Biomedical subjects

J M Marshall

Publications and source records attributed to J M Marshall.

At least 19 recordsLinked to original sources

PubMed2004

The role of platelet activating factor in a neonatal piglet model of necrotising enterocolitis.

BACKGROUND AND AIMS: Necrotising enterocolitis (NEC) is a potentially devastating disorder of preterm infants but its aetiology remains unclear. The aim of these studies was to develop a neonatal piglet model for NEC and to then use the model to investigate the role of platelet activating factor (PAF) in its pathogenesis. METHODS: Anaesthetised newborn piglets were divided into six groups: (i) controls, and groups subjected to (ii) hypoxia, (iii) lipopolysaccharide (LPS), (iv) hypoxia+LPS, (v) hypoxia+LPS and the PAF antagonist WEB 2170, and (vi) PAF. Arterial blood pressure (ABP), superior mesenteric artery blood flow (MBF), mesenteric vascular conductance (MVC), and arterial blood gases were recorded, and intestinal histology was evaluated. RESULTS: Exposure to LPS, hypoxia+LPS, or PAF all caused haemorrhagic intestinal lesions associated with varying degrees of intestinal injury. PAF caused a significant initial decrease in both MVC and MBF whereas hypoxia+LPS caused a significant late reduction in ABP and MBF with a trend towards a decrease in MVC. The effects of hypoxia+LPS on both haemodynamic changes and intestinal injury were ameliorated by WEB 2170. CONCLUSIONS: Administration of hypoxia and LPS or of PAF in the neonatal piglet induces haemodynamic changes and intestinal lesions that are consistent with NEC. These effects are ameliorated by prior administration of WEB 2170, indicating an important role for PAF in the pathogenesis of NEC.

Animals↗

PubMed2002

Chronic hypoxia induces prolonged angiogenesis in skeletal muscles of rat.

Skeletal muscle capillarity and fibre cross-sectional area were investigated within and between diaphragm (Diaph), extensor digitorum longus (EDL), soleus (SOL) and tibialis anterior (TA) muscles of control and chronic hypoxic (12 % O(2) for 6 weeks) adult male Wistar rats (final body mass approximately 355 g). Cryostat sections were stained for alkaline phosphatase activity to depict all capillaries, and for succinic dehydrogenase to demonstrate regional differences in oxidative capacity within the muscles. Hypoxia-induced angiogenesis occurred in all muscles (P < 0.01), with capillary-to-fibre ratio (C:F) being higher in the more active and oxidative muscles, Diaph (27 %) and SOL (26 %), than phasically active and glycolytic muscles, TA (21 %) and EDL (15 %). Diaph, SOL and EDL maintained fibre size, and hence showed an increased capillary density (CD) and reduced intramuscular diffusion distance (DD), whereas TA showed fibre hypertrophy and maintained CD and DD compared to control muscles. The extent of angiogenesis among different regions of muscle varied so as to suggest that muscle fibre size has an additional influence on capillary growth during chronic systemic hypoxia, which is progressive over an extended period of systemic hypoxia.

Animals↗

PubMed2001

Oxygen delivery and oxygen consumption in rat hindlimb during systemic hypoxia: role of adenosine.

1. In anaesthetised rats, the increase in femoral vascular conductance (FVC) evoked by moderate systemic hypoxia is mediated by adenosine acting on A(1) receptors. It is also nitric oxide (NO) dependent: it is attenuated by NO synthase (NOS) inhibition, but restored when baseline FVC is restored by sodium nitroprusside (SNP), a NO donor. However, under these conditions there was in increase in the critical O(2) delivery (D(O2,crit)) at which hindlimb O(2) consumption (V(O2)) becomes directly dependent upon O(2) delivery (D(O2)), indicating that V(O2) is regulated by newly synthesised NO. 2. In the present study, after NOS inhibition, when baseline FVC was restored with SNP infusion, the increases in FVC evoked by breathing 12 and 8 % O(2) were reduced by the A(1) receptor antagonist DPCPX, by 60 and 40 %, respectively (n = 8). The A(2A) receptor antagonist ZM241385 reduced the FVC increase evoked by 12 % O(2) (by 45 %, n = 8), but did not alter that evoked by 8 % O(2). 3. DPCPX also reduced the increases in FVC evoked by graded systemic hypoxia, breathing 14-6 % O(2) and increased D(O2,crit), from 0.64 +/- 0.06 to 0.95 +/- 0.07 ml O(2) min(-1) kg(-1) (control vs. DPCPX). However, ZM241385 (n = 8) had no effect on the FVC increases or on D(O2,crit) (0.70 +/- 0.02 ml O(2) min(-1) kg(-1), n = 8). 4. Thus, the increases in FVC evoked by mild to severe systemic hypoxia are mediated by A(1) receptors. These responses, which are attributable to proximal arteriolar dilatation, help maintain D(O2). Even after NOS inhibition, adenosine still increases FVC via A(2A) (moderate hypoxia only) and A(1) receptors, providing baseline levels of NO are present. Furthermore, adenosine, acting via A(1) receptors, is important in determining D(O2,crit) and therefore in maintaining V(O2). We propose that this is achieved by A(1)-evoked dilatation of terminal arterioles and is mediated by increased synthesis of NO.

Adenosine↗

PubMed2001

Vasodilatation, oxygen delivery and oxygen consumption in rat hindlimb during systemic hypoxia: roles of nitric oxide.

We have investigated the relationship between O2 delivery (DO2) and O2 consumption (VO2) in hindlimb muscle of anaesthetised rats during progressive systemic hypoxia. Since muscle vasodilatation that occurs during hypoxia is nitric oxide (NO) dependent, we examined the effects of the NO synthase (NOS) inhibitor nitro-L-arginine methyl ester (L-NAME). In control rats (n = 8), femoral vascular conductance (FVC) increased at each level of hypoxia. Hindlimb DO2 decreased with the severity of hypoxia, but muscle VO2 was maintained until the critical DO2 value (DO2,crit) was reached at 0.64 +/- 0.06 ml O2 min-1 kg-1; below this VO2 declined linearly with DO2. This is a novel finding for the rat but is comparable to the biphasic relationship seen in the dog. In another group of rats (n = 6), L-NAME caused hindlimb vasoconstriction and attenuated the hypoxia-evoked increases in FVC DO2 was so low after L-NAME administration that VO2 was dependent on DO2 at all levels of hypoxia. In a further group (n = 8), femoral blood flow and DO2 were restored after L-NAME by infusion of the NO donor sodium nitroprusside (20 g x kg(-1) x min(-1). Thereafter, hypoxia-evoked increases in FVC were fully restored. Nevertheless, DO2,crit was increased relative to control (0.96 +/- 0.07 ml O2 min(-1) x kg(-1), P < 0.01). As NOS inhibition limited the ability of muscle to maintain VO2 during hypoxia, we propose that hypoxia-induced dilatation of terminal arterioles, which improves tissue O2 distribution, is mediated by NO. However, since the hypoxia-evoked increase in FVC was blocked by L-NAME but restored by the NO donor, we propose that the dilatation of proximal arterioles is dependent on tonic levels of NO, rather than mediated by NO.

Animals↗

PubMed2001

Roles of adenosine and nitric oxide in skeletal muscle in acute and chronic hypoxia.

In experiments on anaesthetised rats, the roles played by adenosine and nitric oxide (NO) were determined in resting skeletal muscle in acute systemic hypoxia and during acclimation to chronic systemic hypoxia. It is concluded that adenosine acting on A1 receptors, at least in part in an NO-dependent manner, plays essential roles in causing the dilation of proximal and terminal arterioles that helps to maintain muscle O2 consumption when O2 delivery is reduced by acute systemic hypoxia. It is proposed that adenosine and NO are similarly responsible for causing the tonic vasodilation that gradually wanes in the first 7 days of chronic hypoxia and that concomitantly, adenosine and hypoxia stimulate VEGF expression, so increasing venular permeability and triggering angiogenesis. By 7 days of chronic hypoxia, arteriolar remodelling is well established and within 18-21 days, substantial capillary angiogenesis alleviates tissue hypoxia. At this time, vasoconstrictor responses to the sympathetic transmitter norepinephrine are reduced, but dilator responses to adenosine released by acute hypoxia are enhanced, as may be explained by increased sensitivity to NO. Thus, preservation of tissue oxygenation is apparently associated with impaired ability to regulate arterial pressure and vulnerability to further hypoxia.

Acute Disease↗

PubMed2001

Symptoms of musculoskeletal disorders in stage rally drivers and co-drivers.

BACKGROUND: During stage rallying, musculoskeletal injuries may be provoked by the high magnitude of vibration and shock to which the driver and co-driver are exposed. Drivers and co-drivers experience similar exposure to whole body mechanical shocks and vibration but different exposure to hand/wrist stressors. OBJECTIVES: To investigate by a questionnaire study the prevalence of symptoms of musculoskeletal injuries after rallying in 13 professional and 105 amateur stage rally competitors. METHODS: The self administered questionnaire investigated whole body and hand/wrist symptoms of musculoskeletal injury. It was loosely based on the Nordic design. RESULTS: 91% of participants who competed or tested for more than 10 days a year (n=90) reported discomfort in at least one body area after rallying. Problems in the lumbar spine (70%), cervical spine (54%), shoulders (47%), and thoracic spine (36%) were the most common. There was a higher prevalence of cervical spine discomfort for co-drivers (62%) than for drivers (46%). Conversely, there was higher prevalence of discomfort in the hands and wrists for drivers (32%) than co-drivers (9%). The prevalence of low back pain in rally participants is higher than that generally reported for workers exposed to whole body vibration. The prevalence of discomfort in the hand and wrist for rally drivers is similar to that previously reported for Formula 1 drivers. CONCLUSIONS: Most stage rally drivers and co-drivers report symptoms of musculoskeletal injury. It is logical to relate the high prevalence of symptoms of injury to the extreme environment of the rally car.

Adult↗

PubMed2001

Relationship between capillary angiogenesis, fiber type, and fiber size in chronic systemic hypoxia.

Whether chronic hypoxia causes angiogenesis in skeletal muscle is controversial. Male Wistar rats, 5--6 wk of age, were kept at constant 12% O(2) for 3 wk, and frozen sections of their postural soleus (SOL), phasic extensor digitorum longus (EDL), and tibialis anterior (TA) muscles were compared with those of normoxic controls. Capillary supply increased in SOL muscles [capillary-to-fiber ratio (C/F) = 2.55 +/- 0.09 hypoxia vs. 2.17 +/- 0.06 normoxia; capillary density (CD) = 942 +/- 14 hypoxia vs. 832 +/- 20 mm(-2) normoxia, P < 0.01] but not in EDL muscles (C/F = 1.44 +/- 0.04 hypoxia vs. 1.42 +/- 0.04 normoxia; CD = 876 +/- 52 hypoxia vs. 896 +/- 24 mm(-2) normoxia). The predominantly glycolytic cortex of TA muscles showed higher C/F after hypoxia (1.79 +/- 0.09 vs. 1.53 +/- 0.05 normoxia, P < 0.05), whereas the mainly oxidative TA core with smaller fibers showed no change in capillarity. The region of the SOL muscle with large-sized (mean fiber area 2,843 +/- 128 microm(2)) oxidative fibers (90% type I) had a higher C/F (by 30%) and CD (by 25%), whereas there was no angiogenesis in the region with sparse (76%) and smaller-sized (2,200 +/- 85 microm(2)) type I fibers. Thus systemic hypoxia differentially induces angiogenesis between and within hindlimb skeletal muscles, with fiber size contributing either directly (via a metabolic stimulus) or indirectly (via a mechanical stimulus) to the process.

Animals↗

PubMed2001

Roles of norepinephrine and ATP in sympathetically evoked vasoconstriction in rat tail and hindlimb in vivo.

In anesthetized rats, we characterized the contributions of norepinephrine (NE) and ATP to changes in tail and hindlimb (femoral) vascular resistances (TVR and FVR, respectively) evoked by three patterns of sympathetic stimulation: 1) couplets (2 impulses at 20 Hz), 2) short trains (20 impulses at 20 Hz), and 3) a natural irregular pattern previously recorded from a sympathetic fiber innervating the rat tail artery. All stimuli evoked greater changes in TVR than FVR. Judging from the effects of the alpha-adrenoceptor antagonist phentolamine, the purinergic receptor antagonist suramin, or alpha,beta-methylene ATP (which desensitizes P2X receptors), we propose that NE has a major role in the constriction evoked by the couplet, as well as by the short train and by the low- and high-frequency components of the natural pattern, but that considerable synergy occurred between the actions of ATP and NE. This contrasts with previous in vitro studies that indicated that ATP dominates vascular responses evoked by sympathetic stimulation with a few impulses at low frequency and that NE dominates responses to longer trains or at high frequencies.

Adenosine Triphosphate↗

PubMed2000

Fibrinogen E-fragment inhibits the migration and tubule formation of human dermal microvascular endothelial cells in vitro.

Angiogenesis, the development of new blood vessels from an existing vascular bed, is essential for the growth and spread of malignant tumors. Several endogenous angiogenesis inhibitors have been discovered and shown to suppress endothelial cell function in vitro and tumor growth in vivo. Several of these are proteolytic fragments of larger, endogenous proteins. Here we show that a Mr 50,000 polypeptide derived from the plasmin cleavage of fibrinogen, fibrinogen E-fragment, inhibits endothelial cell migration and tubule formation induced by both proangiogenic growth factors, vascular endothelial growth factor and basic fibroblast growth factor, in vitro.

Adult↗

PubMed2000

Adenosine and muscle vasodilatation in acute systemic hypoxia.

Adenosine is released by skeletal and cardiac muscles when their metabolism increases: it serves to couple O2 supply with O2 demand by causing vasodilatation. This review argues that adenosine plays a similar role in skeletal muscle in systemic hypoxia. It accounts for approximately 50% of the increase in muscle vascular conductance and, within muscle, it causes dilatation of individual arterioles, thus maximizing the distribution of O2 and allowing O2 consumption to remain constant when O2 delivery is reduced. In vivo and in vitro studies have indicated that adenosine can induce dilatation in several different ways. This review argues that during systemic hypoxia, adenosine is predominantly released from the endothelium and acts on endothelial A1 receptors to produce dilatation in a nitric oxide (NO)-dependent manner. A1 receptor stimulation increases the synthesis of NO by a process initiated by opening of ATP-sensitive K+ (KATP) channels. Moreover, recent findings suggest that prostaglandins also make a major contribution to the hypoxia-induced dilatation, but that the dilator pathways for adenosine, NO and prostaglandins are interdependent. In addition, adenosine released from the skeletal muscle fibres contributes indirectly to the dilatation by stimulating A1 and A2 receptors on the muscle fibres, opening KATP channels and allowing efflux of K+, which is a vasodilator. Finally, by acting on endothelial A1 receptors, adenosine attenuates the vasoconstrictor effects of constant or bursting patterns of sympathetic activity. This limits the extent to which the sympathetic nervous system can reduce O2 delivery to muscle when it is already compromised by systemic hypoxia.

Adenosine↗

PubMed2000

Quantitative studies of the vasculature of the carotid body in the chronically hypoxic rat.

The carotid bodies of rats made chronically hypoxic by breathing 12% O2 in a normobaric chamber (inspired PO2 91 mmHg) were compared with those of controls. Serial 5-microm sections of the organs were examined using an interactive image analysis system. The total volume of the carotid bodies was increased by 64%. The total vascular volume rose by 103% and was likely due to an increase in size of the large vessels (>12 microm lumen diameter) because the small vessel (5-12 microm lumen diameter) volume did not increase significantly while the small vessel density tended to decrease. The extravascular volume was increased by 57%. Expressed as a percentage of the total volume of the organ, the total vascular volume did not change, but the small vessel volume was significantly decreased from 7.83 to 6.06%. The large vessel volume must therefore have been increased. The proportion occupied by the extravascular volume was virtually unchanged (84 vs 82%). In accordance with these findings, the small vessel endothelial surface area per unit carotid body volume was diminished from 95.2 to 76.5 mm-1, while the extravascular area per small vessel was increased from 493 to 641 microm(2) or by 30%. In conclusion, the enlargement of the carotid body in chronic hypoxia is most likely due to an increase in total vascular volume, mainly involving the "large" vessels, and to an increase in extravascular volume. This is in contrast to our previously published findings indicating that in the spontaneous insulin-dependent diabetic rat the enlargement of the carotid body is due solely to an increase in extravascular volume.

Animals↗

PubMed2000

Abnormal venous function in patients with homozygous sickle cell (SS) disease and chronic leg ulcers.

Chronic leg ulceration is a major cause of morbidity in homozygous sickle cell (SS) disease in Jamaica. These ulcers have features in common with venous ulcers in patients with a normal haemoglobin genotype (AA). Thus we sought to determine whether there is abnormal venous function in the legs of patients with SS disease who have ulcers. Experiments were performed on 15 SS patients with ulcers, and on 15 SS patients and 15 AA subjects with no history of leg ulcers. Changes in venous blood volume of the bottom one-third of the leg induced by venous occlusion and release were studied by air plethysmography, providing indices of segmental venous capacitance (SVC), maximal venous outflow (MVO) and venous emptying time (VET). The changes in volume (ambulatory volume change; AVC) induced by a period of leg exercise were also measured at the ankle (AVCa) and calf (AVCc); venous refilling times at these sites (RTa and RTc respectively) were also measured. Finally, cutaneous red blood cell flux recovery time (FRT) after ankle exercise was assessed by laser Doppler flowmetry. Measurements were also made of haematological variables. SVC, MVO and VET did not differ between the groups, indicating no deep venous obstruction in the SS patients with ulcers. AVCc, AVCa and RTc did not differ among the three subject groups. However, compared with AA subjects, SS patients with ulcers had reduced RTa and FRT. Moreover, RTa and FRT were further shortened in SS patients with ulcers relative to SS patients without ulcers. Since the levels of anaemia were similar in SS patients with and without ulcers, these differences cannot be attributed to differences in arterial flow secondary to anaemia. These results suggest abnormal venous function in SS patients with ulcers, relative to both AA subjects and SS patients without ulcers. We propose that there is incompetence of venous valves draining the ankle region of SS patients with ulcers: the consequent raised venous pressure contributes to the slow healing and, possibly, to the onset of leg ulceration in SS disease.

Adult↗

PubMed1999

Physiological adjustments and arteriolar remodelling within skeletal muscle during acclimation to chronic hypoxia in the rat.

1. We have investigated the physiological and structural changes that occur in skeletal muscle vasculature during acclimation to chronic hypoxia in rats exposed to 12 % O2 in a hypoxic chamber for 7 or 18 days (7CH and 18CH rats, respectively) and in age-matched normoxic (7N and 18N) rats. 2. Under anaesthesia and breathing 12 % O2, 7CH and 18CH rats had lower arterial blood pressure (ABP) than 7N and 18N rats breathing air, but the haematocrit of the CH rats was increased so that their arterial O2 content equalled that of N rats. Blood flow recorded from the iliac or femoral artery and used to compute muscle vascular conductance (MVC: blood flow/ABP) showed that, in 18CH rats, MVC was comparable with that of 18N rats. 3. Maximal MVC induced by infusion of sodium nitroprusside (SNP) was used as an index of structural vascular conductance and compared with the MVC evoked by acute hypoxia (breathing 8 % O2). Hypoxia induced similar increases in MVC in 7N and 7CH rats and in 18N and 18CH rats, even though N rats were switched from air to 8 % O2 and CH rats were switched from 12 to 8 % O2. The MVCs attained with 8 % O2 and SNP were similar in 7N and 18N rats. However, the MVCs attained with 8 % O2 in 7CH and 18CH rats were only approximately 60 % of those evoked by SNP, while the MVC attained with SNP was greater in 18CH than in 18N rats. 4. Vascular casts of the spinotrapezius muscle analysed ex vivo showed that interbranch intervals along primary, secondary and terminal arterioles (22-50, 13-18 and 7-13 microm diameter, respectively) were 30-50 % shorter in 7CH and 18CH rats than in 7N and 18N rats. Further, the proportions of branches that were of the secondary and terminal arteriolar categories were increased such that the mean diameter of the branches was lower in 7CH than in 7N rats and lower in 18CH than in 18N rats. 5. These results indicate that arteriolar remodelling and angiogenesis occurs in skeletal muscle during acclimation to chronic hypoxia, beginning by the 7th day and progressing at least until the 18th day, so that the number of small arterioles and the functional size of the vascular bed is increased. We propose that these structural and functional changes enhance the ability of skeletal muscle to respond to acute hypoxia by facilitating the increase in vascular conductance, blood flow and thereby the O2 that can be delivered to muscle.

Adaptation, Physiological↗

PubMed1999

Adenosine receptor subtypes and vasodilatation in rat skeletal muscle during systemic hypoxia: a role for A1 receptors.

1. In anaesthetized rats we tested responses evoked by systemic hypoxia (breathing 8% O2 for 5 min) and adenosine (i.a. infusion for 5 min) before and after administration of a selective adenosine A1 receptor antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine), or a selective adenosine A2A receptor antagonist ZM 241385. Arterial blood pressure, (ABP), heart rate (HR), femoral blood flow (FBF) and femoral vascular conductance (FVC: FBF/ABP) were recorded together with the K+ concentration in arterial blood ([K+]a) and in venous blood of hindlimb muscle ([K+]v) before and at the 5th minute of hypoxia or agonist infusion. 2. In 12 rats, DPCPX reversed the fall in ABP and HR and the increase in FVC evoked by the selective A1 agonist CCPA (2-chloro-N6-cyclopentyladenosine; i.a. infusion for 5 min). DPCPX also reduced both the increase in FVC induced by hypoxia and that induced by adenosine; the control responses to these stimuli were comparable in magnitude and both were reduced by approximately 50%. 3. In 11 rats, ZM 241385 reversed the fall in ABP and increase in FVC evoked by the selective A2A agonist CGS 21680 (2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadeno sin e hydrochloride; i.a. infusion for 5 min). ZM 241385 also reduced the increase in FVC induced by adenosine by approximately 50 %, but had no effect on the increase in FVC induced by hypoxia. 4. In these same studies, before administration of DPCPX, or ZM 241385, hypoxia had no effect on the venous-arterial difference for K+ ([K+]v-a), whereas after administration of either antagonist, hypoxia significantly reduced [K+]v-a suggesting an increase in hypoxia-induced K+ uptake, or a reduction in K+ efflux. 5. These results indicate that both A1 and A2A receptors are present in hindlimb muscle and can mediate vasodilatation and that A1 and A2A receptors contribute equally to dilatation induced by infused adenosine. However, they suggest that endogenous adenosine released during systemic hypoxia induces dilatation only by acting on A1 receptors. Given previous evidence that adenosine can stimulate receptors on skeletal muscle fibres that are coupled to ATP-sensitive K+ (KATP) channels so promoting K+ efflux, our results allow the proposal that KATP channels may be coupled to both A1 and to A2A receptors and may be stimulated to open by adenosine released during hypoxia, but indicate that, during systemic hypoxia, K+ efflux caused by either receptor subtype makes a very minor contribution to the muscle vasodilatation.

Adenosine↗

PubMed1999

Cellular mechanisms by which adenosine induces vasodilatation in rat skeletal muscle: significance for systemic hypoxia.

1. In anaesthetized rats, we recorded arterial blood pressure (ABP), heart rate (HR), femoral blood flow (FBF) and femoral vascular conductance (FVC). We tested the effects of the nitric oxide (NO) synthesis inhibitor L-NAME (nitro-L-arginine methyl ester), or the ATP-sensitive K+ (KATP) channel inhibitor glibenclamide, on responses evoked by systemic hypoxia (breathing 8% O2 for 5 min) or i.a. infusion for 5 min of adenosine, the NO donor sodium nitroprusside (SNP), the adenosine A1 receptor agonist CCPA (2-chloro-N6-cyclopentyladenosine) or the adenosine A2A receptor agonist CGS 21680 (2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadeno sin e hydrochloride). 2. L-NAME (10 mg kg-1 i.v.) greatly reduced the increase in FVC induced by hypoxia or adenosine, as we have shown before, but had no effect on the increase in FVC evoked by SNP. In addition, L-NAME abolished the increase in FVC evoked by CCPA and greatly reduced that evoked by CGS 21680. These results substantiate the view that muscle vasodilatation induced by systemic hypoxia and infused adenosine are largely NO dependent. They also indicate that muscle dilatation induced by A1 receptor stimulation is entirely NO dependent while that induced by A2A receptors is largely NO dependent; dilatation may also be induced by direct stimulation of A2A receptors on the vascular smooth muscle. 3. Glibenclamide (10 or 20 mg kg-1 i.v.) reduced the increase in FVC induced by hypoxia, preferentially affecting the early part (< 1 min). In addition, glibenclamide greatly reduced the increase in FVC induced by adenosine, but it had no effect on that evoked by SNP. Further, glibenclamide abolished the increase in FVC evoked by CCPA and greatly reduced that evoked by CGS 21680. These results substantiate the view that hypoxia-induced muscle vasodilatation is initiated by KATP channel opening. They also indicate that NO does not induce muscle vasodilatation by opening KATP channels on the vascular smooth muscle, but indicate that the dilatation induced by adenosine and by A2A receptor stimulation is largely dependent on KATP channel opening, while that induced by A1 receptor stimulation is wholly dependent on KATP channel opening. 4. These results, together with previous evidence that hypoxia-induced vasodilatation in skeletal muscle is largely mediated by adenosine acting on A1 receptors, lead us to propose that adenosine is released from endothelium during systemic hypoxia and acts on endothelial A1 receptors to open KATP channels on the endothelial cells and cause synthesis of NO, which then acts on the vascular smooth muscle to cause dilatation. During severe systemic hypoxia we propose that adenosine may also act on A2A receptors on the endothelium to cause dilatation by a similar process and may act on A2A receptors on the vascular smooth muscle to cause dilatation by opening KATP channels.

Adenosine↗

PubMed1999

The cutaneous vasoconstrictor response to venous stasis is normal in subjects with primary Raynaud's disease.

In control subjects and in subjects with primary Raynaud's disease, sudden sound or a mild cool stimulus evokes the pattern of alerting response that includes cutaneous vasoconstriction but vasodilatation in forearm muscle. In control subjects, response habituates on repetition of these stimuli both within experimental sessions and over successive days. However, in subjects with primary Raynaud's disease, the cutaneous vasoconstriction and the muscle vasodilatation persist. We have now tested whether a similar disparity exists for the cutaneous vasoconstriction evoked by venous stasis, a response considered to be a veno-arteriolar reflex mediated by sympathetic fibers, but not requiring transmission through the spinal cord. In 10 subjects with primary Raynaud's disease and in 10 matched controls, a sphygmomanometer cuff on the left arm was inflated to 40 mm Hg for 2 minutes, five times on each of three experimental sessions on days 1, 3, and 5. Cutaneous red cell flux (RCF) was recorded from the pulp and dorsum of the left index finger by using a laser Doppler meter; digital vascular conductance (DCVC) was computed as RCF divided by arterial pressure. The first venous stasis, in session 1, evoked a decrease in pulp and dorsum DCVC in the control and primary Raynaud's subjects. There were no differences between the groups in the magnitudes or durations of these responses. Within session 1, the magnitude of the decrease in DCVC diminished on repetition of venous stasis in the dorsum in controls and in the pulp in primary Raynaud's subjects. We propose these effects reflected the similar reductions in baseline DCVC over time; there was no change in the duration of the responses. Repetition of venous stasis had similar effects in both groups of subjects within sessions 2 and 3. Further, judging from the mean of the responses evoked in each Session the decreases evoked in pulp and dorsum DCVC by venous stasis were fully consistent in magnitude and duration over the three sessions in both groups. These results indicate that the direct constrictor influence of sympathetic fibers upon cutaneous blood vessels is similar in magnitude and similarly reproducible in controls and subjects with primary Raynaud's disease. This reinforces our view that the lack of habituation of the cutaneous vasoconstrictor component of the alerting response in subjects with primary Raynaud's disease reflects impairment of the central neural process of habituation, rather than a peripheral phenomenon, and that this lack of habituation predisposes these subjects to vasospasm.

Adult↗

PubMed1999

The effects of acute and chronic systemic hypoxia on muscle oxygen supply and oxygen consumption in the rat.

The aims of the present study were to evaluate how acute systemic hypoxia affects O2 delivery to skeletal muscle and muscle O2 consumption (VO2) of the rat and to establish how these relationships are altered by chronic systemic hypoxia. Thus, the effects of breathing different concentrations of O2 (air, 12% and 8% O2) upon oxygen delivery and VO2 were studied in hindlimb muscles of control, normoxic (N) rats and of rats that had been made chronically hypoxic in a chamber at 12% O2 for 3-4 weeks (CH) rats. Under anaesthesia, arterial blood pressure, femoral blood flow (FBF), arterial O2 content (Ca,O2) and venous O2 content in the efflux from hindlimb were measured. In N rats, changing the inspirate from air to 12% and 8% O2 for 5 min each, reduced Ca,O2 from 20 +/- 0.3 ml (100 ml)-1 in air to 13 +/- 1.0 ml (100 ml)-1 in 8% O2. FBF did not change significantly (1.7 +/- 0.1 ml min-1 in air) so that O2 delivery to hindlimb muscles fell from 0.28 +/- 0.07 to 0.16 +/- 0.02 ml min-1 in 8% O2. Nevertheless, the VO2 of hindlimb muscle was well maintained: 0.06 +/- 0.02 ml min-1 in air and 0.08 +/- 0.02 ml min-1 in 8% O2. In CH rats breathing 12% O2, Ca,O2 (23 +/- 1.0 ml (100 ml)-1) was comparable to that of N rats breathing air, due to an increase in haematocrit, as were FBF (1.6 +/- 0.2 ml min-1) and O2 delivery (0.39 +/- 0.05 ml min-1). However, VO2 was 2.5-fold greater in CH rats (0.16 +/- 0.03 ml min-1). As in N rats, FBF was well maintained at 1.7 +/- 0.2 and 1.6 +/- 0.2 ml min-1 in 8% O2 and air, respectively. Further, VO2 was also well maintained, at 0.17 +/- 0.02 and 0.12 +/- 0.02 ml min-1 in 8% O2 and air, respectively. These results suggest that, contrary to previous reports, muscle VO2 of the rat is independent of O2 delivery over a wide range of O2 delivery values. They also suggest that muscle VO2 of CH rats is similarly independent of O2 delivery. The novel finding that muscle VO2 has a greater absolute value in CH rats can, we propose, be explained by an increase in VO2 of the vasculature rather than of the skeletal muscle fibres and reflects increased biosynthetic activity of the vessel walls and/or vascular remodelling.

Acute Disease↗

PubMed1999

Cardiovascular responses evoked by mild cool stimuli in primary Raynaud's disease: the role of endothelin.

In control subjects and in subjects with primary Raynaud's disease, sudden sound evokes the pattern of the alerting response, which includes cutaneous vasoconstriction and vasodilatation in forearm muscle. However, whereas this pattern of response habituates on repetition of the sound stimulus in control subjects, both cutaneous vasoconstriction and muscle dilatation persist in subjects with primary Raynaud's disease. The aim of the present study was to test whether a similar disparity exists between control subjects and those with primary Raynaud's disease for the response to mild cool stimuli, and whether the cutaneous response is accompanied by the release of endothelin-1 (ET-1). In nine subjects with primary Raynaud's disease and in nine matched controls, the left hand was placed in cool water at 16 degrees C for 2 min five times on each of three experimental sessions on days 1, 3 and 5, with blood being taken from the venous drainage of the cooled hand before and at the end of the second session. In response to the first cool stimulus in Session 1, the subjects with primary Raynaud's disease showed a decrease in digital cutaneous vascular conductance (DCVC) in both the right and left hands, as indicated by a laser Doppler recording of erythrocyte (red cell) flux divided by arterial pressure, and six of the nine subjects showed an increase in forearm vascular conductance (FVC), as indicated by forearm blood flow measured by plethysmography divided by arterial pressure. On repetition of the stimulus in Session 1, there was no change in the magnitude of the increase in FVC, but the evoked decreases in DCVC became more prolonged in both the right and the left hand. Similar responses occurred in Sessions 2 and 3; in Session 2, the ET-1 concentration increased from a baseline value of 2.15+/-0.26 fM to 2.72+/-0.37 fM after five stimuli. There was no habituation of the increase in FVC over Sessions 1, 2 and 3, judging from the mean changes in each session. Control subjects also showed a decrease in DCVC in both hands, and in eight out of nine subjects there was an increase in FVC in response to the first cool stimulus in Session 1. However, on repetition of the stimulus in Session 1, the increase in FVC habituated, while there was no prolongation of the decrease in DCVC; in addition, the ET-1 concentration did not change in Session 2 in response to the stimulus (2.07+/-0.28 compared with 2.29+/-0.30 fM). Further, the increase in FVC habituated over the three sessions, such that there was a mean decrease in FVC in Session 3. These results indicate that, in subjects with primary Raynaud's disease, there is impairment of the ability of the central nervous system to allow habituation of the cardiovascular components of the alerting response evoked by mild cooling, as with the response to sound. We propose that persistence of the cutaneous vasoconstriction of the alerting response, coupled with increased release of ET-1 secondary to vasoconstriction, prolongs such vasoconstriction and eventually leads to vasospasm.

Adult↗