The mechanisms underlying red blood cell (RBC)-mediated hypoxic vasodilation remain controversial, with separate roles for nitrite () and S-nitrosohemoglobin (SNO-Hb) widely contested given their ...ability to transduce nitric oxide bioactivity within the microcirculation. To establish their relative contribution in vivo, we quantified arterial-venous concentration gradients across the human cerebral and femoral circulation at rest and during exercise, an ideal model system characterized by physiological extremes of O
tension and blood flow.
Ten healthy participants (5 men, 5 women) aged 24±4 (mean±SD) years old were randomly assigned to a normoxic (21% O
) and hypoxic (10% O
) trial with measurements performed at rest and after 30 minutes of cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled simultaneously from the brachial artery and internal jugular and femoral veins with plasma and RBC nitric oxide metabolites measured by tri-iodide reductive chemiluminescence. Blood flow was determined by transcranial Doppler ultrasound (cerebral blood flow) and constant infusion thermodilution (femoral blood flow) with net exchange calculated via the Fick principle.
Hypoxia was associated with a mild increase in both cerebral blood flow and femoral blood flow (P<0.05 versus normoxia) with further, more pronounced increases observed in femoral blood flow during exercise (P<0.05 versus rest) in proportion to the reduction in RBC oxygenation (r=0.680-0.769, P<0.001). Plasma gradients reflecting consumption (arterial>venous; P<0.05) were accompanied by RBC iron nitrosylhemoglobin formation (venous>arterial; P<0.05) at rest in normoxia, during hypoxia (P<0.05 versus normoxia), and especially during exercise (P<0.05 versus rest), with the most pronounced gradients observed across the bioenergetically more active, hypoxemic, and acidotic femoral circulation (P<0.05 versus cerebral). In contrast, we failed to observe any gradients consistent with RBC SNO-Hb consumption and corresponding delivery of plasma S-nitrosothiols (P>0.05).
These findings suggest that hypoxia and, to a far greater extent, exercise independently promote arterial-venous delivery gradients of intravascular nitric oxide, with deoxyhemoglobin-mediated reduction identified as the dominant mechanism underlying hypoxic vasodilation.
Growth differentiation factor (GDF)-15 is implicated in regulation of metabolism and circulating GDF15 increases in response to exercise. The source and regulation of the exercise-induced increase in ...GDF15 is, however not known.
Plasma GDF15 was measured by ELISA under the following conditions: 1) Arterial-to-hepatic venous differences sampled before, during, and after exercise in healthy male subjects (n=10); 2) exogenous glucagon infusion compared to saline infusion in resting healthy subjects (n=10); 3) an acute exercise bout with and without a pancreatic clamp (n=6); 4) healthy subjects for 36 hours (n=17), and 5) patients with anorexia nervosa (n=25) were compared to healthy age-matched subjects (n=25). Tissue GDF15 mRNA content was determined in mice in response to exhaustive exercise (n=16).
The splanchnic bed released GDF15 to the circulation during exercise and increasing the glucagon-to-insulin ratio in resting humans led to a 2.7-fold (P<0.05) increase in circulating GDF15. Conversely, inhibiting the exercise-induced increase in the glucagon-to-insulin ratio blunted the exercise-induced increase in circulating GDF15. Fasting for 36 hours did not affect circulating GDF15, whereas resting patients with anorexia nervosa displayed elevated plasma concentrations (1.4-fold, P<0.05) compared to controls. In mice, exercise increased GDF15 mRNA contents in liver, muscle, and adipose tissue.
In humans, GDF15 is a "hepatokine" which increases during exercise and is at least in part regulated by the glucagon-to-insulin ratio. Moreover, chronic energy deprivation is associated with elevated plasma GDF15, which supports that GDF15 is implicated in metabolic signalling in humans.
In supine humans the main drainage from the brain is through the internal jugular vein (IJV), but the vertebral veins (VV) become important during orthostatic stress because the IJV is partially ...collapsed. To identify the effect of this shift in venous drainage from the brain on the cerebral circulation, this study addressed both arterial and venous flow responses in the "anterior" and "posterior" parts of the brain when nine healthy subjects (5 men) were seated and flow was manipulated by hyperventilation and inhalation of 6% carbon dioxide (CO
). From a supine to a seated position, both internal carotid artery (ICA) and IJV blood flow decreased (P = 0.004 and P = 0.002), while vertebral artery (VA) flow did not change (P = 0.348) and VV flow increased (P = 0.024). In both supine and seated positions the ICA response to manipulation of end-tidal CO
tension was reflected in IJV (r = 0.645 and r = 0.790, P < 0.001) and VV blood flow (r = 0.771 and r = 0.828, P < 0.001). When seated, the decrease in ICA blood flow did not affect venous outflow, but the decrease in IJV blood flow was associated with the increase in VV blood flow (r = 0.479, P = 0.044). In addition, the increase in VV blood flow when seated was reflected in VA blood flow (r = 0.649, P = 0.004), and the two flows were coupled during manipulation of the end-tidal CO
tension (supine, r = 0.551, P = 0.004; seated, r = 0.612, P < 0001). These results support that VV compensates for the reduction in IJV blood flow when seated and that VV may influence VA blood flow.
Background
The effects of vasoconstriction on cardiac stroke volume (SV) and indices of peripheral and intestinal perfusion are insufficiently described.
Methods
In a non‐randomized clinical study, ...30 patients undergoing elective rectal surgery were exposed to modulation of preload. The primary endpoint was intestinal perfusion (flux), measured by single‐point laser Doppler flowmetry. Secondary endpoints were central cardiovascular variables obtained by the LiDCO rapid monitor, the peripheral perfusion index (PPI) derived from the pulse oximetry signal and muscle (StO2) and cerebral oxygenation (ScO2) determined by near‐infrared spectroscopy.
Results
For the whole cohort (n = 30), administration of Phenylephrine during HUT induced a median IQR increase in SV by 22% 14–41, p = .003 and in mean arterial pressure (MAP) by 54% 31–62, p < .001, with no change in PPI, StO2 and ScO2 or flux. In patients who were preload dependent during HUT (stroke volume variation; SSV >10%; n = 23), administration of phenylephrine increased SV by 29% 12–43, p = .01 and MAP by 54% 33–63, p < .001, followed by an increase in intestinal perfusion flux by 60% 15–289, p = .05, while PPI, StO2 and ScO2 remained unchanged. For non‐preload dependent patients (SSV <10%; n = 7), no changes in hemodynamic indices were seen besides an increase in MAP by 54% 33–58, p = .002.
Conclusion
The reflection of vasoconstrictive modulation of preload in systemic cardiovascular variables and indices of perfusion was dependent on preload responsiveness. Administration of phenylephrine to increase preload did not appear to compromise organ perfusion.
Brain function requires oxygen and maintenance of brain capillary oxygenation is important. We evaluated how faithfully frontal lobe near-infrared spectroscopy (NIRS) follows haemoglobin saturation ...(SCap) and how calculated mitochondrial oxygen tension (PMitoO2) influences motor performance. Twelve healthy subjects (20 to 29 years), supine and seated, inhaled O2 air-mixtures (10% to 100%) with and without added 5% carbon dioxide and during hyperventilation. Two measures of frontal lobe oxygenation by NIRS (NIRO-200 and INVOS) were compared with capillary oxygen saturation (SCap) as calculated from the O2 content of brachial arterial and right internal jugular venous blood. At control SCap (78% ± 4%; mean ± s.d.) was halfway between the arterial (98% ± 1%) and jugular venous oxygenation (SVO2; 61% ± 6%). Both NIRS devices monitored SCap (P < 0.001) within ~5% as SvO2 increased from 39% ± 5% to 79% ± 7% with an increase in the transcranial ultrasound Doppler determined middle cerebral artery flow velocity from 29 ± 8 to 65 ± 15 cm/sec. When SCap fell below ~70% with reduced flow and inspired oxygen tension, PMitoO2 decreased (P < 0.001) and brain lactate release increased concomitantly (P < 0.001). Handgrip strength correlated with the measured (NIRS) and calculated capillary oxygenation values as well as with PMitoO2 (r > 0.74; P < 0.05). These results show that NIRS is an adequate cerebral capillaryoxygenation-level-dependent (COLD) measure during manipulation of cerebral blood flow or inspired oxygen tension, or both, and suggest that motor performance correlates with the frontal lobe COLD signal.
New Findings
What is the central question of this study?
Is cardiac output during exercise dependent on central venous pressure?
What is the main finding and its importance?
The increase in cardiac ...output during both rowing and running is related to preload to the heart, as indicated by plasma atrial natriuretic peptide, but unrelated to central venous pressure. The results indicate that in upright humans, central venous pressure reflects the gravitational influence on central venous blood rather than preload to the heart.
We evaluated the increase in cardiac output (CO) during exercise in relationship to central venous pressure (CVP) and plasma arterial natriuretic peptide (ANP) as expressions of preload to the heart. Seven healthy subjects (four men; mean ± SD: age 26 ± 3 years, height 181± 8 cm and weight 76 ± 11 kg;) rested in sitting and standing positions (in randomized order) and then rowed and ran at submaximal workloads. The CVP was recorded, CO (Modelflow) calculated and arterial plasma ANP determined by radioimmunoassay. While sitting, (mean ± SD) CO was 6.2 ± 1.6 l min−1, plasma ANP 70 ± 10 pg ml−1 and CVP 1.8 ± 1.1 mmHg, and when standing decreased to 5.9 ± 1.0 l min−1, 63 ± 10 pg ml−1 and −3.8 ± 1.2 mmHg, respectively (P < 0.05). Ergometer rowing elicited an increase in CO to 22.5 ± 5.5 l min−1 as plasma ANP increased to 156 ± 11 pg ml−1 and CVP to 3.8 ± 0.9 mmHg (P < 0.05). Likewise, CO increased to 23.5 ± 6.0 l min−1 during running, albeit with a smaller (P < 0.05) increase in plasma ANP, but with little change in CVP (−0.9 ± 0.4 mmHg). The increase in CO in response to exercise is related to preload to the heart, as indicated by plasma ANP, but unrelated to CVP. The results indicate that in upright humans, CVP reflects the gravitational influence on central venous blood rather than preload to the heart.
During exercise, neural input from skeletal muscles reflexly maintains or elevates blood pressure (BP) despite a maybe fivefold increase in vascular conductance. This exercise pressor reflex is ...illustrated by similar heart rate (HR) and BP responses to electrically induced and voluntary exercise. The importance of the exercise pressor reflex for tight cardiovascular regulation during dynamic exercise is supported by studies using pharmacological blockade of lower limb muscle afferent nerves. These experiments show attenuation of the increase in BP and cardiac output when exercise is performed with attenuated neural feedback. Additionally, there is no BP response to electrically induced exercise with paralysing epidural anaesthesia or when similar exercise is evoked in paraplegic patients. Furthermore, BP decreases when electrically induced exercise is carried out in tetraplegic patients. The lack of an increase in BP during exercise with paralysed legs manifests, although electrical stimulation of muscles enhances lactate release and reduces muscle glycogen. Thus, the exercise pressor reflex enhances sympathetic activity and maintains perfusion pressure by restraining abdominal blood flow, while brain, skin and muscle blood flow may also become affected because the reflex ‘resets’ arterial baroreceptor modulation of vascular conductance, making BP the primarily regulated cardiovascular variable during exercise.
Purpose
During cycling, the variation in cardiac stroke volume (SVV) is similar to that at rest. However, SVV may be influenced by ventilation at the start of cycling, e.g., by a Valsalva-like ...maneuver used to stabilize the body. This study evaluated the influence of ventilation on SV during initiation of cycling.
Methods
Ten healthy recreationally physical active males (mean ± SD: age 26 ± 3 years, height 184 ± 9 cm, weight 85 ± 9 kg) cycled on an ergometer for four 30 s intervals at submaximal workloads while synchronizing ventilatory and cardiovascular variables derived from gas exchange and arterial pulse contour analysis, respectively.
Results
At exercise onset, cardiac output increased by an instantaneous rise in heart rate and SV (
P
< 0.05). In contrast, blood pressure increased only after 15 s (
P
< 0.05), reflected in a decline in total peripheral resistance from exercise onset (
P
< 0.05). SVV was similar at rest (20 ± 6%) and during exercise (21 ± 5%) except for the first 5 s of exercise when a ~ 2.5-fold elevation (47 ± 6%;
P
< 0.05) was correlated to variation in respiratory frequency (= 0.71,
P
= 0.02) and tidal volume (
R
= 0.66,
P
= 0.04) but not to variation in heart rate or blood pressure. Stepwise multiple regression analysis indicated a respiratory frequency influence on SVV at the onset of ergometer cycling.
Conclusion
The data provide evidence for a ventilatory influence on SVV at the onset of cycling exercise.
This study evaluated whether administration of hydroxyethyl starch (HES) 130/0.4 affects coagulation competence and influences the perioperative blood loss.
Artificial colloids substitute blood ...volume during surgery; with the administration of HES 130/0.4 (Voluven, Fresenius Kabi, Uppsala, Sweden) only a minor effect on coagulation competence is expected.
Eighty patients were scanned for enrollment in the study, and 40 patients fulfilled the inclusion criteria. Two patients withdrew their consent to participate in the study, and 5 patients were excluded. Thus, 16 patients were randomized to receive lactated Ringer's solution and 17 to receive HES 130/0.4.
Among the patients receiving HES 130/0.4, thrombelastography indicated reduced clot strength (P < 0.001) and blinded evaluation of the perioperative blood loss was 2.2 (range 0.5 to 5.0) versus 1.4 (range 0.5 to 2.4) L in the patients who received HES 130/0.4 or lactated Ringer, respectively (P < 0.038). The patients in the lactated Ringer's group, however, received more fluid (P < 0.0001) than those in the HES 130/0.4 group. There was no significant difference between the 2 groups with regard to frequency of reoperations or the length of hospital stay, but use of HES 130/0.4 was both more expensive and less efficacious than the use of lactated Ringer.
Administration of HES 130/0.4 reduced clot strength and perioperative hemorrhage increased by more than 50%, while administration of lactated Ringer's solution provoked an approximately 2.5 times greater positive volume balance at the end of surgery.
Summary
Most near‐infrared spectroscopy (NIRS) apparatus fails to isolate cerebral oxygenation from an extracranial contribution although they use different source‐detector distances. Nevertheless, ...the effect of different source‐detector distances and change in extracranial blood flow on the NIRS signal has not been identified in humans. This study evaluated the extracranial contribution, as indicated by forehead skin blood flow (SkBF) to changes in the NIRS‐determined cerebral oxyhaemoglobin concentration (O2Hb) by use of a custom‐made multidistance probe. Seven males (age 21 ± 1 year) were in a semi‐recumbent position, while extracranial blood flow was restricted by application of four different pressures (+20 to +80 mmHg) to the left temporal artery. The O2Hb was measured at the forehead via a multidistance probe (source‐detector distance; 15, 22·5 and 30 mm), and SkBF was determined by laser Doppler. Heart rate and blood pressure were unaffected by application of pressure to the temporal artery, while SkBF gradually decreased (P<0·001), indicating that extracranial blood flow was manipulated without haemodynamic changes. Also, O2Hb gradually decreased with increasing applied pressure (P<0·05), and the decrease was related to that in SkBF (r = 0·737, P<0·01) independent of the NIRS source to detector distance. These findings suggest that the NIRS‐determined cerebral oxyhaemoglobin is affected by change in extracranial blood flow independent of the source‐detector distance from 15 to 30 mm. Therefore, new algorithms need to be developed for unbiased NIRS detection of cerebral oxygenation.
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