Mini Review
Neuroendocrine function and chronic inflammatory stress
- Michael Harbuz
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- 21 August 2002, pp. 519-525
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The factors regulating susceptibility and severity of autoimmune diseases are poorly understood. That neuroendocrine factors are critical modulators in this regard is self-evident. For example, there are major gender differences in susceptibility with women at greater risk than men of, for example, rheumatoid arthritis (RA) and multiple sclerosis (MS). The hypothalamo-pituitary-adrenal (HPA) axis has rightly attracted a considerable amount of attention. Of particular interest has been the hypothesis that susceptibility to autoimmune disease may be related to an impaired responsiveness of the HPA axis; that is, an inability to mount an appropriate cortisol response with which to down-regulate the immune system might allow the immune system to rampage unchecked and attack self. This hypothesis links regulation of the release from the adrenal gland of the potent anti-inflammatory glucocorticoids to the disease process. Endogenous glucocorticoids are crucial for the regulation of the severity of the disease process. The hypothesis proposing a link between a hyporesponsive HPA axis and susceptibility to disease is compelling. However, evidence from a number of sources has suggested that this may not be the entire story and alterations in the activity of the HPA axis have not been consistently observed in patients with RA. This review will concentrate on recent findings concerning the HPA axis in determining susceptibility to, and in regulating the severity of, inflammatory processes in autoimmune disease. These studies have revealed that a single exposure to endotoxin can confer protection to subsequent development of inflammation in an arthritis model in both neonatal and adult rats. Behavioural differences within a single population of rats are associated with differences in the plasma corticosterone responses to stress. However, relative hyporesponsiveness is not reflected by an increase in the severity of inflammation. In humans with RA the dexamethasone-corticotrophin-releasing factor (CRF) test has revealed two distinct sub-populations of patients. Studies in patients with MS have shown that this is not related to depression but rather to the severity of the disease. A better understanding of these complex neuroendocrine interactions may lead to novel clinical interventions. Experimental Physiology (2002) 87.5, 519-525.
Arterial myogenic properties of the spontaneously hypertensive rat
- Jennifer M. Hughes, Stuart J. Bund
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- 21 August 2002, pp. 527-534
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When subject to a transmural pressure gradient resistance arteries develop a spontaneous, intrinsically initiated contraction which varies according to the pressure stimulus and occurs in the absence of vasoconstrictor agonists. Such pressure-dependent active changes in vascular tone are indicative of the vascular myogenic response and contribute to autoregulation and the setting of total peripheral resistance and hence blood pressure regulation. The myogenic behaviour of blood vessels provides the background tone upon which other vasomotor influences act. Hypertension is associated with a raised vascular resistance and in this article the evidence for increased myogenic activity contributing to the raised vascular resistance is reviewed. Although there are some cases that provide evidence for exaggerated myogenic responsiveness in resistance arteries taken from hypertensive animals it is not possible to conclude that enhanced myogenic contractile responses within normal pressure ranges contribute to the raised total peripheral resistance. However, the myogenic tone of the resistance arteries of the various vascular beds is subject to differing modulatory influences in hypertensive animals and their normotensive controls which may contribute to the aetiology of hypertension. Experimental Physiology (2002) 87.5, 527-534.
Full Length Papers
A simple method for generating a blood pressure-unit activity relationship for central cardiovascular neurons in the rat
- A. Cividjian, N. Rentero, R. McAllen, L. Quintin
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- 21 August 2002, pp. 535-538
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One way to identify central cardiovascular neurons is to consider their barosensitivity, for example by plotting changes in their single unit activity as a function of evoked changes in blood pressure. To simplify the genesis of such pressure-activity relationships, a coronary angioplasty catheter was threaded into the aorta of anaesthetized rats and the balloon inflated to raise the blood pressure mechanically. Here, such a procedure is exemplified for cardiac vagal motoneurons in the medulla oblongata in eight rats. This simplification bypasses potentially problematic surgery and minimizes deterioration of the animal. Experimental Physiology (2002) 87.5, 535-538.
Early myocardial fibrosis is associated with depletion of vasoactive intestinal peptide in rat heart
- Victor Z. C. Ye, George Hodge, James L. C. Yong, Karen A. Duggan
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- 21 August 2002, pp. 539-546
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In this study we sought to determine whether early myocardial fibrosis is associated with depletion of vasoactive intestinal peptide (VIP) in the heart, thereby suggesting a possible pathogenetic role for depletion of myocardial VIP levels in the development of fibrosis in the heart. Spontaneously hypertensive rats (SHRs) and normotensive control Wistar-Kyoto rats (WKYs) were assigned randomly to low, intermediate or high sodium diets and their blood pressure was recorded twice weekly for 4 weeks. At the end of this period the rats were anaesthetised, blood was sampled for plasma VIP concentration and the hearts were harvested for histology and determination of the concentration of VIP in the heart. The degree of myocardial fibrosis increased with increasing dietary sodium intake in both the WKYs (P < 0.001) and the SHRs (P < 0.01). Myocardial VIP concentration decreased with increasing dietary sodium intake in the WKYs (P < 0.01) and in the SHRs (P < 0.01). There was a negative correlation between myocardial VIP concentration and the degree of myocardial fibrosis in both the WKYs (P < 0.0005) and the SHRs (P < 0.005). Dietary sodium intake induces myocardial fibrosis in a dose-dependent manner. Further, in early myocardial fibrosis resulting from increasing dietary sodium intake in both normotensive and hypertensive rats the concentration of VIP in the heart was negatively correlated with the degree of fibrosis. This suggests a possible role for depletion of VIP in the myocardium in the pathogenesis of myocardial fibrosis. Experimental Physiology (2002) 87.5, 539-546.
Myocardial infarction and cardiac remodelling in mice
- Fang Yang, Yun-He Liu, Xiao-Ping Yang, Jiang Xu, Alissa Kapke, Oscar A. Carretero
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- 21 August 2002, pp. 547-555
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We established a mouse model of cardiac dysfunction due to myocardial infarction (MI). For this we ligated the left anterior descending coronary artery in male C57BL/6J mice and assessed healing and left ventricular (LV) remodelling at 1, 2 and 4 days and 1, 2 and 4 weeks after MI. Echocardiography was performed at 1 and 2 weeks and 1, 2, 4 and 6 months after MI. We found that neutrophil infiltration of the infarct border was noticeable at 1-2 days. Marked macrophage infiltration occurred at day 4, while lymphocyte infiltration was apparent at 7-14 days. Massive proliferation of fibroblasts and collagen accumulation began by day 7-14, and scar formation was completed by day 21. LV diastolic dimension increased markedly at 2 weeks and remained at the same level thereafter. LV shortening fraction decreased significantly at 2 weeks and then slowly decreased. In non-infarcted areas of the LV, myocyte cross-sectional area and interstitial collagen fraction increased progressively, reaching a maximum at 4 months. This study provides important qualitative and quantitative information about the natural history of cardiac remodelling after MI in mice. Experimental Physiology (2002) 87.5, 547-555.
Renal sympathetic nerves do not modulate renal responses to haemorrhage in conscious lambs
- Francine G. Smith
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- 21 August 2002, pp. 557-562
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The present study was designed to investigate the renal responses to hypotensive haemorrhage early in life and the role of renal sympathetic nerves in modulating these renal responses. To this end, experiments were carried out in conscious, chronically instrumented lambs with either intact renal nerves (n = 7, Intact) or bilateral renal denervation performed at the time of surgery (n = 5, Denervated). Parameters of renal function were measured before and after 20 % haemorrhage (experiment 1) and 0 % haemorrhage (experiment 2), the latter serving as a time control. The two experiments were performed in random order at intervals of 24-48 h. Within 20 min of hypotensive haemorrhage in intact lambs, glomerular filtration rate decreased by ~60 %; this response was not altered by renal denervation. Since renal plasma flow remained constant after haemorrhage, the filtration fraction also decreased. After 20 % haemorrhage, urinary flow rate decreased in intact lambs; this response was also not altered by renal denervation. Excretion rates of Na+ and K+ as well as urinary osmolality and free water clearance were not altered by haemorrhage in either intact or denervated lambs. These data provide the first description of renal responses to haemorrhage early in life. In addition, the present findings provide new information that renal responses to haemorrhage early in life do not appear to be modulated by renal sympathetic nerves. Experimental Physiology (2002) 87.5, 557-562.
An arterially perfused decerebrate preparation of Suncus murinus (house musk shrew) for the study of emesis and swallowing
- Julia E. Smith, Julian F. R. Paton, Paul L. R. Andrews
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- 21 August 2002, pp. 563-574
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Arterially perfused, decerebrate preparations of the insectivore, Suncus murinus were made to determine whether the emetic reflex could be activated in such a preparation using a range of stimuli shown to be emetic in conscious or anaesthetised Suncus. Efferent phrenic and vagus nerve activities and electromyograms (EMGs) from the temporalis, abdominal oesophagus and trapezius muscles were recorded, as well as longitudinal shortening of the oesophagus and dorso-ventral movements of the thorax. The preparations swallowed spontaneously every 0.6 to 6.5 min. The duration of a swallow was 3.1 ± 0.3 s (recorded as the time taken for the oesophagus to shorten and recover to its resting position) and the oesophagus shortened by 3.5 ± 0.4 mm during a swallow. The emetic reflex was activated by electrical stimulation (30 Hz, 10-20 V, 0.2 ms pulse width, for 30 s) of abdominal vagal afferents (latency < 30 s) or by arterial perfusion with either 40 nM of the capsaicin analogue resiniferatoxin (latency 1.7 ± 0.6 min), 6 µM nicotine (latency 1.6 ± 0.1 min) or 1 µM of the phosphodiesterase IV inhibitor CP-80,633 (latency 8.9 ± 3.9 min). These emetic stimuli produced somatic and visceral movements in Suncus preparations indicative of activation of the emetic reflex. There were pronounced contractions of the thorax that occurred simultaneously with oesophageal shortening and mouth opening, separated by thorax expansion and a burst of phrenic nerve activity. During emetic-like episodes, oesophageal shortenings were only 0.84 ± 0.1 s in duration, faster than the duration of shortening observed during swallowing (cf. swallowing, 3.1 ± 0.3 s; P < 0.0001). The shortening of the oesophagus during emetic-like episodes was 6.2 ± 0.4 mm, which was greater than the shortening seen during swallowing (cf. swallowing, 3.5 ± 0.4 mm; P < 0.0001). We conclude that the emetic reflex can be activated in our Suncus preparations and that this non-sentient small adult animal model can now be used to study the neurophysiology and pharmacology of swallowing and emesis. Experimental Physiology (2002) 87.5, 563-574.
Expression of sarco(endo)plasmic reticulum Ca2+-ATPase slow (SERCA2) isoform in regenerating rat soleus skeletal muscle depends on nerve impulses
- E. Germinario, A. Esposito, M. Midrio, R. Betto, D. Danieli-Betto
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- 21 August 2002, pp. 575-583
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We have examined the influence of innervation on the expression of different isoforms of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) in regenerating rat slow twitch muscle. The process of degeneration/ regeneration was induced by injection of bupivacaine into rat soleus muscle under four different conditions: (1) in the presence of intact motor nerves, (2) after surgical denervation, (3) with nerve impulse conduction blocked by the Na+-channel blocker tetrodotoxin (TTX), and (4) with the axoplasmic flow blocked by vinblastine. Expression of SERCA isoforms was visualized by immunohistochemical and Western blot analysis. In regenerating innervated muscle, SERCA1, the isoform normally expressed in fast twitch fibres, was present after 5 days and was then progressively replaced by SERCA2, the isoform typical of slow twitch fibres. The maximum Ca2+ uptake, measured in single skinned fibres regenerating for 10-21 days, was similar to that of slow adult fibres and significantly lower than that of fast adult fibres. Denervation or TTX treatment prevented the expression of the SERCA2 isoform. Conversely, vinblastine did not affect the expression of SERCA isoforms. These data indicate that nerve impulses play a determinant role in the expression of the SERCA2 isoform. Experimental Physiology (2002) 87.5, 575-583.
Glucose infusion attenuates muscle fatigue in rat plantaris muscle during prolonged indirect stimulation in situ
- Antony D. Karelis, François Péronnet, Phillip F. Gardiner
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- 21 August 2002, pp. 585-592
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Carbohydrate ingestion increases both endurance time to exhaustion during prolonged exercise, and the ability to perform resistance exercise. The mechanism(s)underlying the increased performance following glucose ingestion remain(s) unclear. The purpose of the present study was to verify the hypothesis that glucose infusion could attenuate peripheral muscle fatigue in the anaesthetized rat during prolonged indirect electrical stimulation in situ. For this purpose the plantaris muscle was electrically stimulated (50 Hz for 200 ms every 2.7 s; 5 V; pulse width, 0.05 ms) in situ through the sciatic nerve to perform concentric contractions for 60 min while infusing intravenously either saline alone (7.25 ml kg-1 h-1), or saline and glucose (1 g kg-1 h-1: plasma glucose 11 ± 1.1, vs. 4.9 ± 0.2 mM with infusion of saline) (8 rats per group). Glucose infusion attenuated the reduction in submaximal peak dynamic force (55 % decrease vs. 70 % decrease in rats infused with saline alone, P < 0.05). In a third group of rats (n = 8), infusion of glucose 30 min after the start of stimulation partially restored submaximal peak dynamic force (P < 0.05). Maximum dynamic and isometric forces at the end of the period of stimulation were also higher (P < 0.05) in rats infused with glucose (4.0 ± 0.2 and 4.3 ± 0.2 N, respectively) than saline alone (3.0 ± 0.2 and 3.5 ± 0.2 N, respectively). The beneficial effect of glucose infusion on peripheral muscle force during prolonged stimulation was not associated with a reduction in muscle glycogen utilisation, nor with a reduction of fatigue at the neuromuscular junction, as assessed through maximal direct muscle stimulation (200 Hz for 200 ms; 150 V; pulse width, 0.05 ms). However, changes in M-wave peak-to-peak amplitude, duration and total area suggest that glucose infusion, and/or the associated increase in plasma insulin concentration, may prevent the deterioration of electrical properties of the muscle fibre membrane. Experimental Physiology (2002) 87.5, 585-592.
Fatigue-induced change in corticospinal drive to back muscles in elite rowers
- Rick C. Fulton, Paul H. Strutton, Alison H. McGregor, Nick J. Davey
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- 21 August 2002, pp. 593-600
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This study examined post-exercise changes in corticospinal excitability in five 'elite' rowers and six non-rowers. Transcranial magnetic stimulation (TMS) was delivered to the motor cortex and bilateral electromyographic (EMG) recordings were made from erector spinae (ES) muscles at L3/L4 spinal level and from the first dorsal interosseous (FDI) muscle of the dominant hand. Each subject completed two exercise protocols on a rowing ergometer: a light exercise protocol at a sub-maximal output for 10 min and an intense exercise protocol at maximum output for 1 min. A trial of ten magnetic stimuli was delivered before each of the protocols and, on finishing exercise, further trials of ten stimuli were delivered every 2 min for a 16 min period. Amplitudes of motor-evoked potentials (MEPs) in each of the three test muscles were measured before exercise and during the recovery period after exercise. The non-rowers showed a brief facilitation of MEPs in ES 2 min after light and intense exercise that was only present in the elite rowers after intense exercise. In the period 4-16 min after light exercise, the mean (± S.E.M.) MEP amplitude (relative to pre-exercise levels) was less depressed in the elite rowers (79.4 ± 2.1 %) than in the non-rowers (60.9 ± 2.5 %) in the left ES but not significantly so in the right ES. MEP amplitudes in FDI were significantly larger in the elite rowers, averaging 119.0 ± 3.1 % pre-exercise levels, compared with 101.2 ± 5.8 % in the non-rowers. Pre-exercise MEP latencies were no different in the two groups. After light exercise MEP latencies became longer in the elite rowers (left ES, 16.1 ± 0.5 ms; right ES, 16.1 ± 0.4 ms; dominant FDI, 23.4 ± 0.2 ms) than in the non-rowers (left ES, 15.0 ± 0.3 ms; right ES, 15.2 ± 0.3 ms; dominant FDI, 21.5 ± 0.2 ms). There were no differences in MEP depression or latency between elite rowers and non-rowers after intense exercise. We conclude that the smaller degree of MEP depression in the elite rowers after light exercise reflects less central fatigue within corticospinal control pathways than that seen in the non-rowers. The longer latency of MEPs seen in the elite rowers may reflect recruitment of more slower-conducting fatigue-resistant motor units compared with the non-rowers. These differences may be because the energy requirements for the non-rowers during light exercise are closer to their maximum capacity, leading to more fatigue. This notion is supported by the lack of any difference between groups following intense exercise when both groups were working at their own maximum. Experimental Physiology (2002) 87.5, 593-600.
The effect of resistive breathing on leg muscle oxygenation using near-infrared spectroscopy during exercise in men
- John M. Kowalchuk, Harry B. Rossiter, Susan A. Ward, Brian J. Whipp
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- 21 August 2002, pp. 601-611
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The effect of added respiratory work on leg muscle oxygenation during constant-load cycle ergometry was examined in six healthy adults. Exercise was initiated from a baseline of 20 W and increased to a power output corresponding to 90 % of the estimated lactate threshold (moderate exercise) and to a power output yielding a tolerance limit of 11.8 min (± 1.4, S.D.) (heavy exercise). Ventilation and pulmonary gas exchange were measured breath-by-breath. Profiles of leg muscle oxygenation were determined throughout the protocol using near-infrared (NIR) spectroscopy (Hamamatsu NIRO 500) with optodes aligned midway along the vastus lateralis of the dominant leg. Four conditions were tested: (i) control (Con) where the subjects breathed spontaneously throughout, (ii) controlled breathing (Con Br) where breathing frequency and tidal volume were matched to the Con profile, (iii) increased work of breathing (Resist Br) in which a resistance of 7 cmH2O l-1 s-1 was inserted into the mouthpiece assembly, and (iv) partial leg blood flow occlusion (Leg Occl), where muscle perfusion was reduced by inflating a pressure cuff (~90 mmHg) around the upper right thigh. During Resist Br and Leg Occl, subjects controlled their breathing pattern to reproduce the ventilatory profile of Con. An ~3 min period with respiratory resistance or pressure cuff was introduced ~4 min after exercise onset. NIR spectroscopy data for reduced haemoglobin-myoglobin (Δ[Hb]) were extracted from the continuous display at specific times prior to, during and after removal of the resistance or pressure cuff. While the Δ[Hb] increased during moderate- and heavy-intensity exercise, there was no additional increase in Δ[Hb] with Resist Br. In contrast, Δ[Hb] increased further with Leg Occl, reflecting increased muscle O2 extraction during the period of reduced muscle blood flow. In conclusion, increasing the work of breathing did not increase leg muscle deoxygenation during heavy exercise. Assuming that leg muscle O2 consumption did not decrease, this implies that leg blood flow was not reduced consequent to a redistribution of flow away from the working leg muscle. Experimental Physiology (2002) 87.5, 601-611.
Myocardial response to incremental exercise in endurance-trained athletes: influence of heart rate, contractility and the Frank-Starling effect
- Darren E. R. Warburton, Mark J. Haykowsky, H. Arthur Quinney, Derrick Blackmore, Koon K. Teo, Dennis P. Humen
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- 21 August 2002, pp. 613-622
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Recent evidence indicates that endurance-trained athletes are able to increase their stroke volume (SV) throughout incremental upright exercise, probably due to a progressively greater effect of the Frank-Starling mechanism. This is contrary to the widely held belief that SV reaches a plateau at a submaximal heart rate (irrespective of fitness level), owing to a limitation in the time for diastolic filling. The purpose of this investigation was to evaluate whether endurance-trained athletes rely on a progressively greater effect of the Frank-Starling mechanism throughout incremental exercise. A secondary purpose was to evaluate the effects of postural position on the cardiovascular responses to incremental exercise. Ten male cyclists participated in this investigation. Left ventricular function was assessed throughout incremental exercise in the supine and upright positions (counterbalanced) using radionuclide ventriculography. Stroke volume increased in a linear fashion during incremental exercise in both the upright and supine positions. The increases in cardiac output (Q) throughout incremental to maximal exercise (in both the supine and upright positions) were significantly related to changes in heart rate, myocardial contractility and the Frank-Starling mechanism. Percentage changes in end-diastolic volume and SV were significantly greater in the upright position versus the supine position, reflecting an increased reliance on the Frank-Starling effect to increase Q. We conclude from this investigation that highly trained endurance athletes are able to make progressively increasing usage of the Frank-Starling effect throughout incremental exercise. Postural position has a significant effect on the relative contribution of heart rate, myocardial contractility and the Frank-Starling mechanism to the increase in Q during exercise conditions. Experimental Physiology (2002) 87.5, 613-622.
Combined oral contraceptives do not influence post-exercise hypotension in women
- Karen Birch, Nigel Cable, Keith George
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- 21 August 2002, pp. 623-632
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The aim of the present study was to examine the pattern of cardiovascular recovery from exercise in 15 women (age, 20.3 ± 1.4 years; body mass, 61.5 ± 4.3 kg) across two phases of oral contraceptive (OC) use: 21 days of consumption and 7 days of withdrawal. Cardiovascular recovery was measured in the supine position for 60 min following 30 min of exercise at 60 % maximal rate of oxygen consumption (V˙O2,max). Central and peripheral haemodynamics were assessed during consumption and withdrawal of the OC pill using occlusion plethysmography, Doppler flowmetry and echocardiography. Significant hypotension occurred following exercise (P < 0.05), returning to baseline values after 60 min. The peak hypotension occurred 5 min into recovery. Cardiac output and heart rate were elevated for 60 min following exercise (P < 0.05), whilst stroke volume remained at baseline values. Heart rate was greater throughout recovery during consumption compared to withdrawal (P < 0.05); however, although there was a trend for greater responses during consumption, phase of OC use did not affect the other central cardiovascular variables (P > 0.05). Post-exercise blood flow parameters were not significantly affected by exercise or OC phase; however, calf blood flow was greater, and resistance to flow lower during consumption (P > 0.05). The pattern of post-exercise fluctuations in cardiovascular parameters may differ from those seen in men, whilst oestrogen variation may influence research findings. Experimental Physiology (2002) 87.5, 623-632.
Changes in cerebral blood flow during and after 48 h of both isocapnic and poikilocapnic hypoxia in humans
- Marc J. Poulin, Marzieh Fatemian, John G. Tansley, David F. O'Connor, Peter A. Robbins
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- 21 August 2002, pp. 633-642
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During acclimatization to the hypoxia of altitude, the cerebral circulation is exposed to arterial hypoxia and hypocapnia, two stimuli with opposing influences on cerebral blood flow (CBF). In order to understand the resultant changes in CBF, this study examined the responses of CBF during a period of constant mild hypoxia both with and without concomitant regulation of arterial PCO2. Nine subjects were each exposed to two protocols in a purpose-built chamber: (1) 48 h of isocapnic hypoxia (Protocol I), where end-tidal PO2 (PET,O2) was held at 60 Torr and end-tidal PCO2 (PET,CO2) at the subject's resting value prior to experimentation; and (2) 48 h of poikilocapnic hypoxia (Protocol P), where PET,O2 was held at 60 Torr and PET,CO2 was uncontrolled. Transcranial Doppler ultrasound was used to assess CBF. At 24 h intervals during and after the hypoxic exposure CBF was measured and the sensitivity of CBF to acute variations in PO2 and PCO2 was determined. During Protocol P, PET,CO2 decreased by 13 % (P < 0.001) and CBF decreased by 6 % (P < 0.05), whereas during Protocol I, PET,CO2 and CBF remained unchanged. The sensitivity of CBF to acute variations in PO2 and PCO2 increased by 103 % (P < 0.001) and 28 % (P < 0.01), respectively, over the 48 h period of hypoxia. These changes did not differ between protocols. In conclusion, CBF decreases during mild poikilocapnic hypoxia, indicating that there is a predominant effect on CBF of the associated arterial hypocapnia. This fall occurs despite increases in the sensitivity of CBF to acute variations in PO2/PCO2 arising directly from the hypoxic exposure. Experimental Physiology (2002) 87.5, 633-642.