Kay VL, Rickards CA. The role of cerebral oxygenation and regional cerebral blood flow on tolerance to central hypovolemia. Am J Physiol Regul Integr Comp Physiol 310: R375-R383, 2016. First published December 16, 2015 doi:10.1152/ajpregu.00367.2015Tolerance to central hypovolemia is highly variable, and accumulating evidence suggests that protection of anterior cerebral blood flow (CBF) is not an underlying mechanism. We hypothesized that individuals with high tolerance to central hypovolemia would exhibit protection of cerebral oxygenation (ScO2), and prolonged preservation of CBF in the posterior vs. anterior cerebral circulation. Eighteen subjects (7 male/11 female) completed a presyncope-limited lower body negative pressure (LBNP) protocol (3 mmHg/min onset rate). ScO2 (via near-infrared spectroscopy), middle cerebral artery velocity (MCAv), posterior cerebral artery velocity (PCAv) (both via transcranial Doppler ultrasound), and arterial pressure (via finger photoplethysmography) were measured continuously. Subjects who completed Ն70 mmHg LBNP were classified as high tolerant (HT; n ϭ 7) and low tolerant (LT; n ϭ 11) if they completed Յ60 mmHg LBNP. The minimum difference in LBNP tolerance between groups was 193 s (LT ϭ 1,243 Ϯ 185 s vs. HT ϭ 1,996 Ϯ 212 s; P Ͻ 0.001; Cohen's d ϭ 3.8). Despite similar reductions in mean MCAv in both groups, ScO2 decreased in LT subjects from Ϫ15 mmHg LBNP (P ϭ 0.002; Cohen's dϭ1.8), but was maintained at baseline values until Ϫ75 mmHg LBNP in HT subjects (P Ͻ 0.001; Cohen's d ϭ 2.2); ScO2 was lower at Ϫ30 and Ϫ45 mmHg LBNP in LT subjects (P Յ 0.02; Cohen's d Ն 1.1). Similarly, mean PCAv decreased below baseline from Ϫ30 mmHg LBNP in LT subjects (P ϭ 0.004; Cohen's d ϭ 1.0), but remained unchanged from baseline in HT subjects until Ϫ75 mmHg (P ϭ 0.006; Cohen's d ϭ 2.0); PCAv was lower at Ϫ30 and Ϫ45 mmHg LBNP in LT subjects (P Յ 0.01; Cohen's d Ն 0.94). Individuals with higher tolerance to central hypovolemia exhibit prolonged preservation of CBF in the posterior cerebral circulation and sustained cerebral tissue oxygenation, both associated with a delay in the onset of presyncope.posterior cerebral artery; middle cerebral artery; lower body negative pressure HEMORRHAGE DUE TO TRAUMA IS one of the leading causes of morbidity and mortality worldwide in both the civilian and military settings (1, 2, 13, 22, 32). A major factor contributing to death and disability from severe blood loss is poor tissue perfusion and oxygenation of the vital organs (1, 13, 22). Prolonged cerebral hypoperfusion can lead to neuronal cell death, and if the patient survives, long-term cognitive impairment and physical disability (32). Understanding cerebral hemodynamic responses to blood loss is an essential target for improving survival to hemorrhagic injury, and developing effective therapeutic interventions (35). As there is considerable variability in survival time following hemorrhagic injuries (40), as well as tolerance to simulated hemorrhage (7,15,24,26), it is crucial to determine the rol...

People with schizophrenia have an increased risk of metabolic syndrome, with consequent elevated morbidity and mortality, largely due to cardiovascular disease. Metabolic disorders comprise obesity, dyslipidemia and elevated levels of triglycerides, hypertension, and disturbed insulin and glucose metabolism. The elevated risk of metabolic syndrome in individuals suffering from schizophrenia is believed to be multifactorial, related to a genetic predisposition, lifestyle characteristics and treatment with antipsychotic medications. Relaxin 3 (RLN3, also known as INSL7) is a recently identified member of the insulin/relaxin superfamily that plays a role in the regulation of appetite and body weight control. RLN3 stimulates relaxin-3 receptor 1 (relaxin/insulin-like family peptide receptor 3, RXFP3) and relaxin receptor 2 (relaxin/insulin-like family peptide receptor 4, RXFP4). We have investigated the role of ten polymorphisms in these genes (RLN3 rs12327666, rs1982632, and rs7249702, RLN3R1 rs42868, rs6861957, rs7702361, and rs35399, and RLN3R2 rs11264422, rs1018730 and rs12124383) in the occurrence of metabolic syndrome phenotypes (obesity, diabetes, hypercholesterolemia, hypertrigyceridemia, and hypertension) in a cross-sectional cohort of 419 US Caucasian patients treated with antipsychotic drugs. We found several associations between relaxin polymorphisms and hypecholesterolemia, obesity and diabetes, suggesting a role for the relaxin/insulin pathway in the development of metabolic disturbance observed in patients treated with antipsychotics.

Trauma-induced hemorrhage is a leading cause of disability and death due, in part, to impaired perfusion and oxygenation of the brain. It is unknown if cerebrovascular responses to blood loss are differentiated based on sex. We hypothesized that compared to males, females would have reduced tolerance to simulated hemorrhage induced by maximal lower body negative pressure (LBNP), and this would be associated with an earlier reduction in cerebral blood flow and cerebral oxygenation. Methods: Healthy young males (n=29, 26±4 y) and females (n=23, 27±5 y) completed a step-wise LBNP protocol to presyncope. Mean arterial pressure (MAP), stroke volume (SV), middle cerebral artery velocity (MCAv), end-tidal CO2 (etCO2), and cerebral oxygen saturation (ScO2) were measured continuously. Results: Unexpectedly, tolerance to LBNP was similar between the sexes (males, 1604±68 s vs. females, 1453±78 s; P=0.15). Accordingly, decreases (%Δ) in MAP, SV, MCAv, and ScO2 were similar between males and females throughout LBNP and at presyncope (P≥0.20). Interestingly, while decreases in etCO2 were similar between the sexes throughout LBNP (P=0.16), at presyncope, the %Δ etCO2 from baseline was greater in males compared to females (-30.8±2.6% vs. -21.3±3.0%; P=0.02). Conclusion: Contrary to our hypothesis, sex does not influence tolerance, or the central or cerebral hemodynamic responses to simulated hemorrhage. However, the etCO2 responses at presyncope do suggest potential sex differences in cerebral vascular sensitivity to CO2 during central hypovolemia.

We tested the hypothesis that transmission of arterial pressure to brain tissue oxygenation is low under conditions of arterial pressure instability. Two experimental models of hemodynamic instability were used in healthy human volunteers; (1) oscillatory lower body negative pressure (OLBNP) (N = 8; 5 male, 3 female), and; (2) maximal LBNP to presyncope (N = 21; 13 male, 8 female). Mean arterial pressure (MAP), middle cerebral artery velocity (MCAv), and cerebral tissue oxygen saturation (ScO2) were measured non-invasively. For the OLBNP protocol, between 0 and -60 mmHg negative pressure was applied for 20 cycles at 0.05 Hz, then 20 cycles at 0.1 Hz. For the maximal LBNP protocol, progressive 5 min stages of chamber decompression were applied until the onset of presyncope. Spectral power of MAP, mean MCAv, and ScO2 were calculated within the VLF (0.04-0.07 Hz), and LF (0.07-0.2 Hz) ranges, and cross-spectral coherence was calculated for MAP-mean MCAv, MAP-ScO2, and mean MCAv-ScO2 at baseline, during each OLBNP protocol, and at the level prior to pre-syncope during maximal LBNP (sub-max). The key findings are (1) both 0.1 Hz OLBNP and sub-max LBNP elicited increases in LF power for MAP, mean MCAv, and ScO2 (p ≤ 0.08); (2) 0.05 Hz OLBNP increased VLF power in MAP and ScO2 only (p ≤ 0.06); (3) coherence between MAP-mean MCAv was consistently higher (≥0.71) compared with MAP-ScO2, and mean MCAv-ScO2 (≤0.43) during both OLBNP protocols, and sub-max LBNP (p ≤ 0.04). These data indicate high linearity between pressure and cerebral blood flow variations, but reduced linearity between cerebral tissue oxygenation and both arterial pressure and cerebral blood flow. Measuring arterial pressure variability may not always provide adequate information about the downstream effects on cerebral tissue oxygenation, the key end-point of interest for neuronal viability.

Resistance breathing improves tolerance to central hypovolemia induced by lower body negative pressure (LBNP), but this is not related to protection of anterior cerebral blood flow [indexed by mean middle cerebral artery velocity (MCAv)]. We hypothesized that inspiratory resistance breathing improves tolerance to central hypovolemia by maintaining cerebral oxygenation (ScO), and protecting cerebral blood flow in the posterior cerebral circulation [indexed by posterior cerebral artery velocity (PCAv)]. Eight subjects (4 male/4 female) completed two experimental sessions of a presyncopal-limited LBNP protocol (3 mmHg/min onset rate) with and without (Control) resistance breathing via an impedance threshold device (ITD). ScO (via near-infrared spectroscopy), MCAv and PCAv (both via transcranial Doppler ultrasound), and arterial pressure (via finger photoplethysmography) were measured continuously. Hemodynamic responses were analyzed between the Control and ITD condition at baseline (T1) and the time representing 10 s before presyncope in the Control condition (T2). While breathing on the ITD increased LBNP tolerance from 1,506 ± 75 s to 1,704 ± 88 s ( = 0.003), both mean MCAv and mean PCAv were similar between conditions at T2 ( ≥ 0.46), and decreased by the same magnitude with and without ITD breathing ( ≥ 0.53). ScO also decreased by ~9% with or without ITD breathing at T2 ( = 0.97), and there were also no differences in deoxygenated (dHb) or oxygenated hemoglobin (HbO) between conditions at T2 ( ≥ 0.43). There was no evidence that protection of regional cerebral blood velocity (i.e., anterior or posterior cerebral circulation) nor cerebral oxygen extraction played a key role in the determination of tolerance to central hypovolemia with resistance breathing.