Effects Of Systemic Hypoxia Research Articles

Effects of Systemic Hypoxia on Motor Control Performance and Brain Blood Flow in Healthy, Young Humans

The brain is an oxygen dependent organ of the human body and adequate blood flow is imperative. To maintain adequate perfusion, in response to stimuli like hypoxia, vasodilation occurs. Fine motor control skills are essential, particularly for in‐flight piloting. Despite the possibility of encountering hypoxia in flight conditions, there is a lack of data on how motor control may be impacted by hypoxia and the corresponding changes in brain blood flow. We hypothesized that motor control would be impaired during hypoxia, despite increased cerebral blood flow. A group of seven subjects between the ages of 20 to 22 performed a motor control task in two counterbalanced conditions, the control (21% O2, 0.03% CO2, nitrogen balance) and the hypoxic exposure (10% O2 with nitrogen balance mix). The motor control task consisted of lateral joystick movements to adjust the angle of a computer visual beam to roll and stop a ball into one of 4 targets (40 targets total in MATLAB). Throughout each trial, heart rate (HR; 3‐lead ECG), beat‐beat arterial blood pressure (MAP; finger photoplethysmography), end‐tidal CO2 (sampling line) and bilateral middle cerebral artery velocity (MCAv; transcranial doppler), an indicator of cerebral blood flow (CBF), were measured. The motor control program recorded the time to target, beam angle, and ball velocity. In poikilocapnic conditions, hypoxic and normoxic gas mixtures were delivered via facemask and on average the subjects desaturated to an SpO2value of 84.1 ± 4.9%. Contrary to our hypothesis, hypoxia had minimal impact on motor control based on time to task completion for both individual trials and overall task (188.9 ± 21.9 s vs 194.7 ± 19.9 s p=0.613). Physiologically, as anticipated, hypoxia increased heart rate significantly in the transition from normoxic to hypoxic stimulus (86.1 ± 4.6 vs 75.7 ± 7.3 bpm; p<0.001) but was not significantly greater in hypoxic motor control (82.7 ± 9.0 bpm) than hypoxia alone (p=0.180). During the motor control task, MCAv (average of both sides) was similar in normoxic (51.6 ± 7.7 cm/sec) and hypoxic conditions (54.2 ± 8.7 cm/sec; p=0.414). However, MCA during hypoxic motor control was higher than that in hypoxic rest (49.1±10.3 cm/sec; p=0.025), whereas motor control during normoxia did not significantly increase MBV from rest (49.7 ± 7.4; p=0.17). Results were similar when analyzed based on cerebral vascular conductance (MBV/MAP). The present results suggest that mild systemic hypoxia does not impact performance in a simple motor control task, and this may be because of an increase in brain blood flow.

Effects of systemic hypoxia on human muscular adaptations to resistance exercise training.

Hypoxia is an important modulator of endurance exercise‐induced oxidative adaptations in skeletal muscle. However, whether hypoxia affects resistance exercise‐induced muscle adaptations remains unknown. Here, we determined the effect of resistance exercise training under systemic hypoxia on muscular adaptations known to occur following both resistance and endurance exercise training, including muscle cross‐sectional area (CSA), one‐repetition maximum (1RM), muscular endurance, and makers of mitochondrial biogenesis and angiogenesis, such as peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α), citrate synthase (CS) activity, nitric oxide synthase (NOS), vascular endothelial growth factor (VEGF), hypoxia‐inducible factor‐1 (HIF‐1), and capillary‐to‐fiber ratio. Sixteen healthy male subjects were randomly assigned to either a normoxic resistance training group (NRT, n =7) or a hypoxic (14.4% oxygen) resistance training group (HRT, n =9) and performed 8 weeks of resistance training. Blood and muscle biopsy samples were obtained before and after training. After training muscle CSA of the femoral region, 1RM for bench‐press and leg‐press, muscular endurance, and skeletal muscle VEGF protein levels significantly increased in both groups. The increase in muscular endurance was significantly higher in the HRT group. Plasma VEGF concentration and skeletal muscle capillary‐to‐fiber ratio were significantly higher in the HRT group than the NRT group following training. Our results suggest that, in addition to increases in muscle size and strength, HRT may also lead to increased muscular endurance and the promotion of angiogenesis in skeletal muscle.

Cerebral microvascular rarefaction induced by whole brain radiation is reversible by systemic hypoxia in mice

Whole brain radiation therapy (WBRT) leads to cognitive impairment in 40-50% of brain tumor survivors following treatment. Although the etiology of cognitive deficits post-WBRT remains unclear, vascular rarefaction appears to be an important component of these impairments. In this study, we assessed the effects of WBRT on the cerebrovasculature and the effects of systemic hypoxia as a potential mechanism to reverse the microvascular rarefaction. Transgenic mice expressing green fluorescent protein driven by the Acta2 (smooth muscle actin) promoter for blood vessel visualization were randomly assigned to control or radiated groups. Animals received a clinical series of 4.5 Gy WBRT two times weekly for 4 wk followed by 1 mo of recovery. Subsequently, mice were subjected to 11% (hypoxia) or 21% (normoxia) oxygen for 1 mo. Capillary density in subregions of the hippocampus revealed profound vascular rarefaction that persisted despite local tissue hypoxia. Nevertheless, systemic hypoxia was capable of completely restoring cerebrovascular density. Thus hippocampal microvascular rarefaction post-WBRT is not capable of stimulating angiogenesis and can be reversed by chronic systemic hypoxia. Our results indicate a potential shift in sensitivity to angiogenic stimuli and/or the existence of an independent pathway of regulating cerebral microvasculature.

Cardiovascular and renal effects of systemic hypoxia in chronically instrumented conscious WKY and SHR rats.

The effects of systemic hypoxia upon cardiovascular and renal function in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) are controversial. We examined the effects of systemic normobaric hypoxia (12.5% O2 in N2 for 4 hours) on arterial blood gases (pO2, pCO2, pH), mean arterial pressure (MAP), heart rate (HR), effective renal blood flow (ERBF), glomerular filtration rate (GFR), urine flow (UMV) and renal sodium excretion (U Na V) in conscious unilaterally nephrectomized WKY (n = 12) and SHR (n = 14) chronically instrumented with an arterial, venous and ureter cannula. In WKY hypoxia caused a reduction in arterial pO2 and pCO2 but no change in MAP and HR. In SHR hypoxia induced similar reductions in arterial blood gases, a small decrease in MAP and no change in HR. In both strains hypoxia caused significant increases in ERBF, GFR and U Na V, but insignificant changes in UMV. The hypoxia-induced natriuresis developed 90-120 min after starting the hypoxia. These data indicate that a 4-hour lasting hypoxia has profound effects on sodium excretion in conscious WKY as well as SHR. Systemic hypoxia did not cause significant changes in arterial blood pressure in both rat strains.

Effects of systemic hypoxia and lower body negative pressure on heart rate variability and transfer function gain in humans

Effects of systemic hypoxia and lower body negative pressure on heart rate variability and transfer function gain in humans

The Effects of Systemic Hypoxia on Colon Anastomotic Healing: An Animal Model

Acute postoperative systemic hypoxia occurs frequently in the clinical setting following intestinal resection, as a result of complications such as pneumonia, pulmonary edema, or the acute respiratory distress syndrome. Although it is well established that oxygen is essential for metabolism in general and intestinal anastomotic healing, the mechanisms by which systemic hypoxia affect this process are not clear. The purpose of this study was to establish an animal model to simulate acute systemic hypoxia and to examine the effects on anastomotic healing. We investigated the hypothesis that systemic hypoxia impairs anastomotic healing in the colon by disrupting revascularization via changes in the expression of two putative angiogenic factors: inducible nitric oxide synthase and vascular endothelial growth factor. Phase I: Juvenile male Sprague-Dawley rats underwent carotid artery cannulation. In a controlled environment the FiO2 was incrementally decreased from 21 to 9 percent and the resultant PaO2 measured. Phase II: Animals underwent colonic transection with immediate reanastomosis and were placed in either a normoxic (FiO2 21 percent) or hypoxic (FiO2 11 percent) environment for seven days. Perianastomotic in vivo tissue oxygen saturation was measured before segmental colon resection in each of the animals and at seven days before measurement of anastomotic bursting pressure. Perianastomotic tissue samples were assessed by Western blot assay for the expression of vascular endothelial growth factor and inducible nitric oxide synthase protein. Sections from each tissue sample were taken and evaluated by a pathologist blinded to treatment group for determination of anastomotic healing score. Phase I: Incrementally decreasing the FiO2 resulted in a progressive decrease in PaO2 (r2 = 0.77). Phase II: Animals maintained in a hypoxic environment had a significant decrease in tissue oxygen saturation (73 +/- 9 percent vs. 94 +/- 3 percent; P < 0.0001) and anastomotic bursting pressure (118 +/- 18 mmHg vs. 207 +/- 30 mmHg; P < 0.0001) compared with normoxic controls. Systemic hypoxia induced a significant increase, when compared with normoxic controls, in vascular endothelial growth factor (247.1 +/- 9.5 vs. 142.2 +/- 10.6; P < 0.0001) and inducible nitric oxide synthase (259.6 +/- 21.1 vs. 120.2 +/- 10.9; P < 0.0001) protein expression and led to a significant decrease in the overall wound-healing score. This study validates a new animal model to study the effects of acute systemic hypoxia on colonic anastomotic healing. In this model, systemic hypoxia directly translated into local tissue hypoxia, and anastomotic healing was impaired. Contrary to our original hypothesis, hypoxia led to a significant increase in vascular endothelial growth factor and inducible nitric oxide synthase protein expression at the colonic anastomotic site. Impairment in anastomotic integrity despite upregulation of these angiogenic factors could be a result of the inability of wounded tissue to respond to vascular endothelial growth factor and inducible nitric oxide synthase or alternatively, hypoxia may adversely affect collagen synthesis and deposition directly.

Phentolamine suppresses the increase in arteriolar vasomotion frequency due to systemic hypoxia in hamster skeletal muscle microcirculation

Systemic hypoxia (8%, 11% and 15% oxygen gas mixture inspiration) has been shown to increase the frequency of arteriolar rhythmic diameter changes in hamster skeletal muscle microcirculation. The effects of phentolamine on vasomotion frequency during systemic hypoxia were studied in Syrian hamsters implanted with a plastic chamber in the dorsum skin. Phentolamine (50 μg/100 g body wt.) was injected intravenously before the 20-min exposure to 11% oxygen gas mixture. The microvessels were studied with a fluorescent microscopy technique, using fluorescein isothiocyanate bound to dextran (mol. wt. 150,000) as a tracer. Vessel diameters were measured with a shearing method. Fourier transform and autoregressive modeling were used to assess the time variant features of diameter changes. Under baseline conditions, the arterioles were characterized by rhythmic diameter changes with fundamental frequency related to vessel size. The terminal branchings were dominated by order 3 vessel activity (frequency: 0.08–0.16 Hz) spreading downstream to all daughter arterioles. Systemic hypoxia caused an increase in vasomotion frequency of order 3 arterioles up to 0.3–0.5 Hz (average: 0.40±0.06 Hz) and a significant decrease in mean diameter (−28±5%). Phentolamine completely suppressed the rhythmic changes in diameter of order 3 arterioles that dilated significantly (+30±4%). Therefore, the effects of systemic hypoxia on arteriolar vasomotion appear to be triggered by an increase in sympathetic nervous discharge that induces a rise in frequency up to 0.3–0.5 Hz.

Effects of systemic hypoxia on R-R interval and blood pressure variabilities in conscious rats.

The effects of systemic hypoxia with different levels of CO2 on R-R interval (RRI) and systolic blood pressure (SBP) variabilities were investigated in conscious rats. Wistar rats chronically instrumented for the measurement of blood pressure, electrocardiogram, and renal sympathetic nerve activity (RSNA) were exposed to hypocapnic (Hypo), isocapnic (Iso), and hypercapnic (Hyper) hypoxia. On another day, the rats were treated with atropine and exposed to the same type of hypoxia. Sinoaortic denervation (SAD)-treated rats were exposed to Iso and Hyper, and RRI and SBP variabilities before and during hypoxia were analyzed using the maximum-entropy method with high resolution. With regard to RRI variability, very low frequency (VLF), low frequency (LF), and high frequency (HF) powers all decreased during Hypo, increased during Hyper, and did not change during Iso in intact rats. Changes during Hypo were attenuated by atropine, and those during Hyper were abolished by either atropine or SAD. The ratio of LF power to HF power decreased independently of increases in RSNA during each type of hypoxia. On the other hand, there were no changes in VLF, LF, or HF power in SBP variability during each type of hypoxia in intact rats. In atropine-treated rats, LF power increased during Iso and Hyper and HF power increased during each type of hypoxia. There was no difference in respiratory frequency among the three kinds of hypoxia in both intact and atropine-treated rats. The results suggest that arterial PCO2 level rather than respiration frequency produces changes in powers of RRI variability through changes in parasympathetic nerve activity and that with regard to SBP variability, parasympathetic nerve activity masks changes in LF power that reflect an increase in RSNA and those in HF power that reflect a mechanical consequence of respiration.

The effects of systemic hypoxia on renal function in the anaesthetized rat.

1. In rats anaesthetized with Saffan, renal function was monitored from the left kidney from the 5th minute of spontaneous breathing of 12% O2 for two 20 min periods and during air breathing before, between and after the hypoxic periods. Two groups of animals (I and II) were used, each group comprising two subgroups in which the left kidney was innervated or denervated, respectively; in Group II, renal perfusion pressure (RPP) was maintained during the 2nd hypoxic period by occl97uding the distal aorta. 2. In both subgroups of Group I, both hypoxic periods produced hyperventilation, arterial PO2 falling to approximately 50 mmHg. Concomitantly, mean arterial pressure (MABP) fell by similar extents (approximately 23%, from a baseline level of 140 mmHg during the 2nd hypoxic period). In the innervated subgroup, renal vascular conductance (RVC) increased, but glomerular filtration rate (GFR) fell (by 48 and 6%, respectively, during the 2nd hypoxic period), while urine flow, absolute sodium excretion (UNaV) and fractional sodium excretion (FENa) fell (by 52, 63 and 61%, respectively). Baseline urine flow, UNaV and FENa were higher in the denervated subgroup, but hypoxia produced similar percentage changes from baseline in all variables. 3. In Group II, both subgroups showed similar changes during the 1st hypoxic period as the corresponding subgroups of Group I. However, during the 2nd hypoxic period when the fall in MABP was reduced to approximately 7%, the increase in RVC persisted only in the denervated subgroup; there was no significant change in GFR, urine flow, UNaV or FENa in either subgroup. 4. These results indicate that, in the rat, moderate hypoxia produces antidiuresis and antinatriuresis that are not dependent on the renal nerves, but are dependent on the hypoxia-induced fall in MABP. The fall in renal perfusion pressure (RPP) may directly determine renal function, but reflex influences upon the kidney initiated by, for example, arterial baroreceptor unloading, may play a role. The fall in GFR and increase in RVC, which persisted after denervation or when renal perfusion was controlled, implies a local dilatatory influence acting preferentially on the efferent arterioles.

Response of the medullary respiratory network of the cat to hypoxia.

1. The effect of systemic hypoxia was tested in anaesthetized, immobilized, thoracotomized and artificially ventilated cats with peripheral chemoreceptor afferents either intact or cut. Extracellular recordings from different types of medullary respiratory neurones and intracellular recordings from stage 2 expiratory neurones were made to determine the hypoxia-induced changes in neuronal discharge patterns and postsynaptic activity as an index for the disturbances of synaptic interaction within the network. 2. The general effect of systemic hypoxia was an initial augmentation of respiratory activity followed by a secondary depression. In chemoreceptor-denervated animals, secondary depression led to central apnoea. 3. The effects of systemic hypoxia were comparable with those of cerebral ischaemia following occlusion of carotid and vertebral arteries. 4. In chemoreceptor-denervated animals, all types of medullary respiratory neurones ceased spontaneous action potential discharge during hypoxia. 5. Reversal of inhibitory postsynaptic potentials (IPSPs) and/or blockade of IPSPs was seen after 2-3 min of hypoxia. 6. During hypoxia, the membrane potential of stage 2 expiratory neurones showed a slight depolarization to -45 to -55 mV and then remained stable. 7. The neurone input resistance increased initially and then decreased significantly during central apnoea. 8. Rhythmogenesis of respiration was greatly disturbed. This was due to blockade of IPSPs and, in some animals, to more complex disturbances of phase switching from inspiration to expiration. 9. Central apnoea occurred while respiratory neurones were still excitable as shown by stimulus-evoked orthodromic and antidromic action potentials. 10. The results indicate that the medullary respiratory network is directly affected by energy depletion. There is indication for a neurohumoral mechanism which blocks synaptic interaction between respiratory neurones in chemoreceptor-intact animals.

Effects of systemic hypoxia on the distribution of cardiac output in the rat.

1. Studies were made in unanaesthetized rats of cardiovascular responses induced during 3 min periods of systemic hypoxia (inspirate 8 or 6% O2). Arterial pressure and heart rate were recorded continuously; cardiac index and regional blood flows were measured in normoxia and at the 2nd min of hypoxia by injection of radiolabelled microspheres. Comparisons are made with changes recorded in Saffan-anaesthetized rats during 8% O2 using microspheres and in previous studies using electromagnetic transducers on renal, mesenteric and femoral arteries (Marshall & Metcalfe, 1988a). 2. In unanaesthetized rats, the initial 1-1.5 min of hypoxia evoked behavioural arousal associated with a short-lasting rise in arterial pressure and heart rate. This agrees with our previous proposal that hypoxia activates the brain stem defence areas by stimulating peripheral chemoreceptors. 3. In unanaesthetized rats, these changes were superimposed upon a gradual fall in arterial pressure and tachycardia, the responses being greater during 6 than 8% O2 (cf. Saffan-anaesthetized rats). Further, in all rats at the 2nd min of hypoxia, cardiac index and vascular conductance of most body tissues was increased. It is concluded that the fall in arterial pressure is due to peripheral vasodilatation. 4. In the unanaesthetized rats, the tendency for vascular conductance in kidney, intestine and gastrocnemius muscle to increase (more during 6 than 8% O2) allowed increases in blood flow in the last two regions. These changes accord with those recorded under Saffan anaesthesia. 5. In both unanaesthetized and anaesthetized rats, hypoxia induced pronounced increases in vascular conductance of diaphragm, adrenal gland, cerebral hemispheres, cerebellum and brain stem, the resultant increases in blood flow being larger in the unanaesthetized rats. 6. It is proposed that in unanaesthetized, as in anaesthetized, rats the regional dilator responses predominantly reflect the local dilator effects of tissue hypoxia. Possible dilator factors are considered.

Neural effects of systemic hypoxia and hypercapnia on hindlimb vascular resistance in acute spinal cats.

The effects of systemic hypoxia and hypercapnia on the neurogenic component of hindlimb vascular resistance were studied in 10 unanesthetized acute Cl spinal cats. Hindlimb perfusion pressure (PP) was measured under conditions of constant flow of normoxic and normocapnic blood from a donor cat. Ventilation with 5% CO2 and 10% CO2 in O2 caused increases in PP of 15 +/- 2 (mean +/- SE) mm Hg and 27 +/- 3 mm Hg from a control level of 106 +/- 6 mm Hg during ventilation with 100% O2. Changing the inspired gas mixture from 95% O2 plus 5% CO2 to 12.5%, 10%, 7.5%, or 5% O2 plus 5% CO2 in N2 caused increases in PP of 1.5 +/- 1, 14 +/- 2, 38 +/- 6, and 69 +/- 15 mm Hg respectively from a control level of 121 +/- 9 mm Hg. These vasoconstrictor effects were abolished by ganglionic blockade with hexamethonium (10 mg/kg iv). We conclude that in the acute Cl spinal cat a large part of the population of sympathetic preganglionic neurons in the lumbar spinal cord, controlling vascular smooth muscle of the hindlimb, is excited by systemic hypoxia or hypercapnia over a considerable range of PaO2 and PaCO2 values.

Neural effects of systemic hypoxia on hindlimb vascular resistance in sinoaortic-denervated cats

The effects of systemic hypoxia on the neurogenic component of hindlimb vascular resistance were studied in six sinoaortic-denervated, anesthetized cats with intact central nervous system. Hindlimb perfusion pressure (PP) was measured under conditions of constant flow of normoxic blood from a donor cat. The neural component of the PP was estimated from the change in PP upon administration of hexamethonium (10 mg/kg i.v.). Ventilation of the recipient cat with 12.5% and 10% O2 was associated with an average 35 +/- 15% (SEM) and 13 +/- 10% decrease, respectively, of the estimated neural component of the PP. In contrast ventilation with 7.5% and 5% O2 produced increases of 27 +/- 7% and 58 +/- 10%, respectively, of the estimated neural component of the PP. Both the vasodilator and vasoconstrictor responses were abolished by hexamethonium (10 mg/kg i.v.). The vasodilator response appeared to be due to withdrawal of alpha-adrenergic tone since it was eliminated by constant infusion of phentolamine to the hindlimb (45 micrograms/ml blood/min). We conclude that, in addition to the already known sympatho-excitation seen in the sinoaortic-denervated cat during severe systemic hypoxia, there is also a sympatho-depressant effect which dominates at more moderate levels of systemic hypoxia.

Prostaglandins in the control of blood flow in canine skeletal muscle.

SUMMARY1. The effects of systemic hypoxia, arterial occlusion and muscle exercise on blood flow and oxygen uptake of the hind limb of anaesthetized areflexic dogs were assessed. The control responses were compared to those elicited after administration of meclofenamic acid (2 mg/kg, i.v.).2. Meclofenamic acid reduced resting blood flow by approximately 20%.3. The increase in blood flow during 6 min periods of hypoxia was inversely related to arterial oxygen saturation and this relationship was not altered significantly by meclofenamic acid.4. The magnitude of the reactive hyperaemias following arterial occlusion for 5‐40 s was dependent on the occlusion time. The peak changes in vascular conductance relative to the resting values were similar before and after administration of meclofenamic acid.5. Direct stimulation of the muscles of the hind limb with 0.5‐5 Hz produced frequency‐dependent increases in blood flow and oxygen uptake to the limb. Although these responses were depressed after meclofenamic acid, the relationship between blood flow and oxygen uptake was not changed. The responses to stimulation with 10 Hz were not affected by meclofenamic acid.6. An isolated chick rectum, superfused with re‐oxygenated venous blood from the hind limb during muscle stimulation at 10 Hz showed an initial relaxation, followed by contraction. The contraction was abolished after administration of meclofenamic acid.7. From these results it appears that the release of prostaglandins is not essential for hyperaemais associated with vessel occlusion, systemic hypoxia or muscle exercise.

Systemic hypoxia and hyperoxia, and liver blood flow and oxygen consumption in the greyhound.

The effects of systemic hypoxia upon liver blood flow and oxygen consumption were studied in a group of six pentobarbitone anaesthetised greyhounds. The effect of systemic hyperoxia upon the same factors were also studied in a further group of six greyhounds.

Effects of sytemic hypoxia and hypercapnia on cutaneous and muscle vasoconstrictor neurones to the cat's hindlimb.

1. Reactions of cutaneous and muscle vasoconstrictor neurones to the hindlimb on systemic hypoxia and systemic hypercapnia were investigated in chloralose anaesthetized cats. Mainly four types of preparations were used: brain intact and decrebrate (pontomedullary) animals with and without carotid sinus (CSN) and vagal nerves (VN). 2. In brain intact animals with intact CSN and VN most cutaneous vasoconstrictor neurones were depressed and most muscle vasoconstrictor neurones were excited during systemic hypoxia and hypercapnia. The responses to hypercapnia were smaller than those to hypoxia. 3. In brain intact deafferented animals and in decerebrate animals with and without intact CSN and VN systemic hypoxia and hypercapnia induced excitation in both cutaneous and muscle vasoconstrictor neurones. The responses to hypoxia were significantly smaller in deafferented preparations when compared to those in preparations with intact CSN and VN. Furthermore in muscle vasoconstrictor neurones the size of the responses was not significantly different in decerebrate preparations from that in brain intact preparations. 4. These results indicate a distinct neuronal organization of the chemoreceptor reflexes in the vasoconstrictor systems in the brain stem. Suprapontine brain structures are most important for producing the inhibition of the cutaneous vasoconstrictor neurones during hypoxia and hypercapnia.