bluuebunny/crossref_metadata_2025 huggingface dataset:
Relative susceptibility of endothelium and myocardial cells to ischaemia‐reperfusion injury
Authors: MANKAD P.S. , AMRANI M. , ROTHERY S. , SEVERS N.J. , YACOUB M.H.
Published: October 2003

We have investigated the timescale, extent and sequence of endothelial, myocardial and smooth muscle cell dysfunction following ischaemia‐reperfusion in the isolated rat heart. Myocardial function in the form of aortic flow was evaluated in the working heart preparation. Vasodilatation induced by endothelium‐dependent agent 5‐hydroxytryptamine (5‐HT) and endothelium‐independent substance glyceryl trinitrate (GTN) was used to assess endothelial and smooth muscle function, respectively. The percentage recovery of 5‐HT response and aortic flow (endothelial vs. myocardial function) plus 5‐HT response and GTN effect (endothelial function vs. smooth muscle response) after a period of ischaemia was statistically analysed by Wilcoxon's signed rank test. A possible correlation between structural and functional changes in coronary vascular endothelium after ischaemia was also explored by comparing endothelial dysfunction with morphological assessment of endothelial damage seen after ischaemia. The experiments were performed at two clinically relevant temperatures of 20 °C and 4 °C. There was no significant difference in the percentage recovery of aortic flow and 5‐HT response or in 5‐HT response and GTN effect after 30 min of unprotected ischaemia at 4 °C. The same duration of ischaemia at 20 °C led to significantly better recovery of GTN effect as compared with 5‐HT response, but there was no difference in the recovery of aortic flow and 5‐HT response. Sixty minutes of unprotected ischaemia at both temperatures caused significantly better recovery of aortic flow and GTN effect as compared with 5‐HT response; 60 min of ischaemia protected by an infusion of a cardioplegic solution (protected ischaemia) at 4 °C had no significant effect on the recovery of the three parameters. Periods of 90, 120, 180 and 240 min of protected ischaemia at 4 °C, and 60, 90 and 120 min of protected ischaemia at 20 °C resulted in significantly better recovery of aortic flow compared with 5‐HT response and of GTN effect as compared to 5‐HT response. This demonstrates varying susceptibility of different cell types to ischaemic injury and highlights the strong vulnerability of endothelium to ischaemic damage as compared with myocytes and smooth muscle cells. Furthermore, there was lack of correlation between post‐ischaemic endothelial dysfunction and microscopically assessed structural damage.
Effect of a new nitric oxide donor on the biomechanical performance of the isolated ischaemic rat heart
Authors: SZEKERES M. , DÉZSI L. , MONOS E. , METSÄ‐KETELÄ T.
Published: October 2003

The effect of a new nitric oxide (NO) donor, a meso‐ionic 3‐aryl substituted oxatriazole‐5‐imine derivative, GEA 3162 was studied on constant flow‐perfused ischaemic Langendorff rat heart. The perfusion was kept constant at a rate of 16 mL min−1. Ischaemia was induced by a low flow rate of 0.8 mL min−1 for 30 min, and was followed by a 40‐minute reperfusion. In the first set of experiments the effects of GEA 3162‐infusion were examined on perfusion pressure, left ventricular pressure, heart rate and left ventricular dP/dt. GEA 3162 infusion did not affect the pre‐ischaemic maximum of left ventricular pressure. During reperfusion, maximal left ventricular pressure, maximal and minimal dP/dt values in the GEA 3162‐treated group significantly exceeded those of the untreated controls (by 19.3, 36.0 and 18.0%, respectively). During reperfusion, perfusion pressure increased continuously in the control group indicating an increasing coronary resistance, but it was kept at a continuous low level with GEA 3162 treatment. In a second set of experiments bradykinin was infused in order to test the endothelial function before ischaemia and during late reperfusion. Bradykinin elicited significant vasodilation in the control group during reperfusion, meanwhile it did not cause further change in coronary resistance in the GEA 3162‐infused group. We suggest, that GEA 3162 may have a protective effect on isolated rat heart in ischaemia and reperfusion, that results in an improved cardiac performance compared with untreated hearts.
Effects of ubiquinone‐10 supplementation and high intensity training on physical performance in humans
Authors: MALM C. , SVENSSON M. , EKBLOM B. , SJÖDIN B.
Published: October 2003

This study investigated the effects of oral supplementation with ubiquinone‐10 (Q10) (n = 9) compared with a placebo (n = 9) on aerobic and anaerobic physical performance over 22 days of supplementation. The supplementation period included 5 days of high intensity anaerobic training between days 11 and 14. The results demonstrated, that on an anaerobic (10 × 10 s) cycling test, the␣placebo group showed a significantly greater improvement than the Q10‐group after a supplementation and training period (P < 0.001). Further, the Q10 group had a significantly lower increase in total work performed during the seven training sessions (15 × 10 s) compared with the placebo group (P < 0.001). There was a significant increase in maximal blood lactate accumulation during cycling in the both groups, when compared with levels before the training and recovery period. There was no significant difference between the groups, either in VO2max determined during running, or in submaximal and peak VO2, Rate of Perceived Exertion, respiratory quotient, blood lactate concentration or heart rate determined during submaximal and maximal cycling. Although insignificant␣(P = 0.1–0.3), there was evidence of higher submaximal VO2 (55–80% of VO2peak) during cycling in the Q10‐group compared with the placebo group after training and recovery. It is concluded that with high intensity anaerobic training, there was a significantly greater increase in anaerobic performance in the placebo group compared with the Q10 group. The results suggest less increase in physical performance with Q10 supplement and high intensity anaerobic training, compared with placebo.
Altered antioxidant enzyme defences in insulin‐dependent diabetic men with increased resting and exercise‐induced oxidative stress
Authors: ATALAY M. , LAAKSONEN D. E. , NISKANEN L. , UUSITUPA M. , HÄNNINEN O. , SEN C. K.
Published: October 2003

Impaired antioxidant defences may predispose to the increased resting and exercise‐induced oxidative stress found in patients with insulin‐dependent diabetes mellitus (IDDM). We investigated major erythrocyte antioxidant enzyme activities at rest and in response to sustained, moderate intensity physical exercise in young diabetic men (n = 9) previously reported to have markedly elevated plasma lipid peroxidation and blood glutathione levels compared with control men (n = 13) (Laaksonen et al. 1996). At rest, erythrocyte glutathione reductase activity was 15% higher in the diabetic group (P = 0.049). Se‐glutathione peroxidase and glutathione‐S‐transferase activities were similar in both groups. Red cell Cu, Zn‐superoxide dismutase and catalase activities were lower in the IDDM group (P = 0.033 and P = 0.023, respectively). After 40 min of exercise at 60% of the subjects' peak oxygen consumption, Se‐glutathione peroxidase activity rose by about 14% in the control group (P = 0.003), but not in the IDDM group (P = 0.47). Exercise did not cause significant changes in other enzyme activities in either group. To conclude, lower erythrocyte Cu, Zn‐superoxide dismutase and catalase activity in young men with IDDM at rest may contribute to increased oxidative stress. On the other hand, increased glutathione reductase activity may represent a compensatory upregulation of glutathione homeostasis in response to increased oxidative stress. Upregulation of Se‐glutathione peroxidase activity in response to physical activity appeared to be impaired in men with IDDM.
Effects of scorpion venom on central and peripheral circulatory response in an open‐chest dog model
Authors: TARASIUK A. , JANCO J. , SOFER S.
Published: October 2003

Scorpion venom can induce in dogs severe haemodynamic changes leading to rapid rise in systemic blood pressure and cardiac output, followed by reduction of cardiac output and blood pressure within 1 h. The decrease in cardiac output is not related to myocardial dysfunction (Tarasiuk et al. 1994). We hypothesized that scorpion venom affects cardiac output by reducing venous return to the heart. Venous return was studied by steady‐state measurements of cardiac output, the pressure gradient and resistance to venous return, in 16 dogs following injection of 0.05 mg kg−1 venom obtained from the scorpion species Leiurus quinquestriatus. In eight of the 16 dogs, atropine (0.1 mg kg−1) was given 15 min prior to venom injection (n = 4) or 85 min (n = 4) after venom administration. In five additional dogs, the stability of the preparation over time was evaluated following the same protocol without the injection of the venom. At 15 min, the venom induced an increase in blood pressure (80%) and cardiac output (250%) (P < 0.001) with little effect on heart rate. At 90 min, cardiac output and heart rate declined considerably below baseline (P < 0.001). Atropine prevented the decrease in heart rate, but did not affect the reduction of cardiac output. Five minutes after venom injection, mean circulatory pressure increased by 300% (P < 0.001), which was accompanied by a rightward shift of the venous return curve with no effect on resistance to venous return. At 120 min, mean circulatory pressure recovered and resistance to venous return remained at 40% (P < 0.01) above baseline. This study indicates that, in dogs, scorpion venom affects cardiac output by modifying the determinants of venous return. The initial increase in cardiac output is related to increased mean circulatory pressure since resistance to venous return did not change. The later fall in cardiac output is related to the reduction of mean circulatory pressure and increased resistance to venous return.
Circadian blood pressure and systemic haemodynamics during 42 days of 6° head‐down tilt
Authors: VOOGEL A. J. , STOK W. J. , PRETORIUS P. J. , MONTFRANS G. A. VAN , LANGEWOUTERS G. J. , KAREMAKER J. M.
Published: October 2003

Head‐down tilted bedrest is a ground‐based microgravity simulation model. Since in this position the influence of chief external determinants of circadian blood pressure variation, i.e. activity and posture, are reduced, it may reveal endogenous oscillatory factors. The effects of 42 days of 6° head‐down tilt on the circadian profiles of continuous finger blood pressure, heart rate, stroke volume, cardiac output and total peripheral resistance were analysed. In seven healthy volunteers (25–31 years) twelve 22 h Portapres registrations were performed: two in an ambulatory baseline period, eight during 42 days of head‐down tilt, and two during recovery. Stroke volume was estimated by a pulse contour method (`Modelflow') from the finger arterial blood pressure tracing. Head‐down tilt rapidly reduced circadian BP variation, especially for diastolic blood pressure. No effect of long‐term head‐down tilt on blood pressure level was observed. The day‐night difference in heart rate was essentially unaffected. Cardiac output was maintained through an increase of heart rate and simultaneous decline of stroke volume. Our observations confirm the overriding importance of physical activity and orthostatic load on the diurnal variation of BP. The time‐frame of the changes in stroke volume and heart rate during head‐down tilt might point to a contribution of other factors besides a reduction of circulating blood volume affecting cardiovascular performance under these conditions.
Exogenous endothelin‐1 causes peripheral insulin resistance in healthy humans
Authors: OTTOSSON‐SEEBERGER A. , LUNDBERG J.M. , ALVESTRAND A. , AHLBORG G.
Published: October 2003

In states of insulin resistance, increased plasma levels of endothelin‐1 and a disturbed vascular reactivity have been reported. In order to investigate the effects of endothelin‐1 on peripheral insulin sensitivity and the vasoactive interactions between insulin and endothelin‐1, six healthy subjects were studied on two different occasions with the euglycaemic hyperinsulinaemic clamp technique combined with an intravenous infusion of either endothelin‐1 (4 pmol kg−1 min−1) or 0.9% sodium chloride. During the endothelin‐1 infusion, arterial plasma endothelin‐1 levels rose 10‐fold. The endothelin‐1 infusion reduced insulin sensitivity as demonstrated by a 31 ± 7% decrease in whole‐body glucose uptake (P < 0.05) and a 26 ± 11% fall in leg glucose uptake (P < 0.05) compared with the control protocol. During the state of hyperinsulinaemia, exogenous endothelin‐1 increased mean arterial blood pressure by 8 ± 1% (P < 0.05) and decreased splanchnic and renal blood flow by 30 ± 6% (P < 0.001) and 20 ± 4% (P < 0.001), respectively. However, the endothelin‐1 infusion did not lower skeletal muscle blood flow measured as leg and forearm blood flow. In summary, exogenous endothelin‐1 induced insulin resistance in healthy humans by reducing insulin‐dependent glucose uptake in skeletal muscle without decreasing skeletal muscle blood flow. Furthermore, endothelin‐1 also preserved its vasoactive potency in the presence of hyperinsulinaemia.
Serotonin inhibition of 1‐methylxanthine metabolism parallels its vasoconstrictor activity and inhibition of oxygen uptake in perfused rat hindlimb
Authors: RATTIGAN S. , APPLEBY G. J. , MILLER K. A. , STEEN J. T. , DORA K. A. , COLQUHOUN E.Q. , CLARK M. G.
Published: October 2003

The effect of serotonin (5‐HT) on the metabolism of infused 1‐methylxanthine (1‐MX), a putative substrate of capillary endothelial xanthine oxidase (XO), and on the distribution of infused fluorescent microspheres (15 μm) by the artificially constant‐flow perfused rat hindlimb preparation was investigated. 1‐MX (5–100 μM) caused a slight inhibition of oxygen uptake (V˙O2) but was not vasoactive, either alone or with 5‐HT. 1‐MX was converted to 1‐methylurate (1‐MU) and this conversion was inhibited by allopurinol and xanthine. 5‐HT (0.35 μM), which caused vasoconstriction and decreased V˙O2, also inhibited the conversion of 1‐MX, indicated by a lowered venous perfusate steady‐state 1‐MU:1‐MX ratio from 1.14 ± 0.02 to 0.71 ± 0.02 (P < 0.001), which is equivalent to the rate of conversion decreasing from 0.83 ± 0.03 to 0.63 ± 0.05 nmol min−1 g−1. This change closely followed the time course for changes in V˙O2 and perfusion pressure and all three changes reversed in parallel when 5‐HT was removed. Recoveries of 1‐MU plus 1‐MX at all times were high (100 ± 5%). 5‐HT did not act to inhibit XO. When compared with vehicle alone, 5‐HT had either no effect (plantaris, gastrocnemius white, tibialis, extensor digitorum longus, vastus and thigh), or increased microsphere content (soleus and gastrocnemius red, P < 0.05) of muscles with only bone showing a significant decrease (P < 0.05). Since 5‐HT did not inhibit XO or alter the net flow to individual muscles in this constant‐flow model, the inhibition of conversion of 1‐MX to 1‐MU is concluded to be the result of a 5‐HT‐mediated decrease in the access of 1‐MX to capillary XO within individual muscles. Possibilities include the redirection of flow to capillaries either in muscle or in connective tissue closely associated with muscle, where resistance is low and effective surface area is less. 1‐MX has potential as a marker for muscle nutritive flow.
Vasomotion in rat diaphragm microcirculation at rest and during stepwise arterial pressure reduction
Authors: CHEN C. W. , LEE C. H. , HSIUE T. R. , CHANG H. Y.
Published: October 2003

The effect of haemorrhagic hypotension on the incidence, frequency and relative amplitude of vasomotion in rat diaphragm microcirculation was assessed by laser Doppler flowmetry (LDF). Graded bleeding to four hypotension levels (80, 60, 40 and 30% of the control state) were performed in 24 Sprague–Dawley rats. The incidence of vasomotion was 83% in the control state, 96% at the 80% level, 100% at the 60% level, 96% at the 40% level, and 46% at the 30% level. The median fundamental frequency of vasomotion determined manually during the control state and at the hypotension levels (in descending order) was 4.11 (range, 3.29–5.58) cycles min−1 (cpm), 4.48 (3.21–5.92) cpm, 4.20 (3.5–5.56) cpm, 4.01 (3.33–5.36) cpm, 3.71 (3.25–4.49) cpm (P < 0.01 from the fundamental frequency at 80 and 60% hypotension levels). The median relative amplitudes determined manually during the control state and descending hypotension levels were 44.5% (range, 24.9–135.9%), 69.4% (26.6–147.2%), 84.0% (40.3–177.1%) (P < 0.01 from resting and last stage of bleeding), 90.40% (26.2–189.6%) (P < 0.01 from resting and last stage of bleeding), 69.2% (35.6–93.2%). We concluded first that during the resting condition, vasomotion was frequently present in diaphragm microcirculation, which is distinct from other vascular beds of skeletal muscles. Second, the relative amplitude of vasomotion during haemorrhagic hypotension plotted against decreasing blood pressure exhibited a reverse U‐shaped curve with a maximum at 40–60% of the control blood pressure, while the frequency of vasomotion remained relatively constant until the last stage of haemorrhage and centred around 3–5 cpm.
Acute microcirculatory changes after scalding of the rat paw
Authors: LÖFGREN O. , GAZELIUS B. , LUNDEBERG T.
Published: October 2003

A scalding model in the anaesthetized rat was used to measure acute circulatory reactions after heat exposure. Local blood flow of both hindpaws was recorded simultaneously and continuously by laser Doppler flowmetry before, during and for 2 hours following scalding. The scalding injury was inflicted by dipping the right hindpaw into hot water at 60 °C for 20 s. Concomitantly, the mean arterial blood pressure (MAP) was displayed on a chart recorder. MAP was obtained by cannulation of the common carotid artery. Oedema formation was calculated by measuring the volume changes of the hindpaws in a plethysmometer before and 30, 60 and 120 min after scalding. Scalding was followed by a biphasic increase of cutaneous circulation. During the first minute after heat provocation, an immediate increase in blood perfusion of about 400% was recorded, followed by a slow decrease of circulation. At 30 min after scalding, there was a secondary phase of increased microcirculation of approximatelly 230%. A slow decline of cutaneous circulation then followed, and after about 60 min the value was stabilized at ≈100% above pre‐burn level throughout the observation time. Almost no change of perfusion was observed on the contralateral unscalded paw. The scalding injury was followed by a progressive oedema formation on the scalded paw, measured by a volume increase of ≈72% during the observation period, whereas the non‐scalded paw showed no change. MAP remained at a stable level throughout the experiment except for a short‐lasting transient increase of ≈10% at the same time as the first peak of blood perfusion. We could thus confirm that scalding in the present model is accompanied by an immediate and marked increase in the peripheral circulation of the scalded paw followed by a later propagation of oedema, and that these inflammatory changes do not appear to be related to central haemodynamic alterations.
Rate of oxidative phosphorylation in isolated mitochondria from human skeletal muscle: effect of training status
Authors: TONKONOGI M. , SAHLIN K.
Published: October 2003

Muscle oxidative function has been investigated in subjects with various training status (VO2 max, 41–72 mL O2 kg−1 body wt min−1, n=10). Mitochondria were isolated from biopsies taken from m. vastus lateralis. Maximal mitochondrial oxygen consumption (QO2) and ATP production (MAPR) were measured with polarographic and bioluminometric techniques, respectively. The yield of mitochondria, calculated from the fractional activity of citrate synthase (CS), averaged 26%. With pyruvate + malate, the respiratory control ratio was 5.7 ± 0.4 (X ± SE) and the P/O ratio was 2.83 ± 0.02, which demonstrates that the isolated mitochondria were functionally intact. QO2 was significantly correlated to aerobic training status expressed as muscle CS activity (r=0.86), VO2 max (r=0.84) and lactate threshold (r=0.83) but not to the fibre type composition. A highly significant correlation (r=0.93) was observed between ATP production calculated from QO2 and MAPR, but ATP production derived from QO2 was higher than MAPR both for pyruvate + malate (255%) and for α‐ketoglutarate (23%). QO2 extrapolated to a temperature of 38 °C averaged 68 mL O2 min−1 kg−1 wet wt, which is similar to previous findings in vitro and in vivo during the post‐exercise period. However, calculated muscle O2 utilization during exercise was three‐ to fivefold higher than QO2 measured on isolated mitochondria. It is suggested that additional factors exist for activation of mitochondrial respiration during exercise. It is concluded that muscle oxidative function can be quantitatively assessed from the respiration of mitochondria isolated from needle biopsy specimens and that QO2 is closely correlated to whole‐body VO2 max.
Radiotelemetrically recorded blood pressure and heart rate changes in relation to plasma catecholamine levels during parturition in the conscious, unrestrained goat
Authors: HYDBRING E. , MACDONALD E. , OLSSON K.
Published: October 2003

The aim of this study was to investigate the extent of sympathetic nervous system activation during parturition in four unrestrained goats. Chronically implanted radiotelemetry devices registered heart rate and arterial blood pressure around the clock and blood was sampled for determination of plasma adrenaline and noradrenaline concentrations before, during and after labour. Two goats delivered two kids after moderately intensive abdominal contractions. A third goat had dystocia, and was treated with prostaglandin F2α. One normal kid and one mummified foetus were delivered manually. After milking, a third kid was born spontaneously. The fourth goat experienced severe abdominal contractions and delivered one kid. Mean blood pressure was 69 ± 2 mmHg the day before parturition, increased gradually during the labour pains, and reached a maximal value of 120 ± 7 mmHg when the head of the first kid was visible (P ≤ 0.05). Heart rate was 134 ± 4 beats min−1 the day before parturition and peaked when the first kid was born (159 ± 6 beats min−1, P ≤ 0.05), as did plasma adrenaline concentration (from 0.4 ± 0.2 nmol L−1 to 2.7 ± 1.2 nmol L−1, P ≤ 0.05). The concentration of noradrenaline increased from 4.8 ± 2.3 nmol L−1 to 12.2 ± 8.4 nmol L−1 (P ≤ 0.05), when the head of the first kid was visible. Expulsion of the second and third kids caused relatively smaller increases in blood pressure, heart rate and catecholamines than those seen with the first born kid. It is concluded that changes in pressure, heart rate and catecholamines during parturition are related to the different phases of labour and not to its duration or severity.
Effects of pretreatment with an indeno‐indole compound on lipid peroxidation in the cortex and medulla of rabbit kidneys after ischaemia‐reperfusion
Authors: SØRENSEN V. , NILSSON U. , PETTERSSON S. , SCHERSTÉN T. , SJÖQUIST P. O. , SVENSSON L. , JONSSON O.
Published: October 2003

The effects of 60 min of ischaemia with or without reoxygenation in vivo or in vitro on lipid peroxidation in cortical and medullary tissue from rabbit kidneys were measured as production of thiobarbituric acid‐reactive substances (TBARS). Lipid peroxidation was more pronounced in medullary tissue compared with cortical tissue. The highest TBARS production was found in medullary slices subjected to reoxygenation in vitro immediately after 1 h of ischaemia. Reperfusion in vivo before reoxygenation in vitro attenuated the TBARS formation during subsequent in vitro incubation. Pretreatment of the rabbits with an indeno‐indole compound (code name H 290/51) reduced the TBARS formation after 60 min of ischaemia and reoxygenation in vitro towards control values.
Influence of muscle mass and work on post‐exercise glucose and insulin responses in young untrained subjects
Authors: BRAMBRINK J.K. , FLUCKEY J.D. , HICKEY M.S. , CRAIG B.W.
Published: October 2003

The 18 h post‐exercise glucose and insulin responses of six male and six female subjects were measured following one‐ or two‐leg cycling to determine the influence of muscle mass involvement and work. Each subject performed three exercise trials on a Cybex Met 100 cycle ergometer: (1) two‐leg exercise for 30 min at 60% of the two‐leg VO2 max; (2) one‐leg exercise for 30 min at 60% of one‐leg VO2 max; and (3) one‐leg exercise (one‐legTW) at 60% of the one‐leg VO2 max with the total work performed equal to that of the two‐leg trial (duration ≈50 min). These trials were preceded by 2 days of inactivity and followed by an 18 h post‐exercise 75 g oral glucose tolerance test (OGTT). The glucose response during the baseline OGTT demonstrated that the subjects had normal glucose tolerance with fasting serum glucose levels of 5.1 mM, and 1 and 2 h serum glucose less than 7.8 mM, respectively. The 18 h post‐exercise glucose responses were significantly lower following the two‐leg trial (P < 0.05), with the area under the curve values being 129.9 mM h−1 less than the resting control level. The 18 h post‐exercise insulin AUC response of the two‐leg trial was significantly lower than either of the one‐leg responses (14.7 pM below the one‐leg and 5.0 pM below the one‐leg TW) but was not associated with a change in C‐peptide. The 18 h post‐exercise insulin levels of the one‐leg and one‐legTW trials were above or near the resting control values, but were not accompanied by a significant change in C‐peptide. In conclusion, the data presented here show that the amount of muscle tissue utilized during an exercise bout can influence both the glucose and insulin responses, whereas the amount of total work employed during the exercise had no effect on either of these parameters.
Effect of inhaled nitric oxide on endotoxin‐induced hypoxaemia in rabbits
Authors: HELLER H. , HOFFMANN G. , SCHOBERSBERGER W. , SCHUSTER K.‐D.
Published: October 2003

In five mechanically ventilated rabbits, we studied the property of inhaled nitric oxide in helping to treat hypoxaemia which was induced by intravenous endotoxin (Escherichiacoli‐derived lipopolysaccharide, serotype 0111: B4). We used measurements of arterial partial pressure of oxygen to check a therapeutic nitric oxide benefit. Pulmonary artery pressure was continuously monitored. Furthermore, we determined the single‐breath diffusing capacity for nitric oxide. Measurements of plasma nitrite/nitrate concentration served as an indicator of endogenous nitric oxide output. The first infusion of endotoxin led to a transient pulmonary vasoconstriction, whereas arterial partial pressure of oxygen was permanently reduced by 30 ± 10 mmHg (mean ± SD), attaining minimal values of 48 ± 3.4 mmHg due to additional endotoxin. Single‐breath diffusing capacity for nitric oxide declined by 20 ± 5.5% of baseline values until the experiments were concluded. Endotoxin induced an increase in plasma nitrite/nitrate concentration in the five rabbits as well as in the control animals (four rabbits) without exogenous nitric oxide supply. During the 25 inhalations of nitric oxide (3–50 ppm), arterial oxygenation did not change significantly. Thus endotoxin permanently impaired pulmonary gas exchange without inducing pulmonary hypertension. Inhaled nitric oxide did not improve arterial oxygenation during endotoxaemia.
Effects of the β2‐adrenergic agonist clenbuterol on capillary geometry in cardiac and skeletal muscles in young and middle‐aged rats
Authors: SUZUKI J. , GAO M. , XIE Z. , KOYAMA T.
Published: October 2003

The effects of 10 day clenbuterol administration on cardiac and skeletal muscle capillarities were studied, particularly in terms of the distribution of arteriolar and venular capillaries and their capillary density, in young (10‐week‐old) and middle‐aged (37‐week‐old) male Wistar rats. Rats of the treated groups were fed a diet containing 2 mg kg−1 clenbuterol hydrochloride. In both young and middle aged rats, clenbuterol treatment increased the body wt and the weights of the heart and hindlimb muscles. The mean fibre cross‐sectional area was significantly increased after the treatment in the left ventricle, soleus, plantaris and both deep and superficial portions of gastrocnemius (P< 0.01). In the left ventricle, the total capillary density and the density of venular capillaries were decreased after the treatment in both young (9 and 13%, respectively) and middle‐aged rats (10 and 11%, respectively). A decrease in total capillary density was also observed in all skeletal muscles examined. In both young and middle‐aged rats, the capillary‐to‐fibre (C:F) ratio and the proportion of each capillary did not change after the treatment in both the left ventricle and skeletal muscles. Clenbuterol significantly decreased the activity of succinate dehydrogenase in all skeletal muscles examined (P< 0.01). These results suggest that clenbuterol increased the diffusion distance for oxygen in the left ventricle and skeletal muscles. These changes may reduce the oxygen supply to tissues and increase muscle fatigability.
Effects of aminoguanidine and L‐NAME on histamine‐induced blood pressure drop in the rat
Authors: NILSSON B.‐O. , KOCKUM I. , ROSENGREN E.
Published: October 2003

Mean arterial blood pressure changes in response to i.v. administration of histamine were monitored in the anaesthetized rat in the absence or presence of the diamine oxidase (DAO) inhibitor aminoguanidine (AMG, 10 mg kg−1). AMG prolonged the duration of the transient drop in blood pressure induced by a bolus injection of histamine (0.05 mg kg−1) by 34%. In animals pretreated with AMG, no potentiation of the decrease in pressure in response to a 10 min infusion of histamine was observed. However, when infusion was stopped, the time needed for pressure recovery was twice as long in animals treated with AMG as in controls. Blood samples were taken prior to infusion and during the recovery phase and the quantities of histamine were determined by liquid chromatography. The prolonged recovery phase observed in animals pretreated with AMG was associated with five times higher levels of histamine. The duration of histamine‐induced hypotension (0.01 mg kg−1) was 50% shorter in the presence of the nitric oxide synthase inhibitor L‐NAME (10 mg kg−1). We suggest that DAO, through elimination of histamine from the bloodstream, is important for the recovery from histamine‐induced hypotension, and that the duration of histamine‐induced pressure drop is influenced by formation of nitric oxide.
Decreased capacitance response with age in lower limbs of humans – a potential error in the study of cardiovascular reflexes in ageing
Authors: LÄNNE T. , OLSEN H.
Published: October 2003

The cardiovascular regulation in humans depends to a major extent on sympathetic reflexes originating from volume receptors in the arterial as well as the cardiopulmonary region. With experimental approaches, such as lower body negative pressure (LBNP) and tilting, signs of reduced efficiency with ageing have been shown. However, a confounding factor may be an age‐related decline in venous capacitance response of the lower limbs, reducing the decrease in central blood volume and thus the deactivation of baro/cardiopulmonary receptors. This potential error was addressed in the present study. Central hypovolaemic stress was produced by LBNP 60 cmH2O in 10 young (mean age 23, range 20–25 years) and 10 old males (mean age 65, range 61–70 years). Changes in tissue volume of the calf were studied by strain gauge volumetric technique. Transmission of negative pressure to the calf muscle was studied in two young and two old volunteers. The haemodynamic response to hypovolaemic circulatory stress was attenuated in the old as compared with the young subjects, with a less marked increase in heart rate and peripheral resistance. Further, in the old subjects, the decrease in systolic blood pressure, pulse pressure and forearm blood flow was attenuated. Transmission of negative pressure to the calf was equal in both groups. The capacitance response was reduced with age from 2.27 ± 0.14 to 1.64 ± 0.13 mL 100 mL−1 (P < 0.005). However, the net capillary fluid filtration was unchanged. The reduced capacitance function might partly explain the declining reflex responses with age in humans, and thus seems to be of considerable importance when studying cardiovascular sympathetic reflex responses in ageing.
Effects of endurance training on oxidative capacity and structural composition of human arm and leg muscles
Authors: TURNER D.L. , HOPPELER H. , CLAASSEN H. , VOCK P. , KAYSER B. , SCHENA F. , FERRETTI G.
Published: October 2003

Six healthy subjects performed endurance training of the same duration with legs and arms consecutively. Performance and muscle structure were measured before and after training in lower and upper limbs. Training induced similar increases in maximal oxygen consumption (6 ± 1 vs. 7 ± 2 mL min−1 kg−1: legs vs. arms, P > 0.05) and mitochondrial volume in leg and arm muscles (42 ± 12 vs. 31 ± 11%: legs vs. arms, P > 0.05). The gain in mitochondrial volume after training was achieved solely by increasing the fraction of mitochondria (+40 ± 11%, P < 0.05) in the same muscle volume (+2 ± 2%, P > 0.05) in the legs. In contrast, increased muscle volume (+14 ± 3%, P < 0.05), in addition to a tendency for an increase in mitochondrial fraction (+16 ± 11%, P > 0.05), occurred in the arms after training. Thus, similar improvements in muscle oxidative capacity in upper and lower limbs were brought about by different mechanisms. It is suggested that due to infrequent use and a lack of load‐bearing function, arm muscle volume is underdeveloped in untrained, sedentary or detrained/injured subjects and that the mode of endurance training used in this study is sufficient to enlarge arm muscle volume as well as aerobic capacity.
H2‐receptor antagonist reduces food intake and weight gain in rats by non‐gastric acid secretory mechanisms
Authors: STØA‐BIRKETVEDT G. , LØVHAUG N. , VONEN B. , FLORHOLMEN J.
Published: October 2003

The H2‐receptor antagonist cimetidine reduces appetite and weight in overweight healthy subjects and in overweight subjects with type II diabetes mellitus. The aim of this study was to characterize the mechanisms of this effect in rodents. Drugs were administered three times a day, 30 min before 1 h periods of free access to food. In one group of rats (n=9), cimetidine (8 mg) treatment resulted in significantly lower cumulative food intake than in a control group (n=9). The total intakes of food during the observation period of 22 days were 325.3 ± 29.1 g and 346.3 ± 16.7 g in the cimetidine and control groups, respectively. During the observation period, the weight gain in the cimetidine group was 63.3 ± 15.8 g, which was significantly lower than the weight gain of 74.8 ± 14.2 g in the control group, i.e. the cimetidine induced a 15.4% reduction in the weight gain during the observation period of 22 days. The weight gained per weight of food ingested was 0.20 ± 0.04 (g/g) and 0.22 ± 0.04 (g/g) in the cimetidine and control groups, respectively (NS). In other experiments, ranitidine (3 mg) and famotidine (0.4 mg), but not omeprazole (0.4 mg), taken three times a day for 8 days reduced the weight gain when compared with a control group (n=7 in each group). We therefore conclude that the effects of the H2‐receptor antagonists are not mediated by inhibitory mechanisms on the gastric acid secretion.
Temporal changes in spinal cord expression of mRNA for substance P, dynorphin and enkephalin in a model of chronic pain
Authors: DELANDER G. E. , SCHÖTT E. , BRODIN E. , FREDHOLM B. B.
Published: October 2003

We have used a partial sciatic nerve ligation model to examine the time course for changes in the expression of mRNA for three peptides related to pain transmission at spinal sites (dynorphin, enkephalin and substance P), during the development of allodynia. Enhanced expression of mRNA for dynorphin and substance P was observed in the dorsal horn on the same side as the partial nerve ligation. Increased expression of dynorphin mRNA was biphasic. The initial increases in expression of dynorphin mRNA occurred at 3 h, and a secondary peak was observed 1–3 days after surgery. The secondary increases coincided roughly with increased substance P mRNA expression. However, both dynorphin and substance P mRNA returned to control values after 1 week despite continuing allodynia. No significant changes in expression of mRNA for enkephalin were observed. The elevation of substance P mRNA in intrinsic spinal cord neurons may be secondary to changes in immediate early genes c‐fos and jun‐B, whereas the expression of dynorphin and enkephalin mRNA is differently regulated. The results also suggest that changes in the expression of the three neuropeptides are not critically involved in the development and maintenance of chronic pain or allodynia.
Oxygen, pHi and arrest of biosynthesis in brine shrimp embryos
Authors: HAND S.C.
Published: October 2003

Embryos of the brine shrimp Artemia franciscana are able to withstand bouts of environmental anoxia for several years by entering a quiescent state, during which time metabolism is greatly depressed. Within minutes of oxygen removal, intracellular pH (pHi) drops at least 1.0 unit. This acidification has been strongly implicated in the arrest of both catabolic and anabolic processes in the cytoplasm. A global arrest of cytoplasmic translation accompanies the transition into anoxia or into aerobic acidosis (artificial quiescence imposed by intracellular acidification with CO2 in the presence of oxygen). Similarly, protein synthesis in isolated mitochondria from these embryos is also reduced markedly in response to acidic pH (80% reduction) or anoxia (79% reduction). The constancy of mRNA levels during quiescence indicates that protein synthesis is likely to be controlled at the translational level.

Mitochondrial matrix pH is 8.2 during protein synthesis assays performed at the extramitochondrial pH optimum of 7.5. When this proton gradient is abolished with the K+/H+ ionophore nigericin, the extramitochondrial pH optimum for protein synthesis displays an alkaline shift of ≈0.7 pH unit. These data suggest the presence of proton‐sensitive translational components within the mitochondrion. The oxygen dependency of mitochondrial protein synthesis is not explained simply by blockage of the electron transport chain or by the increased redox state. Whereas oxygen deprivation substantially depresses protein synthesis by 77% after 1 h, normoxic incubations with saturating concentrations of cyanide or antimycin A have only a modest effect (36% reduction, cyanide; 20%, antimycin A). This cyanide‐ and antimycin‐insensitive, but hypoxia‐sensitive, inhibitory signature for the arrest of protein synthesis suggests the presence of a molecular oxygen sensor within the mitochondrion.
Effects of bradykinin, histamine and serotonin on pulmonary vascular resistance and permeability
Authors: BREIL I. , KOCH T. , BELZ M. , VAN ACKERN K. , NEUHOF H.
Published: October 2003

The effects of bradykinin, histamine and serotonin on vascular resistance and microvascular permeability were investigated in isolated cell‐free perfused rabbit lungs. The capillary filtration coefficient was determined from the slope of lung weight changes over periods of venous pressure elevation before application of bradykinin (n=6), histamine (n=6) and serotonin (n=6), and 5, 20 and 50 min afterwards. To prevent rapid inactivation of bradykinin by the angiotensin‐converting enzyme in the pulmonary circulation, the bradykinin effects were additionally studied in the presence of the angiotensin‐converting enzyme inhibitor captopril (n=6). Bolus application of each substance resulted in a short‐lasting increase in the pulmonary vascular resistance (3.7–9.1 mmHg), which was most pronounced in the bradykinin+captopril group. The capillary filtration coefficient was significantly increased after histamine application, and to an even greater extent after serotonin application, whereas bradykinin on its own, as well as bradykinin given in the presence of captopril, had no measurable influence on capillary filtration in the lung. As a result of the first bradykinin challenge, there was an immediate massive generation of prostacyclin, which could not be further augmented by a second application. Histamine injection entailed a delayed onset of prostacyclin generation after the second stimulation, whereas no prostacyclin increase was measured in the serotonin‐treated lungs. Thromboxane A2 generation was exclusively observed after the first serotonin application. The data exemplify different pathophysiological characteristics of bradykinin, histamine and serotonin on lung barrier function. Histamine and serotonin induce oedema formation by enhancing microvascular permeability, whereas bradykinin does not.
No further improvement of ischaemic myocardial metabolism by combining preconditioning with β‐blockade: an in vivo experimental study in the pig heart using a microdialysis technique
Authors: WIKSTRO~DM B. G. , RONQUIST G. , A. WALDENSTRÖM
Published: October 2003

Adenine nucleotides, lactate and pyruvate were monitored by microdialysis in pig hearts, comprising four experimental groups. Two preconditioned groups, one β‐blocked by metoprolol (0.3 mg kg‐1 body wt; n=6) and the other (n=7) without β‐blockade. Two groups were not preconditioned, one β‐blocked (n=6) and one without β‐blockade (n=7). Probes were inserted into ischaemic and non‐ischaemic myocardium. Preconditioning consisted of four consecutive 10 min periods of ischaemia each separated by 20 min of reperfusion. All animals were subjected to 40 min of index ischaemia followed by 25 min of reperfusion. Myocardial cAMP content was determined in biopsies after the final reperfusion and was found low in the β‐blocked groups. Lactate levels during index ischaemia exceeded the basal level 4–6‐fold in dialysate. Adenosine concentration reached 12 μmol L‐1 during the first preconditioning period while an attenuation was typical for the following three preconditioning periods. The sum of the concentrations of adenosine, inosine and hypoxanthine was significantly lower during index ischaemia in the preconditioned groups displaying a peak value of 115 μmol L‐1. The corresponding value for unpreconditioned hearts was 230 μmol L‐1. The part of adenosine was 5% and less than 1%, respectively. Pyruvate concentration decreased during each brief ischaemic period of preconditioning rising to a higher level of reperfusion. The decrease in pyruvate was smaller in the controls during index ischaemia. The effects of β‐blockade and preconditioning on ischaemic metabolism were comparable and the results of the two treatments were not additive in this respect.
Gender‐related differences in the regulatory influence of thyroid hormone on the expression of myosin isoforms in young and old rats
Authors: LARSSON L. , YU F.
Published: October 2003

The effects of 4 weeks of thyroid hormone (3,5,3′‐triiodothyronine, T3) treatment on the expression of myosin heavy chain (MyHC) isoforms were examined in young (3–6 months) and old (20–24 months) female rats, and compared with those in age‐matched male rats (Larsson et al. 1995). In control rats, ageing was associated with a type IIA to I MyHC isoform switching in the slow‐twitch soleus and a type IIB to IIX MyHC isoform switching in the fast‐twitch extensor digitorum longus muscle (EDL). Gender‐ and muscle‐specific differences were observed in the regulation of MyHC isoforms by T3. In the soleus, dramatic downregulation of the type I and upregulation of the type IIA MyHC isoform were observed in both females and males, but upregulation of the IIX MyHC isoform was observed only in male rats. In EDL, T3 treatment had no significant influence on the MyHC isoform composition in the males irrespective of the age of the animal. In the females, on the other hand, T3 treatment resulted in a significant MyHC transformation from IIA to IIB, probably via IIX myosin, in spite of the fact that type IIA mRNA has been reported to be downregulated in both females and males. It is concluded that the regulation of MyHC isoforms by thyroid hormone differs between females and males, presumably as a result of a gender‐related difference in the translational or post‐translational regulation of MyHC synthesis.
Acid‐base balance and O2 transport at high altitude
Authors: SAMAJA M. , MARIANI C. , PRESTINI A. , CERRETELLI P.
Published: October 2003

Ear lobe blood pHa, PaCO2, PaO2, and O2 saturation (SaO2) were measured in healthy Caucasians and Sherpas at 3400 m (Namche Bazaar, Nepal, n=4/5), 5050 m (Pyramid Laboratory, Lobuche, Nepal, n=20/5) and 6450 m (Camp II of Mt Everest, n=11/7). In the investigated altitude range, pHa increased progressively with altitude from 7.463±0.005 (mean±SE) to 7.496±0.006 in Caucasians whereas it remained essentially constant (7.45–7.46) in Sherpas. At all altitudes, PaCO2 was higher in Sherpas than in Caucasians (P<0.02). By contrast, PaO2 and SaO2 were the same in Caucasians and Sherpas at all investigated altitudes. Moreover, in Caucasians sojourning for 3 weeks at 5050 m, PaCO2 kept decreasing whereas pHa, PaO2 and SaO2 remained constant. These data suggest that: (1) respiratory alkalosis was a common finding both in Caucasians and Sherpas; (2) at 6450 m, Sherpas were less alkalotic due to higher PaCO2 than Caucasians, possibly a consequence of a blunted ventilatory response; (3) at 6450 m, SaO2 and PaO2 were the same in Caucasians and Sherpas despite different PaCO2 values. The latter finding could be the consequence of one or more of the following adjustments in Sherpas: (1), an increased efficiency of alveolar O2 transfer, i.e. smaller alveolar‐arterial O2 gradient; (2) a decreased (arterial – mixed venous) O2 difference, possibly due to increased cardiac output; (3) a reduced increase of the [2,3‐DPG]/[Hb] ratio; but not (4) an elevated gas exchange ratio (R). It is concluded that both physiological and biochemical variables contribute to optimize the O2 transport at altitude. Apparently a more efficient adaptation to hypoxia allows Sherpas to limit alkalosis through a lower ventilatory drive and to maintain SaO2 at the same PaO2 by decreasing the [2,3‐DPG]/[Hb] ratio.
Glutathione status and reactive oxygen generation in tissues of young and old exercised rats
Authors: OHKUWA T. , SATO Y. , NAOI M.
Published: October 2003

The effects of exercise on the generation of active oxygen species and radical‐scavenging capacity were studied in physically active and sedentary young and old rats. Exercise increased the hydroxyl radical content in all tissues of physically active young rats, except in the plasma. In old rats, the basal level of the radical increased significantly in plasma, heart, and skeletal muscles, but decreased in liver; and physical activity decreased it to that of young rats in most cases. With exercise, the content of reduced glutathione increased in plasma, heart, and skeletal muscles of young rats, whereas that of oxidized glutathione markedly decreased in liver and increased in brain and white gastrocnemius muscle. The total glutathione levels in these tissues changed in a similar way, indicating that glutathione was released from the pool in the liver. In rats allowed to run voluntarily for 5 weeks, the effects were more pronounced than in the sedentary rats. The ratio of reduced to total glutathione, which indicates the capacity to reduce glutathione, increased in plasma, heart, and soleus muscle of sedentary young rats after exercise, and increased further in those undergoing physical activity. In old rats, the reduced glutathione level increased in plasma, heart, liver, and brain, even though the total decreased. These results suggest that physical activity enhances the endogenous ability to defend against oxidative stress. In old rats, even though glutathione synthesis is decreased, the regenerating capacity seems to be increased in order to compensate for the increased oxidative stress.