-[superscript]1, P<0.05) were greater in rats that received beetroot juice compared to control. The relative differences in blood flow and vascular conductance for the 28 individual hindlimb muscles and muscle parts correlated positively with their percent type IIb + d/x muscle fibers (blood flow: r=0.74, vascular conductance: r=0.71, P<0.01 for both). Conclusion: These data support the hypothesis that NO [subscript]3 [superscript]- supplementation improves vascular control and elevates skeletal muscle O [subscript]2 delivery during exercise predominantly in fast-twitch type II muscles, and provide a potential mechanism by which NO [subscript]3 [superscript]- supplementation improves metabolic control.

Doctor of Philosophy / Department of Anatomy and Physiology / Timothy I. Musch / Nitric oxide (NO) is synthesized via distinct NO synthase (NOS) enzymes and constitutes an essential cardiovascular signaling molecule. Whereas important vasomotor contributions of endothelial NOS (eNOS) have been well-described, the specific vasomotor contributions of nNOS-derived NO in healthy subjects during exercise are unknown. The purpose of this dissertation is to test the global hypothesis that nNOS-derived NO is a critical regulator of exercising skeletal muscle vascular control. Specifically, we utilized the selective nNOS inhibitor S-methyl-L-thiocitrulline (SMTC) to investigate the effects of nNOS-derived NO on skeletal muscle vascular function within established rodent models of exercise performance. The first investigation (Chapter 2) identifies that nNOS inhibition with SMTC increases mean arterial pressure (MAP) and reduces rat hindlimb skeletal muscle blood flow at rest whereas there are no effects during low-speed (20 m/min) treadmill running. In Chapter 3 it is reported that nNOS inhibition with SMTC reduces blood flow during high-speed treadmill running (>50 m/min) with the greatest relative effects found in highly glycolytic fast-twitch muscles and muscle parts. Chapter 4 demonstrates that nNOS-derived NO modulates contracting skeletal muscle blood flow (increases), O2 consumption (VO2, increases), and force production (decreases) in the rat spinotrapezius muscle and thus impacts the microvascular O2 delivery-VO2 ratio (which sets the microvascular partial pressure of O2, PO2mv, and represents the pressure head that drives capillary-myocyte O2 diffusion). In Chapter 5 we report that systemic administration of the selective nNOS inhibitor SMTC does not impact lumbar sympathetic nerve discharge. This reveals that the SMTC-induced peripheral vascular effects described herein reflect peripheral nNOS-derived NO signaling as opposed to centrally-derived regulation. In conclusion, nNOS-derived NO exerts exercise-intensity and muscle fiber-type selective peripheral vascular effects during whole-body locomotor exercise. In addition, nNOS-derived NO modulates skeletal muscle contractile and metabolic function and, therefore, impacts the skeletal muscle PO2mv. These data identify novel integrated roles for nNOS-derived NO within healthy skeletal muscle and have important implications for populations associated with reduced NO bioavailability and/or impaired nNOS structure and/or function specifically (e.g., muscular dystrophy, chronic heart failure, advanced age, etc.).