bluuebunny/crossref_metadata_2025 huggingface dataset:
Capsaicin can abolish spontaneous tone in guinea‐pig trachealis
Authors: Skogvall S. , Arner A. , Grampp W.
Published: March 2003

The properties of spontaneous tone in isolated preparations of guinea‐pig tracheal smooth muscle were examined. Experiments with control preparations revealed that 5–15 min after stretching the muscle with 0.15 mN, the spontaneous tone assumed a plateau value from which it declined gradually during the following hour. During the plateau, the force amounted to ∼35% and 1 h later to ∼20% of a maximum KC1 contraction. The tone was independent of tetrodotoxin, atropine and propranolol. Indomethacin quickly and completely relaxed the tone in 15 of 21 preparations. However, four preparations retained some tone even after 1 h of treatment. Exposure to the C‐fibre influencing drug capsaicin resulted in a dose‐dependent, reversible suppression of spontaneous tone, normally preceded by a transient increase in force. No spontaneous tone at all remained after 1 h of 10 μM capsaicin. This effect was also found in preparations pretreated with tetrodotoxin, atropine and propranolol. Preparations, deprived of spontaneous tone by capsaicin‐treatment, contracted distinctly when exposed to 10 μM arachidonic acid. This contraction was almost completely abolished by indomethacin, which indicates that the prostaglandin synthesis is functioning after capsaicin treatment and, thus, that inhibition of this synthesis is not responsible for the capsaicin effect. Exposure to phosphoramidon increased the spontaneous tone almost threefold. Addition of 3 nM neurokinin A in the permanent presence of capsaicin gave weaker contractions in preparations where prostaglandin synthesis had been abolished by indomethacin, as compared to contractions in preparations with intact prostaglandin synthesis. The data indicate that a continuous release of tachykinins from sensory C‐fibres is essential for the generation of spontaneous tone and that a combination of tachykinins and prostaglandins determine the size of the tone in this preparation.
Influence of local haemodynamics on leucocyte rolling and chemoattractant‐induced firm adhesion in microvessels of the rat mesentery
Authors: XIE  , HEDQVIST  , LINDBOM
Published: March 2003

Tissue hyperaemia, oedema formation and leucocyte accumulation are characteristic features of the inflammatory process referable to changes at the microcirculatory level. Here, we used intravital fluorescence video microscopy to assess relationships among haemodynamical parameters, leucocyte rolling, and chemoattractant‐induced firm adhesion in small venules (13−24 μM) of the rat mesentery. The rolling leucocyte flux in these vessels was directly proportional to the total leucocyte flux (r = 0.76, P < 0.001), which in turn closely correlated to the venular blood flow (r = 0.77, P < 0.001). Consequently, the rolling to total leucocyte flux fraction, averaging 39 ± 15%, did not vary with the blood flow and showed no correlation to either blood flow velocity (r = −0.15, P = 0.42) or wall shear rate (r = −0.06, P = 0.77), indicating that the extent of leucocyte rolling is not primarily dependent on the fluid viscous drag at physiological blood flow rates in vivo. Stimulation of the mesentery with the chemoattractant fMLP (10−6 M) induced firm adhesion of rolling leucocytes. It was found that the number of adherent leucocytes in individual vessels was directly related to the rolling leucocyte flux (r = 0.78, P < 0.001) and hence to the venular blood flow (r = 0.47, P < 0.05), while there was no correlation to the wall shear rate (r = 0.27, P = 0.24). The dependence of the firm adhesive response on the blood flow level and the delivery rate of leucocytes was confirmed at the whole organ level. Thus, leucocyte accumulation in rat skin lesions was markedly enhanced when a vasodilator was co‐administered with the chemotactic stimulus compared with chemotactic stimulation alone. The data indicate that, within a physiological blood flow range, the leucocyte response to chemotactic stimulation is largely independent of the prevailing hydrodynamic shear forces. Instead, manifestation of the firm adhesive response, because of its dependence on the preceding rolling interaction, is clearly related to the blood flow level in the microvessels, which emphasizes the significance of tissue hyperaemia in inflammation.
Swelling of sarcoplasmic reticulum in the periphery of muscle fibres after isometric contractions in rat semimembranosus lateralis muscle
Authors: Willems  , Huijing  , Fridén
Published: March 2003

The decline in isometric force, swelling of sarcoplasmic reticulum and loss of desmin was measured in semimembranosus lateralis muscle of male Wistar rats immediately after a short series of brief (500 ms) maximal isometric contractions. For the active muscle, the series ended below (protocol A) and just over muscle optimum length (protocol AA). In one protocol, the muscle remained passive and was extended to lengths just over muscle optimum length (protocol P). After all experimental protocols, no loss of desmin was observed and sarcomere appearance was normal. Protocol A produced swelling (87%) of the sarcoplasmic reticulum but no decline in isometric force. Protocol AA produced larger swelling (147%) of the sarcoplasmic reticulum and an isometric force decline (<49%) at short muscle lengths. Swelling of sarcoplasmic reticulum was observed mainly in the periphery of muscle fibres. Protocol P did not result in swelling of the sarcoplasmic reticulum and isometric force decline. It is concluded that swelling of the sarcoplasmic reticulum in the periphery of muscle fibres after brief maximal isometric contractions is associated with muscle force and not muscle length.
Increased metabolism of infused 1‐methylxanthine by working muscle
Authors: Youd J.M. , Newman J.M.B. , Clark M.G. , Appleby G.J. , Rattigan S. , Tong A.C.Y. , Vincent M.A.
Published: March 2003

Exogenous substrates for capillary endothelial enzymes have potential as markers for changes in capillary recruitment (albeit nutritive flow). The metabolism of infused 1‐methylxanthine (1‐MX) to 1‐methylurate (1‐MU) by capillary endothelial xanthine oxidase of the constant‐flow perfused rat hindlimb was shown previously to decrease with oxygen uptake (V˙O2) when nutritive flow was decreased. In the present study, the metabolism of 1‐MX was investigated under conditions when V˙O2 and nutritive flow are known to increase during muscle contraction. The constant‐flow red blood cell‐perfused rat hindlimb at 37 °C was used with sciatic nerve stimulation, and perfusate samples from whole hindlimb and working muscles taken for analysis of oxygen, lactate, 1‐MX and 1‐MU. Flow to muscle was assessed separately using fluorescent microspheres and was found to increase 2.3‐fold to the working muscles while flow to the non‐working leg muscles decreased to compensate. The activity of xanthine oxidase of whole muscle extracts was not altered by contraction. Samples from the vein draining the working muscles, and microsphere measurements of flow, indicated increased V˙O2 (5.5‐fold to 249.2 ± 43.1 μmol h−1 g−1, P < 0.001), and 1‐MX conversion (2.5‐fold to 1.87 ± 0.25 μmol h−1 g−1, P < 0.01) (SEM are shown). It is concluded that as 1‐MX metabolism parallels V˙O2, this substrate may be a useful indicator of changes in capillary (nutritive) surface area in muscle.
Neuroactive steroids: their mechanism of action and their function in the stress response
Authors: Zinder  , Dar
Published: March 2003

Steroids are usually identified as genomic regulators, yet recently a body of evidence has accumulated demonstrating specific plasma membrane effects, as well as coordinative effects, of some steroids on both membrane and intracellular receptors. The resulting rapid (<1 min) modulation of cellular activity has strongly suggested a non‐genomic, and possibly modulatory, role for certain steroid compounds, and dramatic effects on membranes of excitable as well as other tissues have been demonstrated. Steroid synthesis and metabolism have been shown to exist in the CNS, and the effects have been seen in both the central and peripheral nervous systems. The major groups of neuroactive steroids, and their metabolites, have been progesterone, deoxycorticosterone, and some androgens, notably dihydroxyepiandrosterone (DHEA). These compounds show increased concentrations both in blood and in the brain following stress and they have also been associated with anxiolytic effects and antiepileptic activity. In the periphery, some of these compounds show remarkable inhibitory effects on the secretion of catecholamines and other neurotransmitters. The mechanism for the majority of the effects of these steroids is via their effect on receptor‐mediated binding to ligand‐gated ion channels. Activation of the GABAA receptor complex, resulting in the opening of its central chloride channel, is the major target of the neuroactive steroids, resulting in re‐polarization of the plasma membrane and inhibition of further neuronal firing. The anxiolytic, anti‐convulsant and sedative‐hypnotic actions of these neuroactive steroids have resulted in their being used as therapeutic agents for the treatment of anxiety, epilepsy, insomnia, and possibly for the alteration of pain thresholds.
Calphostin C is an inhibitor of contraction, but not insulin‐stimulated glucose transport, in skeletal muscle
Authors: Ihlemann  , Galbo  , Ploug
Published: March 2003

Wortmannin selectively impairs insulin‐stimulated glucose transport in skeletal muscle. To search for an inhibitor specific for contraction‐stimulated glucose transport, we screened a number of calmodulin and PKC inhibitors for their ability to impair contraction‐ and insulin‐stimulated 2‐deoxyglucose uptake in incubated rat soleus muscles. In concentrations that did not reduce contraction‐induced force output, among calmodulin inhibitors W‐7 inhibited both contraction‐ and insulin‐stimulated glucose transport by up to 50% (P < 0.05), while Calmidazolium impaired only insulin‐stimulated glucose transport (P < 0.05), and Trifluoperazine and Phenoxybenzamine did not influence glucose transport. In concentrations that did not reduce force generation, among PKC inhibitors Calphostin C specifically inhibited contraction‐stimulated glucose transport (P < 0.05), whereas insulin‐stimulated transport was impaired by Rottlerin and Bisindolylmaleimide I (P < 0.05), and both contraction‐ and insulin‐stimulated glucose transport were inhibited by RO‐31‐8220 (P < 0.05). Calphostin C did not reduce contraction‐induced increase in AMP‐activated protein kinase (AMPK) activity. In conclusion, we have identified specific inhibitors of both contraction‐ and insulin‐stimulated glucose transport. Both calmodulin and different isoenzymes of the PKC family may be involved in contraction‐ and insulin‐stimulated glucose transport. Calphostin C does not influence glucose transport during contractions via stimulation of AMPK. Calphostin C may be used to unravel signal transduction in contraction‐stimulated glucose transport.
Role of the sarcoplasmic reticulum in the modulation of rat cardiac action potential by stretch
Authors: Han  , Tavi  , Weckström
Published: March 2003

We have investigated the role of sarcoplasmic reticulum (SR) in the modulation on rat action potentials by stretch. The action potentials were recorded intracellularly from rat atrial myocytes in an isolated atrial preparation with small, physiological stretch produced by pressure (1–3 mmHg) inside the atria. The SR function was inhibited by pharmacological interventions, either with ryanodine (100 nmol L–1), thapsigargin (10 nmol L–1) or caffeine (1 mmol L–1). The duration of action potentials was increased by stretch from 1 to 3 mmHg. The repolarization indices APD30% (P < 0.05), APD60% (P < 0.01), and APD90% (P < 0.01) were all increased significantly (n=10). Ryanodine, thapsigargin, and caffeine inhibited this prolongation, or even reversed the effect with repolarization indices APD30% (P < 0.05) and APD60% (P < 0.05) which decreased in stretch with thapsigargin treatment. As a conclusion, we suggest that the SR and the intracellular calcium balance play an important role in the modulation of the shape of the rat atrial action potential during stretch.
Cl– transport in the lobster stretch receptor neurone
Authors: Theander  , Edman  , Fåhraeus  , Akoev  , Grampp
Published: March 2003

Experiments were performed to identify mechanisms underlying non‐leakage and non‐H+/HCO3−‐linked transmembrane Cl− transports in the slowly adapting stretch receptor neurone of the European lobster, using intracellular microelectrode and pharmacological techniques. In methodological tests, it was established that direct estimates of intracellular Cl− with ion‐sensitive microelectrodes are statistically identical with indirect estimates by means of a GABA method, where 1–2 m
M GABA is transforming the cell’s membrane voltage into its Cl− equilibrium voltage from which the Cl− concentration is inferred by the Nernst equation. From experiments using sodium orthovanadate and ethacrynic acid, supposed to block primary Cl− pumps, and bumetanide, supposed to block Na–K–Cl co‐transporters, it appeared that neither of the two Cl−transport systems exists in the stretch receptor neurone. It could be shown, however, that the cell is equipped with an electroneutral K–Cl co‐transporter that (a) is blockable by furosemide in high (Km ≈ 350 μM), by 4‐acetamido‐4′‐isothiocyanato‐stilbene‐2,2‐disulphonic acid (SITS) in medium‐high (Km ≈ 35 μM), and by 4,4′‐diisothiocyanostilbene‐2,2′‐disulphonic acid (DIDS) in low (Km ≈ 15 μM) doses, (b) is (transiently) activatable by (1 m
M) n‐ethylmaleimide, (c) is not suppressed by extracellular Rb+ or NH4+, and (d) is not directly coupled to any transmembrane transports of Na+, H+ or HCO3−. From functional tests, with varying transmembrane K+ and Cl− gradients, evidence obtained that the K–Cl co‐transporter is able to reverse its transport direction and to adjust its transport rate in a considerable range. As a whole, the results speak in favour of the K–Cl co‐transporter being responsible (a) for normally keeping the intracellular Cl− concentration at low levels, for an optimization of the cell’s inhibitory system, and (b) for achieving fast transmembrane shifts of K+ (and Cl−), as a means of stabilizing the cell’s membrane excitability in conditions of varying extracellular K+ concentrations.
Adverse changes in fibre type and myosin heavy chain compositions of human jaw muscle vs. limb muscle during ageing
Authors: Monemi  , Kadi  , Liu  , Thornell  , Eriksson
Published: March 2003

This review shows that human jaw muscles not only have unique fibre type and myosin heavy chain (MyHC) compositions but also undergo muscle and region‐specific changes in fibre composition during ageing. Alterations in the masseter and the lateral pterygoid muscles in the elderly are opposite to those reported for limb and trunk muscles, whereas changes in the anterior and posterior bellies of the digastric muscle resemble those of limb and trunk muscles. We conclude that age‐related alterations in fibre type composition and MyHC expression are muscle and region specific, probably reflecting muscular differences in genetic programs and epigenetic influences.
Effect of salt intake on jejunal dopamine, Na+,K+‐ATPase activity and electrolyte transport
Authors: Lucas‐Teixeira  , Serrão  , Soares‐Da‐Silva
Published: March 2003

The present study addresses the question of the relevance of salt intake on jejunal dopamine, Na+,K+‐ATPase activity and electrolyte transport. Low salt, but not high salt, intake for 2 weeks increased dopamine levels in the jejunal mucosa accompanied by a marked decrease in
L‐3,4‐dihydroxyphenylalanine tissue levels. By contrast, in rats fasted for 72 h the effect of refeeding for 24 h with a low salt diet failed to change dopamine tissue levels, although it significantly increased those of
L‐3,4‐dihydroxyphenylalanine. By contrast, high salt intake markedly increased the tissue levels of both dopamine and
L‐3,4‐dihydroxyphenylalanine, without changes in dopamine/
L‐3,4‐dihydroxyphenylalanine tissue ratios. Tissue levels of both
L‐3,4‐dihydroxyphenylalanine and dopamine in control conditions (normal salt intake for 2 weeks) were markedly higher (P < 0.05) than in rats submitted to 72 h fasting plus 24 h refeeding. The effect of fasting for 72 h followed by 24 h refeeding was a marked decrease in jejunal Na+,K+‐ATPase activity, particularly evident for rats fed a normal salt and high salt diets during the refeeding period. Basal short circuit current was similar in rats fed a normal salt diet for 2 weeks and 24 h, and the type of diet failed to alter basal short circuit current after refeeding with normal, low and high salt diets. On the other hand, the effect of prolonged low salt intake was a marked decrease in jejunal Na+,K+‐ATPase activity and basal short circuit current, whereas high salt intake failed to alter enzyme activity and basal short circuit current. In rats fed for 2 weeks a high salt diet ouabain was found to be more potent in reducing jejunal short circuit current than in rats fed normal and low salt diets. The effect of furosemide was more marked in rats fed for 2 weeks high and low salt diets than in animals receiving a normal salt intake. Dopamine (up to 1 μmol L–1) was found not to alter Na+,K+‐ATPase and basal short circuit current in jejunal epithelial sheets, in rats fed with normal, low and high salt diets for 2 weeks and 24 h.
Concerted actions of renal endothelial and macula densa NO systems in the maintenance of extracellular fluid volume
Authors: Braam  , Turkstra  , Koomans
Published: March 2003

It is now clear that nitric oxide (NO) exerts a substantial influence on renal function and that the kidney has a high capacity to produce NO. However, there are at least two different NO systems in the kidney. The interplay between NO generated by the endothelium and by the macula densa is considered in this review. It seems that endothelial NO increases in response to an increase in perfusion pressure and an increase in distal delivery, whereas macula densa NO decreases upon a sustained increase in distal delivery. Furthermore, evidence is accumulating that macula densa NO may well mediate renin release. Though seemingly in contrast, both the response of the endothelial NO and of the macula densa NO system seem appropriate to restore a perturbation of fluid balance. The function of the tubuloglomerular feedback (TGF) mechanism is likely to be influenced by both sources of NO, because of the close proximity of these NO producing cells to the vascular smooth muscle cells of the afferent arteriole. The endothelial NO system seems to be responsible for short‐term, dampening actions to increased afferent arteriolar tone elicited by activation of the TGF system. The macula densa NO system, on the other hand, is probably adapting TGF responses to sustained increases in distal delivery. The analysis presented in this paper is an attempt to integrate the function of the two NO systems into physiological regulation. The exact role of the medullary NOS enzymes remains to be further elucidated.
Na+–Ca2+ exchange current from rabbit isolated atrioventricular nodal and ventricular myocytes compared using action potential and ramp waveforms
Authors: Convery  , Hancox
Published: March 2003

We measured and compared Na–Ca exchanger current (INa–Ca) from rabbit isolated ventricular and atrioventricular (AV) nodal myocytes, using action potential (AP) and ramp voltage commands. Whole cell patch‐clamp recordings were made at 35–37 °C; INa–Ca was measured as 5 m
M nickel (Ni)‐ sensitive current with major interfering voltage and calcium‐activated currents blocked. In ventricular cells a 2‐s descending ramp elicited INa–Ca showing outward rectification and a reversal potential (Erev) of –13.1 ± 1.2 mV (n = 12; mean ± SEM). With a ventricular AP as the voltage command, the profile of INa–Ca followed the applied waveform closely. The current–voltage relation during AP repolarization was almost linear and showed an Erev of –38.3 ± 5.3 mV (n = 6). As INa–Ca depended on the applied voltage waveform, comparisons between the two cell types utilized the same command waveform (a series of AV nodal APs). In ventricular myocytes this elicited INa–Ca that reversed near –38 mV and was inwardly directed during the pacemaker potential. This command was also applied to AV node cells; mean INa–Ca density at all voltages encompassed by the AP (–70 to +30 mV) did not differ significantly from that in ventricular myocytes (P > 0.05,
ANOVA). This finding was confirmed using brief (250 ms) voltage ramp protocols (P > 0.1
ANOVA). These data represent the first direct measurements of AV nodal INa–Ca and suggest that the exchanger may be functionally expressed to similar levels in the two cell types. They may also suggest a possible role for INa–Ca during the pacemaker potential in AV node as inward INa–Ca was observed over the pacemaker potential range even with bulk internal Ca buffered to a low level.
Hypothermia affects the phagocytic activity of rat peritoneal macrophages
Authors: Salman  , Bergman  , Bessler  , Alexandrova  , Beilin  , Djaldetti
Published: March 2003

To examine the effect of hypothermia on the phagocytic capacity of rat peritoneal macrophages for latex particles, male Wistar rats were exposed to 4 °C for 8 and 72 h. While the shorter exposure to cold did not affect body temperature and macrophage function, animals exposed to 4 °C for 72 h showed a mean decrease of their body temperature by 1.5 °C. The superoxide anion production was significantly increased whereas the number of phagocytic cells decreased. In addition, the mean number of latex particles engulfed by each individual cell was lower than that of controls. Peripheral blood mononuclear cells (PBMC) of these animals showed lower mitogen response to phytohaemagglutinin (PHA), while that for concanavalin A (Con‐A) remained unchanged. Peritoneal macrophages exposed in vitro to 24 °C for 60 min showed a decreased phagocytic capacity in comparison with macrophages kept at 37 °C, an observation suggesting the development of an indigenous cell defect for phagocytosis at lower temperatures. On the other hand, the effect of additional humoral factor(s) on macrophage activity, such as an increase in serum level of catecholamines and corticosterone, cannot be excluded. The results of the study may contribute to understanding the predisposition to infections during exposure to cold.
Structural and functional limits for oxygen supply to muscle
Authors: Hoppeler H. , Weibel E.R.
Published: March 2003

Environmental oxygen is transported by the respiratory cascade to the site of oxidation in active tissues. Under conditions of heavy exercise it is ultimately the working skeletal muscle cells that determine the aerobic demand as over 90% of energy is spent in muscle cells. Oxygen is transported in the circulation bound to haemoglobin of erythrocytes while substrates are transported in the plasma. The supply of oxygen must be continuous because there are only minimal oxygen stores in the body of most mammalian species while substrates are stored in significant quantities both within muscle cells as also in organismic substrate stores. The pathways for oxygen and substrates ultimately converge in muscle mitochondria. In mammals, a structural limitation of carbohydrate and lipid transfer from the microvascular system to muscle cells is reached at a moderate work intensity (i.e. at less than 50% of V˙O2max). At higher work rates intracellular substrate stores must be used for oxidation. It is therefore not surprising to find larger intramyocellular carbohydrate and lipid stores in ‘athletic’ species as well as in endurance‐trained human athletes. The transfer limitations for carbohydrates and lipids presumably occur on the level of the sarcolemma. These findings imply that the design of the respiratory cascade from lungs to muscle mitochondria has to be analysed with regard to satisfying the demand for oxygen of the working muscle cells. Substrate stores are replenished at low flux rates during periods of rest and are stored intracellularly. They are therefore locally available to mitochondria for aerobic work at high intensities.
Sex differences in pressure diuresis/natriuresis in rabbits
Authors: Evans  , Stevenson  , Bergström  , Denton  , Madden  , Gribben  , Weekes  , Anderson
Published: March 2003

We tested for sex‐related differences in the pressure diuresis/natriuresis relationships in anaesthetized, renally denervated rabbits, using an extracorporeal circuit to perfuse the left kidney with the rabbit’s own blood, through a series of step‐wise increases in renal artery pressure (RAP) (from 65 to 130 mmHg). Urine flow, sodium excretion, and the fractional excretions of sodium and urine increased with increasing RAP, and were greater in male than in female rabbits at all levels of RAP‐tested. However, these apparent sex‐related differences in the acute pressure diuresis/natriuresis relationships were not reflected in alterations in chronic regulation of mean arterial pressure (MAP). Thus, in rabbits on a normal salt diet (0.85 g day−1), resting conscious MAP was significantly greater in males (87 ± 3 mmHg) compared with females (77 ± 1 mmHg). Chronically increasing daily salt intake to 4.98 g day−1 for 28 days had no significant effect on resting conscious MAP in either sex. Thus, although our observations indicate sex differences, at least under the present experimental conditions, in the factors regulating extracellular fluid volume, these do not appear to have a major impact in setting the level of MAP in the long term.
Brief intense exercise followed by passive recovery modifies the pattern of fuel use in humans during subsequent sustained intermittent exercise
Authors: Christmass M. A. , Dawson B. , Goodman C. , Arthur P. G.
Published: March 2003

The role of work period duration as the principal factor influencing carbohydrate metabolism during intermittent exercise has been investigated. Fuel oxidation rates and muscle glycogen and free carnitine content were compared between two protocols of sustained intermittent intense exercise with identical treadmill speed and total work duration. In the first experiment subjects (n=6) completed 40 min of intermittent treadmill running involving a work : recovery cycle of 6 : 9 s or 24 : 36 s on separate days. With 24 : 36 s exercise a higher rate of carbohydrate oxidation approached significance (P=0.057), whilst fat oxidation rate was lower (P ≤ 0.01) and plasma lactate concentration higher (P ≤ 0.01). Muscle glycogen was lower post‐exercise with 24 : 36 s (P ≤ 0.05). Muscle free carnitine decreased (P ≤ 0.05), but there was no difference between protocols. In the second experiment a separate group of subjects (n=5) repeated the intermittent exercise protocols with the addition of a 10‐min bout of intense exercise, followed by 43 ± 5 min passive recovery, prior to sustained (40 min) intermittent exercise. For this experiment the difference in fuel use observed previously between 6 : 9 s and 24 : 36 s was abolished. Carbohydrate and fat oxidation, plasma lactate and muscle glycogen levels were similar in 6 : 9 s and 24 : 36 s. When compared with the first experiment, this result was because of reduced carbohydrate oxidation in 24 : 36 s (P ≤ 0.05). There was no difference, and no change, in muscle free carnitine between protocols. A 10‐min bout of intense exercise, followed by 43 ± 5 min of passive recovery, substantially modifies fuel use during subsequent intermittent intense exercise.
Influence of ruminal water‐loading on renal sodium excretion and water intake following feeding in sheep
Authors: Mathai M. L. , Thomson C. E. , Mckinley M. J.
Published: March 2003

We investigated the effect of ruminal water loading before feeding on the natriuretic and drinking responses that follow feeding. Six sheep fed 800 g of chaff drank 1360 ± 150 mL during the 5 h immediately following feeding and increased renal Na excretion. Plasma Na concentration increased by 4 mmol L–1 and plasma osmolality by 9 mosmol kg–1 within 1.5 h and remained elevated. A rumen load of water administered before feeding prevented the increases in plasma Na and osmolality without affecting feeding. The natriuresis, water drinking and vasopressin secretion in response to feeding were abolished. Total sodium excreted during the experiment was halved in water‐loaded animals compared with untreated animals (30.4 ± 2.1 mmol–1 cf. 63.8 ± 2.9 mmol–1; P < 0.01). Ruminal loading with isotonic saline caused a 33% reduction in postprandial drinking, however, reducing cerebrospinal fluid NaCl concentration abolished postprandial drinking and natriuresis. Intravenous infusion of isotonic dextran appeared to delay the onset of water intake without changing the total volume of water drunk, suggesting a role of plasma volume in initiating drinking. We conclude from the data that central osmoregulatory mechanisms that include increased sodium excretion as well as thirst and vasopressin release are activated following food intake by sheep.
Skeletal muscle disorders in heart failure
Authors: Lunde P. K. , Sjaastad I. , Schiøtz Thorud H.‐M. , Sejersted O. M.
Published: March 2003

Heart failure is associated with reduction of exercise capacity that cannot be solely ascribed to reduced maximal oxygen uptake (V˙O2max). Therefore, research has focused on changes in skeletal muscle morphology, metabolism and function. Factors that can cause such changes in skeletal muscle comprise inactivity, malnutrition, constant or repeated episodes of inadequate oxygen delivery and prolonged exposure to altered neurohumoural stimuli. Most of these factors are not specific for the heart failure condition. On the other hand, heart failure is more than one clinical condition. Congestive heart failure (CHF) develops gradually as a result of deteriorating contractility of the viable myocardium, myocardial failure. Is it possible that development of this contractile deficit in the myocardium is paralleled by a corresponding contractile deficit of the skeletal muscles? This question cannot be answered today. Both patient studies and experimental studies support that there is a switch to a faster muscle phenotype and energy metabolism balance is more anaerobic. The muscle atrophy seen in many patients is not so evident in experimental studies. Few investigators have studied contractile function. Both fast twitch and slow twitch muscles seem to become slower, not faster as might be expected, and this is possibly linked to slower intracellular Ca2+cycling. The neurohumoural stimuli that can cause this change are not known, but recently it has been reported that several cytokines are increased in CHF patients. Thus, the changes seen in skeletal muscles during CHF are partly secondary to inactivity, but the possibility remains that the contractility is altered because of intracellular changes of Ca2+metabolism that are also seen in the myocardium.
Neural control: novel evaluation of stretch reflex sensitivity
Authors: Nakazawa K. , Yamamoto S.‐I. , Ohtsuki T. , Yano H. , Fukunaga T.
Published: March 2003

We evaluated the stretch reflex activities of the elbow flexor and extensor muscles considering the relationship between the reflex electromyographic (EMG) responses and their corresponding standardized muscle stretch velocities. Specifically, muscular stretch velocity was estimated by using ultrasonograms. Stretch reflex EMG responses were elicited in the biceps brachii, brachioradialis and triceps brachii with a ramp‐and‐hold rotation at the elbow joint, which consisted of various angular velocities for the extension‐ or flexion‐direction. The whole muscle stretch velocity induced by each ramp‐and‐hold rotation was calculated on the basis of fibre length changes associated with the elbow joint angle. A linear regression equation was fitted to the relation between the whole muscle stretch velocity and the reflex EMG responses, and the variables from the equation were used to quantify sensitivity of each reflex EMG component. The reflex EMG responses were increased as the ramp‐and‐hold rotational velocity increased. There were no significant differences in the recorded magnitudes of reflex EMG responses with equivalent joint rotational velocity between the brachioradialis and the triceps brachii medial head. These muscles showed the highest reflex responses in the flexor and extensor muscles, respectively. To the contrary, the reflex EMG response elicited by the standardized muscle stretches was significantly greater in the extensor muscles, indicating a higher reflex sensitivity. This was because of the lower muscle stretch velocity of the triceps brachii with an equivalent elbow joint rotation. The stretch reflex sensitivity in both the elbow flexor and extensor muscles might be regulated so as to make the reflex responses the same when the equivalent joint rotational velocity is applied to these muscles.
Neutrophil–endothelial cell interactions during the development of tolerance to ischaemia/reperfusion in isolated cells
Authors: Cepinskas G. , Rui T. , Kvietys P. R.
Published: March 2003

Ischaemia/reperfusion (I/R) tolerance refers to the phenomenon by which the inflammation and associated sequelae induced by I/R is ameliorated by an I/R challenge imposed 24 h earlier. The development of I/R tolerance is dependent on the synthesis of new proteins. In vivo and in vitro studies provide support for nitric oxide synthase (NOS), antioxidant enzymes, and heat shock proteins (HSPs) as the effector proteins. Activation of the nuclear transcription factor, NFκB, appears to be a prerequisite for the development of I/R tolerance. In vitro approaches using anoxia/reoxygenation (A/R) to mimic I/R have provided insights into the complexity of the development of I/R tolerance, i.e. different cells may use different signalling pathways to develop A/R tolerance and influence the responses of adjacent cells during the process. The use of cells from genetically altered mice is expediting attempts to unravel specific mechanisms involved in the development of A/R tolerance.
Inducible nitric oxide synthase (iNOS) and regulation of leucocyte/endothelial cell interactions: studies in iNOS‐deficient mice
Authors: Hickey M. J. , Granger D. N. , Kubes P.
Published: March 2003

It is well established that constitutive production of nitric oxide is central to numerous processes in the microvasculature, including controlling the trafficking of inflammatory leucocytes. However, during many inflammatory responses induction of inducible nitric oxide synthase (iNOS) increases nitric oxide production. The role of iNOS‐derived nitric oxide in modulating leucocyte recruitment is less well understood, although recent studies using iNOS‐deficient mice have begun to examine this issue. This article describes much of the work that implicates iNOS as having a role in controlling leucocyte recruitment, including the intravital microscopy studies which revealed that iNOS‐deficient mice have elevated leucocyte–endothelial cell interactions during endotoxaemia. Furthermore in additional studies, we compared expression of endothelial adhesion molecules in wild‐type and iNOS‐deficient mice, under conditions in which iNOS was expressed. Adhesion molecule expression was measured using an in vivo dual radiolabel immunoassay. To induce iNOS, mice were treated with either 1 or 50 μg of bacterial lipopolysaccharide (LPS), and 4 h later expression of P‐selectin, E‐selectin and vascular cell adhesion molecule‐1 was determined in eight different tissues. In nearly all cases, adhesion molecule expression did not differ between the two types of mice, either in the absence of an inflammatory stimulus, or following LPS treatment. These findings indicate that iNOS does not regulate expression of endothelial adhesion molecules either under basal conditions, or during the endotoxaemic response. This further suggests that alterations in leucocyte function may mediate the modulating effect of iNOS on leucocyte recruitment.
Effects of rhythmic muscle compression on arterial blood pressure at rest and during dynamic exercise in humans
Authors: Nishiyasu T. , Sone R. , Tan N. , Maekawa T. , Kondo N.
Published: March 2003

This study was designed to examine the hypothesis that a rhythmic mechanical compression of muscles would affect systemic blood pressure regulation at rest and during dynamic exercise in humans. We measured the changes in mean arterial pressure (MAP) occurring (a) at rest with pulsed (350 ms pulses at 50 pulses min–1) or static compression (50 and 100 mmHg) of leg muscles with or without upper thigh occlusion, and (b) during 12‐min supine bicycle exercise (75 W, 50 r.p.m.) with or without pulsed compression (50, 100, 150 mmHg) of the legs in synchrony with the thigh extensor muscle contraction. At rest with thigh occlusion, MAP increased by 4–8 mmHg during static leg compression, and by 5–9 mmHg during pulsed leg compression. This suggests that at rest pulsed leg compression elicits a reflex pressor response of similar magnitude to that evoked by static compression. During dynamic exercise without leg compression, MAP (having risen initially) gradually declined, but imposition of graded pulsed leg compression prevented this decline, the MAP values being significantly higher than those recorded without pulsed leg compression by 7–10 mmHg. These results suggest that the rhythmic increase in intramuscular pressure that occurs during dynamic exercise evokes a pressor response in humans.
Unravelling mechanisms of action of angiotensin II on cardiorespiratory function using in vivo gene transfer
Authors: Paton J. F. R. , Boscan P. , Murphy D. , Kasparov S.
Published: March 2003

We review recent and ongoing work from our laboratory that has shed novel insights into the effects of angiotensin II (ANGII) on the baroreflex at the level of the nucleus of the solitary tract (NTS). The NTS is the site of termination for baroreceptor afferents and is a potentially powerful region for neuronal modulation. ANGII applied to this nucleus attenuated the cardiac vagal and cardiac sympathetic components of the baroreceptor reflex. This effect was antagonized by blockade of either γ‐amino butyric acid receptors or nitric oxide synthase within the NTS. Interestingly, nitric oxide donors microinjected into the NTS mimicked the effect of ANGII. Using an adenovirus we showed that ANGII activated the endothelial isoform of nitric oxide synthase. The NTS was transfected to express a dominant negative truncated mutant form of endothelial nitric oxide synthase that prevented the depressant effect of ANGII on the baroreflex. Endothelial nitric oxide synthase was present in both neurones and endothelium in the NTS. A possibility is that ANGII activation of endothelial nitric oxide synthase is calcium dependent. However, in most NTS neurones tested, ANGII failed to elevate intracellular calcium concentration. We conclude that ANGII activates endothelial nitric oxide synthase to release nitric oxide which enhances γ‐amino butyric acid transmission destined for circuitry mediating the baroreflex. We discuss the contribution of endothelial cells within the nucleus of the solitary tract as a potential target for both circulating and/or centrally produced ANGII. These data have relevance to patients with essential hypertension and left heart failure, conditions in which ANGII activity is elevated and the baroreceptor reflex is depressed.
Inflammatory bowel disease: pathogenesis and targets for therapeutic interventions
Authors: Panés J.
Published: March 2003

Ulcerative colitis and Crohn’s disease are chronic inflammatory bowel diseases (IBDs) with a chronic relapsing course. The aetiology of these diseases remains unknown, but in the last decade an increase in experimental models of IBD has led to expansion of our understanding in various aspects of the aetiology and pathogenic mechanisms of IBD. A growing body of evidence coming from these models indicates that an immune response against gut constituents is of critical importance for intestinal inflammation and the subsequent destruction of the mucosa. For this reason, research on IBD has focused intensely on the immune and non‐immune cell subsets as well as the soluble mediators involved in normal and dysregulated immune responses. An appreciation of the current knowledge of the pathogenesis of IBD is of paramount importance for the understanding of current, and development of new, treatment modalities.
Characterization of voltage‐gated calcium currents in freshly isolated smooth muscle cells from rat tail main artery
Authors: Petkov G. V. , Fusi F. , Saponara S. , Gagov H. S. , Sgaragli G. P. , Boev K. K.
Published: March 2003

The aim of the present study was to characterize voltage‐gated Ca2+currents in smooth muscle cells freshly isolated from rat tail main artery in the presence of 5 mmol L–1external Ca2+. Calcium currents were identified on the basis of their voltage dependencies and sensitivity to nifedipine, Ni2+and cinnarizine. In the majority of the cells studied, T‐ and L‐type currents were observed, while the remaining cells showed predominantly L‐type currents. In the latter group of cells, holding potential change from –50 to either –70 or –90 mV increased the corresponding inward current amplitude while its voltage activation threshold remained unchanged. The steady state inactivation of L‐type Ca2+channels showed half‐maximal inactivation at –38 mV. A Ca2+‐dependent inactivation was also evident. Nifedipine (3 μmol L–1) blocked L‐type but not T‐type Ca2+currents. Ni2+(50 μmol L–1) as well as cinnarizine (1 μmol L–1) suppressed the nifedipine‐resistant, T‐type component of the currents. At higher concentrations, both Ni2+(0.3–1 mmol L–1) and cinnarizine (10 μmol L–1) blocked the net inward current. Replacement of Ca2+with 10 mmol L–1Ba2+significantly increased the amplitude of L‐type Ca2+currents. These results demonstrate that smooth muscle cells freshly isolated from rat tail main artery may be divided into two populations, one expressing both L‐ and T‐type and the other only L‐type Ca2+channels. Furthermore, this report shows that in arterial smooth muscle cells cinnarizine potently inhibited T‐type currents at low concentrations (1 μmol L–1) but also blocked L‐type Ca2+currents at higher concentrations (10 μmol L–1).
Serosal application of Ba2+ induces oscillatory chloride secretion via activation of submucosal cholinergic neurones in guinea‐pig distal colon
Authors: NISHIKITANI M. , KOKUBO A. , TAKEMURA H. , SAIGENJI K. , KAWAHARA K.
Published: March 2003

The enteric nervous system regulates ion and fluid secretion in the mammalian intestine at both resting and stimulated conditions. To determine the type and activation mechanism of neurones involved, mucosa–submucosa sheets isolated from guinea‐pig distal colon were studied in vitro in Ussing chambers. Serosal addition of 0.5–1 mM barium (Ba2+), a potassium (K+) channel inhibitor, caused oscillatory increases in short‐circuit current (Isc). Mean values of the size and frequency of Isc were 369.1 μA cm–2 and 2.3 min–1. The oscillatory Isc induced by the low concentrations of Ba2+ was blocked by either higher concentrations of Ba2+ (2–5 mM) or other K+ channel inhibitors, such as tetraethylammonium (TEA) (1 mM) and quinine (20 mM). The Ba2+‐induced oscillatory Isc was also inhibited by tetrodotoxin (TTX) and atropine. In a nominally Ca2+ free solution plus serosal addition of 0.1 mM ethylene glycol‐bis (β‐aminoethyl ether) N,N,N′,N′‐tetraacetic acid (EGTA), a Ca2+ chelator, the oscillatory Isc slowed and diminished. Further, the Ba2+‐induced oscillatory Isc was partially inhibited by apical addition of 100 μM 5′‐nitro‐2‐(3‐phenylpropylamino)benzoic‐acid (NPPB), a Cl– channel inhibitor, and completely disappeared in a low Cl– solution (11 mM) on both sides. On the other hand, application of either cimetidine, a histamine H2 receptor antagonist, or hexamethonium, a nicotinic antagonist, to the serosal side did not affect the Ba2+‐induced oscillatory Isc. In conclusion, the Ba2+‐induced oscillatory Isc is the transepithelial Cl– current which is stimulated by activation of cholinergic neurones in submucosal plexus of guinea‐pig distal colon.
Increased phasic activity of dopaminergic neurones in the rat ventral tegmental area following pharmacologically elevated levels of endogenous kynurenic acid
Authors: ERHARDT S. , ENGBERG G.
Published: March 2003

Kynurenic acid (KYNA) is an antagonist of ionotropic glutamate receptors, preferentially blocking the glycine‐site of the N‐methyl‐D‐aspartate (NMDA) receptor. In the present electrophysiological study, the firing pattern of dopamine (DA) neurones of rat ventral tegmental area (VTA) was investigated following pharmacologically elevated endogenous levels of KYNA by means of an inhibitor of kynurenine 3‐hydroxylase (PNU 156561A). Pre‐treatment with PNU 156561A (40 mg kg–1, i.v., 5–9 h) caused a threefold increase in endogenous KYNA in whole brain levels and also evoked a significant increase in firing rate and bursting activity of VTA DA neurones. Administration of D‐cycloserine (2–128 mg kg–1, i.v.), a partial agonist at the glycine‐site of the NMDA‐receptor, was found to reverse the increase in firing rate and bursting activity as induced by elevated concentrations of KYNA. The electrophysiological effects of elevated KYNA levels were in all essential mimicked by administration of the NMDA‐receptor antagonist MK 801 (0.05–1.6 mg kg–1, i.v.). Thus, the effects of elevated endogenous brain KYNA observed in the present study are likely to be carried out by NMDA receptor antagonism. In conclusion, this study shows that an increase in endogenous KYNA levels produces significant actions on the tonic afferent control of the firing pattern of VTA DA neurones. Given the psychotomimetic effects of NMDA‐receptor antagonists, e.g. phencyclidine and ketamine, the state of hyperactivity of mesocorticolimbic DA system induced by elevated levels of KYNA may represent a pathophysiological condition analogous to that seen in schizophrenic patients.
Analysis of myogenic mechanisms in renal autoregulation
Authors: KIIL F.
Published: March 2003

To examine whether local myogenic mechanisms account for autoregulation of renal blood flow, a theoretical analysis was undertaken on a model of the pre‐glomerular vascular tree consisting of a main and a short, narrow juxtaglomerular segment. At atmospheric extravascular pressure in vitro data are consistent with a relationship r=r0(1 + k – pk) between radius (r) and transmural pressure (p) at p > 60 mmHg, where k can be estimated from in vitro data and r=r0 at complete autoregulatory vasodilation. After introducing r=r0(1 + k – pk), Poiseuille's formula was integrated along the main segment, Δx long, between arterial pressure P1 and P2 at the end of the main segment. At the lowest autoregulatory pressure P1=65 mmHg pre‐glomerular blood flow is F=5Kr04/Δx. At P1=140 mmHg a pressure drop of only 17 mmHg to P2=123 mmHg is sufficient to fulfil the criterion for complete autoregulation: F=5Kr04/Δx. Thus, 80% of the total pre‐glomerular vascular resistance is localized to the juxtaglomerular segment. Loop diuretics may abolish juxtaglomerular contractility. Calculated flow/pressure relationships after eliminating juxtaglomerular contractility are similar to those obtained after administering ethacrynic acid. If a constant tension hypothesis (r=60r0/p) rather than the transmural pressure hypothesis [r=r0(1 + k – pk)] applies, complete autoregulation is maintained to P2=89 mmHg, but the effect of loop diuretics is not mimicked. In conclusion, high juxtaglomerular contractility may be attributed to a myogenic mechanism only if extravascular pressure in the juxtaglomerular segment is subatmospheric.