bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of neurohumoral blockade on heart rate and blood pressure responses to haemorrhage in isoflurane anaesthetized rats
Authors: Ullman
Published: March 2003

Four groups of Sprague–Dawley rats were anaesthetized with isoflurane (ISO) (1.7% end‐tidal concentration) in 40% oxygen, and mechanically ventilated. The animals were bled 15 mL kg–1 b.w. from the femoral vein over 10 min, followed by an observation period of 30 min. Ten minutes before haemorrhage each group of animals was pre‐treated with intravenous injection/infusion of either: isotonic saline (Group B; CON; n=7), vasopressin V1‐receptor antagonist [d(CH2)5Tyr(Me)AVP; 10 μg kg–1] (Group C; AVP‐a; n=7), the non‐selective angiotensin II receptor antagonist saralasin (10 μg kg–1 min–1) (Group D; SAR; n=7) or hexamethonium (10 mg kg–1) (Group E; HEX; n=7). A separate group of conscious animals were pre‐treated with isotonic NaCl and subjected to the same haemorrhage protocol (Group A; AW; n=7). Mean arterial pressure (MAP), heart rate (HR) and blood gases were observed during the experiments. Only pre‐treatment with SAR and HEX reduced MAP significantly. The pre‐haemorrhage HR was only affected by HEX, which caused a reduction by 17%. The HR was significantly lower at the end of haemorrhage compared with pre‐haemorrhage levels in all groups except that group treated with HEX. In that group the HR changed in the opposite direction. The ability to maintain MAP during haemorrhage, and the post‐haemorrhage period, was significantly impaired in the groups treated with AVP‐a, SAR or HEX compared with the group receiving NaCl. It is concluded that autonomic nervous activity is of major importance for the maintenance of MAP during isoflurane anaesthesia, whereas circulating angiotensin II and vasopressin levels contribute to a much smaller degree in this regard. General anaesthesia in combination with different degrees of neurohumoral blockade impairs the haemodynamic responses to blood loss, seen in conscious individuals. The impairment involves both the early and late phases during haemorrhage, as well as the post‐bleeding recovery period. All three neurohumoral systems (autonomic nervous activity, angiotensin II and vasopressin) are of importance for regulating MAP during and after haemorrhage, although the autonomic nervous outflow appears to contribute to a larger extent.
Myosin heavy chain mRNA and protein distribution in immobilized rat skeletal muscle are not affected by testosterone status
Authors: Harjola  , Jänkälä  , Härkönen
Published: March 2003

The effects of testosterone treatment and gonadectomy on myosin heavy chain (MHC) messenger RNA (mRNA) and protein expression after 1 week’s immobilization were studied in male rat gastrocnemius muscle. In the testosterone‐treated group silastic testosterone capsules were implanted subcutaneously before immobilization. The gonadectomized animals were castrated at 5 weeks of age. One group of eugonadal animals served as the immobilized control group, and another as the sedentary control group. Immobilization was performed at 9 weeks of age by bilateral hindlimb casting. The body and muscle masses, and the amount of type IIa MHC mRNA decreased significantly (P < 0.01) in the immobilized animals by ~30, 40 and 50%, respectively, regardless of the serum testosterone levels which ranged from 1.1 ± 0.4 to 59 ± 14 nmol L−1. In the immobilized testosterone‐treated group the proportion of type IIx MHC mRNA increased to 14% of the total MHC mRNA (P=0.02, compared with control). The MHC protein distribution did not change significantly. There were no significant differences in any parameters between the three immobilized groups. In conclusion, neither the lack nor excess of testosterone significantly altered the changes caused by immobilization. Therefore, it seems that lack of mechanical loading is a far more important determinant of MHC expression than the male sex hormone status.
Pro‐ and macroglycogenolysis in contracting rat skeletal muscle
Authors: Derave  , Gao  , Richter
Published: March 2003

Glycogen is present in skeletal muscle in smaller acid‐insoluble proglycogen particles and larger acid‐soluble macroglycogen particles. The present study was designed to investigate the relative contribution of pro‐ and macroglycogen to glycogenolysis during muscle contractions. Rats were subjected to a glycogen‐depleting exercise bout and refed with either a carbohydrate‐rich or fat‐rich diet, resulting in widely different muscle glycogen contents. The following day, isolated hindlimbs were perfused and electrically stimulated to contract for 10 min. Pre‐ and postcontraction muscle samples of soleus, white and red gastrocnemius were analysed for pro‐ and macroglycogen. Contractions caused significant reductions in both pro‐ and macroglycogen in all glycogen groups and muscle types. In glycogen‐supercompensated gastrocnemius muscles, the relative utilization of macroglycogen was significantly higher than the relative utilization of proglycogen. In muscles with normal to low initial glycogen contents, proglycogen was much more abundant than macroglycogen and therefore contributed more to glycogenolysis in absolute numbers. In conclusion, both proglycogen and macroglycogen are suitable substrates during skeletal muscle contractions, although macroglycogen, when amply available, seems to be more easily broken down. This may provide an explanation for the dependence of the glycogenolytic rate on the total muscle glycogen content.
Energy‐related metabolites during and after induced myocardial infarction with special emphasis on the reperfusion injury after extracorporeal circulation
Authors: Zemgulis V. , Ronquist G. , Bjerner T. , Henze A. , Waldenström A. , Thelin S. , Wikström G.
Published: March 2003

In the clinical setting great efforts have been made with contradictory results to operate upon acutely myocardial ischaemic patients. The reasons for the absence of clear‐cut results are not well understood nor are they scientifically explored. To resolve this problem further, we attempted to design an experimental in vivo model to mimic acute myocardial ischaemia followed by extracorporeal circulation (ECC) and reperfusion. One of the main targets of our protocol was monitoring of myocardial energy metabolism by microdialysis (MCD) during the periods of coronary occlusion (60 min), hypothermic (30 °C) ECC and cardioplegia (45 min), followed by reperfusion with (30 min) and without (60 min) ECC. In eight anaesthetized, open‐chest pigs, myocardial lactate, pyruvate, adenosine, taurine, inosine, hypoxanthine and guanosine were sampled with MCD in both ischaemic and non‐ischaemic areas. Myocardial area at risk and infarct size were quantified with the modified topographical evaluation methods. The principal finding with this experimental setup was a biphasic release pattern of lactate, adenosine, taurine, inosine, hypoxanthine and guanosine from ischaemic myocardium. Lactate levels were equally high in reperfused ischaemic and non‐ischaemic myocardial tissue. Pyruvate demonstrated consistently higher values in non‐ischaemic myocardium throughout the experiment. A pattern was discernible, lactate being a marker of compromised cell energy metabolism, and taurine being a marker of disturbed cell integrity. Of special interest was the increased level of pyruvate in microdialysates of non‐ischaemic myocardium as compared with its ischaemic counterpart. In conclusion, we found disturbances in energy metabolism and cell integrity not only in ischaemic but also in non‐ischaemic tissue during reperfusion implying that non‐ischaemic myocardium demonstrated an unexpected accumulation of lactate and pyruvate. These new findings could at least partly be explicatory to the increased risk of heart surgery in connection with acute myocardial infarction.
Cell volume‐induced changes in K+ transport across the rat colon
Authors: Ribeiro R. , Heinke B. , Diener M.
Published: March 2003

The effect of cell swelling and cell shrinkage on K+ transport across the rat colonic epithelium was studied by measuring unidirectional fluxes, uptake and efflux of 86Rb+, a marker for K+. Exposure to a hypotonic medium stimulated the secretory, serosa‐to‐mucosa flux of K+, whereas exposure to a hypertonic medium inhibited the absorptive, mucosa‐to‐serosa flux of K+ in the distal, but not in the proximal colon. Neither manoeuvre had any effect on the uptake of K+ across the apical or the basolateral membrane. Cell swelling induced a sustained increase in the apical and basolateral K+ efflux from both colonic segments, whereas cell shrinkage reduced the efflux. Ba2+ (10–2 mol l–1) inhibited the swelling‐induced stimulation of the apical, quinine (10–3 mol l–1) that of the basolateral K+ efflux in the distal colon. Incubation of the tissue in Ca2+‐free buffer or La3+, which blocks Ca2+‐influx into the epithelium, strongly reduced the basal K+ efflux across the basolateral membrane. The same was observed with brefeldin A, a blocker of the transport of newly synthesized proteins out of the endoplasmatic reticulum. Swelling‐induced K+ efflux, however, was not reduced. In the presence of colchicine, an inhibitor of the polymerization of microtubules, swelling evoked only a transient increase in mucosal efflux, which, especially in the proximal colon, fell after 6 min to the level of the isotonic control period. These results demonstrate that the cell volume is involved in the regulation of transepithelial K+ transport across the rat colonic epithelium and suggest a role of the cytoskeleton in the control of a part of the volume‐sensitive K+ channels.
Prolactin and lipopolysaccharide treatment increased apoptosis and atresia in rat ovarian follicles
Authors: Besnard N. , Horne E. A. L. , Whitehead S. A.
Published: March 2003

Follicular atresia is associated with the presence of increased macrophages within the follicle. What is not known is whether, in the adult rat, macrophages are instrumental in inducing apoptosis and/or atresia or whether they are simply secondary to a hormonally mediated event. As prolactin is an immunoreactive hormone and stimulates the expression of monocyte chemoattractant, the present experiments compared the effects of prolactin treatment with that of an immune challenge with lipopolysaccharide (LPS) on the invasion of macrophages into the follicular and luteal compartments of the ovary and the occurrence of apoptosis/atresia in relation to macrophage invasion. Rats were treated for 3 days with either prolactin or LPS and ovaries obtained at pro‐oestrus or oestrus. Prolactin and LPS increased the number of atretic vs. healthy follicles (P < 0.008, χ2) in pro‐oestrus ovaries and increased the mean number of apoptotic cells and macrophages (P < 0.05 for some groups). Macrophages were typically observed in the thecal layer, apoptotic cells in the granulosa cell layer, although 84% follicles which had macrophages within the granulosa cell layer also contained relatively high numbers of apoptotic nuclei. Prolactin and LPS treatment in vivo reduced the progesterone response to follicle stimulating hormone (FSH) (P < 0.001) in cultures of ovarian dispersates but did not inhibit the response to forskolin. In contrast, prolactin or LPS added in vitro to the cultures inhibited the progesterone response to forskolin. Results show that both prolactin and LPS increase follicular apoptosis and atresia and reduce the progesterone response to FSH.
The physiology of inflammatory myopathies: an overview
Authors: Lundberg I. E.
Published: March 2003

The idiopathic inflammatory myopathies (IIMs) encompass a group of muscle disorders of unknown origin and pathogenesis characterized by symmetrical, proximal muscle weakness and by inflammatory infiltrates in muscle tissue. The mechanisms behind the loss of muscle function are largely unknown. It is often anticipated that the muscle weakness is caused by the inflammatory cells. However, inflammatory infiltrates are not always present in the muscle tissue and the infiltrates sometimes have a patchy distribution, which makes it difficult to explain the generalized muscle weakness merely by infiltration of inflammatory cells. We investigated patients at different stages of myositis: early myositis without detectable inflammatory infiltrates, active myositis with pronounced inflammatory infiltrates and chronic myositis with persisting muscle weakness but without detectable inflammatory cells in muscle tissues. In these studies, a better correlation was observed between the clinical symptoms and involvement of the capillaries with expression of the cytokine interleukin (IL)‐1α and by the presence of major histocompatibility complex (MHC) class I expression on muscle fibres. Whether these molecules could affect muscle function is not known. Using phosphorus P‐31 magnetic resonance spectroscopy decreased values of adenosine triphosphate (ATP) and phosphocreatine (PCr) levels were observed at rest. These metabolic abnormalities were further accentuated by exercise and increased PCr levels correlated with improved clinical status. The underlying mechanisms responsible for these biochemical abnormalities have not been defined but could be related to a disturbed tissue oxygenation.
Immunological capabilities of skeletal muscle cells
Authors: Nagaraju K.
Published: March 2003

Muscle is the target of immunological injury in several muscle diseases. It is important therefore to understand the immunological capabilities of muscle cells themselves. Although it is conventional to discuss the effects of the immune system on other cells, tissues or organs, the system’s boundaries cannot be sharply drawn, and in an increasing number of ways, the immunological capabilities of non‐immune tissues are recognized as determining the course of immune‐inflammatory processes. Muscle cells have an inherent ability to express and respond to a variety of immunologically relevant surface molecules, cytokines, and chemokines under inflammatory conditions. The ability of muscle cells to process and present antigens to the immune cells is currently debated; thus, this review is aimed at examining the immunological capabilities of skeletal muscle cells in vitro and in vivo.
Intermittent hypoxia improves atrial tolerance to subsequent anoxia and reduces stress protein expression
Authors: Mohan R. M. , Golding S. , Paterson D. J.
Published: March 2003

We tested the hypothesis that 21 days of intermittent hypoxia (IH) increases the tolerance of the spontaneously beating guinea‐pig double atria preparation to acute in‐vitro hypoxia, and reduces cardiac stress protein expression. A total of 28 guinea‐pigs were divided into four groups: (i) IH; (ii) IH + in‐vitro hypoxia (IH + IV); (iii) control (CON); (iv) control + in‐vitro hypoxia (CON + IV). The IH animals were exposed to 8% O2/0.3% CO2 for 12 h day–1 for 21 days. Normoxic controls were exposed to room air for the same duration. Acute in‐vitro hypoxia (20, 10, 5 and 0% O2 in 5% CO2) was introduced into the atrial preparation. Heat shock protein (Hsp) 70 and Hsp90 content were determined by Western blotting. Intermittent hypoxia groups demonstrated typical responses to chronic hypoxic exposure, characterized by significantly (P < 0.05) lower body weights, reduced growth rates and increased heart weight/body weight ratios. In the CON + IV group, in‐vitro hypoxia reduced heart rate (20% O2, –30 ± 8 beats min–1; 10% O2, –34 ± 8 beats min–1; 5% O2, –37 ± 9 beats min–1 and 0% O2, –51 ± 9* beats min–1: *P < 0.05 vs. 20% O2). At 0% O2, the decrease in the rate response was significantly attenuated in the IH + IV (–30 ± 8 beats min–1; n=10) compared with the CON + IV (–51 ± 9 beats min–1; n=10). IH significantly reduced atrial Hsp70 and Hsp90 expression, however, levels of both proteins were unchanged in the ventricle. Furthermore, Hsp90 and to a lesser degree Hsp70 in the atria remained suppressed following in‐vitro hypoxia in the IH group. Our results show that the increased resistance of the isolated atria to anoxia following IH may contribute to the concomitant reductions in basal and hypoxia‐induced Hsp expression as the overall stress response is reduced.
In vivo determination of muscle viscoelasticity in the human leg
Authors: Fukashiro S. , Noda M. , Shibayama A.
Published: March 2003

The purpose of this study was to examine the methodological validity of the free vibration technique for determining individual viscoelastic characteristics of the human triceps surae muscle‐tendon complex (MTC) in vivo. Six subjects sat with first phalangeal joint of the forefoot on the edge of a force‐plate. The special frame on the knee was loaded with weight (0–40 kg) for testing. Oscillations of the triceps surae MTC system were initiated with a hand‐held hammer by tapping the weight. In order to keep the same posture, the output of the force plate was displayed on the oscilloscope and subjects were asked to maintain the beam on the oscilloscope at a particular location in relation to a reference line. The damped oscillations in conjunction with the equation of motion of a damped mass‐spring model were used to calculate the viscosity of muscle (b) and the elasticity of muscle fibres and tendon (k) in each subject, considering moment arm of the ankle joint. With this arrangement, we have obtained high reproducibility in this method. The coefficient of variations (CVs) of b and k in five trials at each weight were quite small (range: 0.5–18.7% in b and 1.0–15.1% in k). There were no significant differences in viscoelastic coefficients between right and left legs. Therefore, it appears that free vibration technique, used here, is adequate in describing the viscoelastic characteristics of the triceps surae in vivo in humans.
G protein‐coupled receptor signalling in in vivo cardiac overload
Authors: Rapacciuolo A. , Esposito G. , Naga Prasad S. V. , Rockman H. A.
Published: March 2003

Cardiac myocytes respond to biomechanical stress by initiating cellular processes that lead to hypertrophy. Although cardiac hypertrophy is a response to increased stress on the heart, it is associated with elevated plasma catecholamine levels and an increase in cardiac morbidity and mortality. Understanding the cellular signals that initiate the hypertrophic response will be of critical importance to identify pathways that mediate the maladaptive deterioration of the hypertrophic heart to one of cardiac failure. This review will focus on the role of G protein‐coupled receptors in the activation of signalling pathways in the heart, such as the mitogen activated protein kinase and phosphoinositide‐3 kinase pathways.
Dynamics of cardiac wound healing following myocardial infarction: observations in genetically altered mice
Authors: Blankesteijn W. M. , Creemers E. , Lutgens E. , Cleutjens J. P. M. , Daemen M. J. A. P. , Smits J. F. M.
Published: March 2003

Recent improvements in the clinical management of acute myocardial infarction (MI) have resulted in a dramatic decrease in mortality because of this condition. This implies that more patients enter the process of infarct healing. This is a highly complex cascade of events which, although studied for decades, is still not completely understood. An increasing number of genetically altered mice can now be studied in a mouse model of MI, to investigate the contribution of the product of the targeted gene to the infarct healing process. In this review, we will discuss the defects in infarct healing that have been observed in null mutants for plasminogen, urokinase‐type plasminogen activator (u‐PA), matrix metalloproteinases (MMPS), thrombospondin‐2 and dishevelled‐1. These studies provide new insights in the infarct healing process itself, but may also help to define new diagnostic and therapeutic targets in humans suffering from MI.
Nerve growth factor increases airway responses and decreases levels of exhaled nitric oxide during histamine challenge in an in vivo guinea‐pig model
Authors: Friberg S. G. , Höglund C. Olgart , Gustafsson L. E.
Published: March 2003

There is a growing body of evidence supporting the idea that nerve growth factor (NGF) may be involved in the development of asthma‐associated symptoms, such as airway hyper‐responsiveness. Increased levels of NGF have recently been described in serum and in the airways of asthmatics. We have examined whether exhaled nitric oxide (NO) levels might be altered during the increased airway responses upon NGF treatment in guinea‐pigs in vivo. Intravenous (i.v.) administration of histamine normally elicits a rapid peak in insufflation pressure (IP) and in exhaled NO, followed by a period of decreased concentrations of exhaled NO. Anaesthetized guinea‐pigs were pre‐treated intravenously with either saline, 4 or 80 ng kg–1 NGF 30 min before i.v. challenge with 16 μg kg–1 histamine. At 80 ng kg–1 NGF significantly enhanced the airway obstruction caused by histamine, whereas the peak acute increase in exhaled NO was not enhanced. Following the increase, came a rapid drop, an effect enforced in the NGF treated animals. Subsequently, the time to return to 90% of resting exhaled NO was increased, from 12 min in saline‐treated animals to 48 min in NGF‐treated animals. Our data confirm that NGF can enhance airway responses to histamine. Moreover, our study shows a decrease in exhaled NO following a histamine challenge, an effect enhanced by NGF. A reduced ability to release exhaled NO may be a mechanism for increased airway responses during elevated NGF levels. The interaction between NGF and airway NO formation, and its relation to airway responses, merit further investigation.
Renal cortical accumulation of hyaluronan in adult rats exposed neonatally to angiotensin‐converting enzyme inhibition
Authors: Nilsson A. B. M. , Johnsson C. , Friberg P. , Hansell P.
Published: March 2003

Neonatal inhibition of the renin–angiotensin system [angiotensin‐converting enzyme (ACE) inhibition] in the rat results in long‐term abnormal renal morphology and function, including interstitial inflammation and fibrosis. Hyaluronan (hyaluronic acid, HA) has pathological implications in inflammatory diseases and renal ischaemia‐reperfusion injury. The present study aimed at determining if renal cortical HA in the adult rat is correlated to the abnormal morphology and function in rats treated neonatally with the ACE inhibitor enalapril. In adult control rats (23 weeks old), the cortical HA content was very low [about 5 μg g–1 dry weight (d.w.)] and about 1% of the papillary HA content. In rats treated neonatally with enalapril (days 3–13), the cortical HA level was 15 times that in control rats already at 21 days after birth, and it persisted at this level during adulthood (at 23 weeks). At 13 weeks the enalapril‐treated animals showed markedly reduced ability (–53%) to concentrate urine during 24‐h thirst provocation. At 21 days as well as at 23 weeks the enalapril‐treated kidneys displayed morphological changes, such as papillary atrophy, dilation of the tubules and cellular infiltration of the cortical tissue. Histochemical staining confirmed the HA quantification assay and revealed a patchy staining for HA located in the same regions as the infiltrating cells. In conclusion, neonatal treatment with the ACE inhibitor enalapril results in renal morphological and functional abnormalities during adulthood. Cortical HA levels are already seriously elevated at day 21 and coexist with infiltrating cells. Besides the known effects of angiotensin II in development, the accumulation of HA in these kidneys may be involved in the genesis of at least the cortical abnormalities in enalapril‐treated animals because of the proinflammatory effects and water‐binding properties of HA.
Effects of different types of K+ channel modulators on the spontaneous myogenic contraction of guinea‐pig urinary bladder smooth muscle
Authors: Imai T. , Okamoto T. , Yamamoto Y. , Tanaka H. , Koike K. , Shigenobu K. , Tanaka Y.
Published: March 2003

In the present study, effects of different types of K+ channel modulators on the spontaneous rhythmic contractile activity were examined in guinea‐pig urinary bladder smooth muscle (UBSM). Guinea‐pig UBSM exhibited myogenic rhythmic contraction in the presence of atropine (1 μM), phentolamine (1 μM), propranolol (1 μM), suramin (10 μM) and tetrodotoxin (1 μM). Nisoldipine (100 nM) or diltiazem (10 μM) substantially diminished UBSM contractile activity. Nisoldipine‐resistant component of UBSM rhythmic contraction was further inhibited by gadolinium (200 μM). Iberiotoxin (50 nM), a selective blocker of large‐conductance, voltage‐gated Ca2+‐activated K+ (KCa) (BK) channel, dramatically increased both contraction amplitude and frequency whereas NS‐1619 (30 μM), which increases BK channel activity, decreased them. Apamin (100 nM), a selective blocker of small‐conductance, KCa (SK) channel, increased contraction amplitude but decreased frequency. A blocker of voltage‐gated K+ (Kv) channel, 4‐aminopyridine (100 μM), significantly increased contraction frequency. E‐4031, a blocker of a novel inwardly rectifying K+ channel, i.e. the human ether‐a‐go‐go‐related gene (HERG) K+ channel, significantly increased contraction amplitude. Glibenclamide (1–10 μM) (KATP channel blocker) and Ba2+ (10 μM) (conventional Kir channel blocker) did not exhibit conspicuous effects on spontaneous contractile activity of UBSM. These findings imply that two types of KCa (BK and SK) channels have prominent roles as negative feedback elements to limit extracellular Ca2+ influx‐mediated guinea‐pig UBSM contraction by regulating both amplitude and frequency. It was also suggested that both non‐KCa type of K+ (Kv and HERG‐like K+) channels may contribute to the regulation of UBSM myogenic rhythmic contraction.
The repeated bout effect and heat shock proteins: intramuscular HSP27 and HSP70 expression following two bouts of eccentric exercise in humans
Authors: Thompson H. S. , Clarkson P. M. , Scordilis S. P.
Published: March 2003

Exercise‐induced damage significantly and predictably alters indirect indicators of muscle damage after one bout of damaging exercise but this response is dampened following a second bout of the same exercise performed 1–6 weeks later. Previously we have described a marked increase in the levels of heat shock proteins (HSPs) HSP27 and HSP70 in human biceps muscle following one bout of high‐force eccentric exercise. The purpose of the present study was to examine the intramuscular HSP27 and HSP70 response following two identical bouts of exercise [bout 1 (B1) and bout 2 (B2), separated by 4 weeks] relative to indirect indices of muscle damage. Ten human subjects performed 50 high‐force eccentric contractions with their non‐dominant forearm flexors; muscle damage of the biceps brachii was evaluated 48 h post‐exercise with indirect indices [serum creatine kinase (CK) activity, soreness, isometric maximal voluntary contraction (MVC) force and relaxed arm angle] and immunoblotting of high ionic strength muscle biopsy extracts for both HSPs. Not unexpectedly, the indirect indicators of damage changed dramatically and significantly (P < 0.01) after B1 but had a much smaller response after B2. The magnitude of the HSP response was the same after both bouts of exercise, though the control and exercised samples of B2 demonstrated a lower basal HSP expression. Thus, though both indirect and cellular indicators of exercise‐induced muscle damage demonstrate an adaptation consequent to the first bout of exercise, these adaptations are quite different. It is possible that the lower basal HSP expression of the cellular response mediates the attenuation of damage associated with B2 as indicated by indirect indices.
Dysregulation of angiotensin II synthesis is associated with salt sensitivity in the spontaneous hypertensive rat
Authors: HODGE G. , YE V. Z. C. , DUGGAN K. A.
Published: March 2003

(1) Salt sensitive hypertension, which occurs as a result of treatment with nitric oxide synthase inhibitors, is associated with a loss of the usual down‐regulatory effect of dietary sodium on angiotensin II (Ang II) synthesis. In the spontaneous hypertensive rat (SHR), which suffers a relative NO deficiency, the hypertension is in part salt sensitive. We sought to determine therefore whether the salt sensitive component to the hypertension was associated with a loss of the regulatory effect of dietary sodium on Ang II synthesis.

(2) Male SHR were placed on low, intermediate or high salt diets for 4 weeks and their blood pressure recorded. After 4 weeks, blood was collected for determination of renin, angiotensinogen, Ang I, Ang II and aldosterone concentrations, as well as ACE activity.

(3) The increase in systolic blood pressure in rats on the high salt diet was significantly greater than in those on the low (P < 0.005) and intermediate salt diets (P < 0.0005). Plasma renin and aldosterone concentrations and ACE activity decreased with increasing dietary sodium. However, the concentrations of Ang II and angiotensinogen both increased in the rats on the high salt diet (Ang II: P < 0.05; angiotensinogen: P < 0.05).

(4) We conclude that the hypertension in the SHR is in part salt sensitive and that this salt sensitive component is associated with a loss of the normal down‐regulatory effect of dietary sodium on Ang II and angiotensinogen synthesis.
Twenty‐four‐hour non‐invasive monitoring of systemic haemodynamics and cerebral blood flow velocity in healthy humans
Authors: DIAMANT M. , HARMS M. P. M. , IMMINK R. V. , VAN LIESHOUT J. J. , VAN MONTFRANS G. A.
Published: March 2003

Acute short‐term changes in blood pressure (BP) and cardiac output (CO) affect cerebral blood flow (CBF) in healthy subjects. As yet, however, we do not know how spontaneous fluctuations in BP and CO influence cerebral circulation throughout 24 h. We performed simultaneous monitoring of BP, systemic haemodynamic parameters and blood flow velocity in the middle cerebral artery (MCAV) in seven healthy subjects during a 24‐h period. Finger BP was recorded continuously during 24 h by Portapres and bilateral MCAV was measured by transcranial Doppler (TCD) during the first 15 min of every hour. The subjects remained supine during TCD recordings and during the night, otherwise they were seated upright in bed. Stroke volume (SV), CO and total peripheral resistance (TPR) were determined by Modelflow analysis. The 15 min mean value of each parameter was assumed to represent the mean of the corresponding hour. There were no significant differences between right vs. left, nor between mean daytime vs. night time MCAV. Intrasubject comparison of the twenty‐four 15‐min MCAV recordings showed marked variations (P < 0.001). Within each single 15‐min recording period, however, MCAV was stable whereas BP showed significant short‐term variations (P < 0.01). A day–night difference in BP was only observed when daytime BP was evaluated from recordings in the seated position (P < 0.02), not in supine recordings. Throughout 24 h, MCAV was associated with SV and CO (P < 0.001), to a lesser extent with mean arterial pressure (MAP; P < 0.005), not with heart rate (HR) or TPR. These results indicate that in healthy subjects MCAV remains stable when measured under constant supine conditions but shows significant variations throughout 24 h because of activity. Moreover, changes in SV and CO, and to a lesser extent BP variations, affect MCAV throughout 24 h.
Adenosine induces prolonged anti‐β‐adrenergic effects in guinea‐pig papillary muscle
Authors: ARVOLA L. , HASSAF D. , MELNIKOV A. L. , HELGESEN K. G. , YTREHUS K.
Published: March 2003

A sustained anti‐β‐adrenergic effect of adenosine has been reported. This study was initiated to investigate this topic and especially elucidate the role of protein kinase C (PKC). Contractile force amplitude and action potential duration at 90% repolarization (APD90) were measured in guinea‐pig papillary muscles before and after 5 min challenge with 5 nm isoproterenol. Protocols contained 30 min exposure to the test agents adenosine 33 μm (ado), adenosine + PKC‐inhibitor bisindolylmaleimide 20 nM (ado + BIM), PKC‐activator 1,2‐dioctanoyl‐sn‐glycerol 10 μm (DOG) and α‐agonist phenylephrine 5 μm (phe). Isoproterenol was given at the end of test exposure and after 15 min washout. Results are mean ± SEM of percentage‐change, P ≤ 0.05 considered significant and labelled *. The first isoproterenol challenge significantly increased contractile force (27 ± 7%*) in the control group. Responses in the test groups were 2 ± 4 (ado), 1 ± 5 (ado + BIM), 14 ± 4* (DOG), 0 ± 2% (phe). After washout of adenosine, DOG and phenylephrine, isoproterenol induced 3 ± 8 (ado), 23 ± 5* (ado + BIM), 13 ± 5* (DOG), 15 ± 7% (phe) increase in test groups compared with 22 ± 5%* increase in contractile force in the control group. After 45 min washout of adenosine the inotropic response was still significantly reduced compared with control (29 ± 4 vs. 79 ± 8%*). Isoproterenol stimulation shortened APD90 in controls at both time points (5 ± 1%* and 4 ± 1%*), with no significant shortening in test groups. Adenosine induces sustained anti‐β‐adrenergic effects on contractile force as well as APD90. A role for PKC in signal transduction is supported with respect to contractile force.
P2Y receptor‐induced EDHF vasodilatation is of primary importance for the regulation of perfusion pressure in the peripheral circulation of the rat
Authors: MALMSJÖ M. , CHU Z. M. , CROFT K. , ERLINGE D. , EDVINSSON L. , BEILIN L. J.
Published: March 2003

Extracellular nucleotides have been shown to induce vasodilatation of conductance arteries by release of the endothelium‐derived hyperpolarizing factor (EDHF). As small resistance arteries are of greater importance for blood pressure regulation, a whole rat mesenteric arterial bed preparation was used in the present study when evaluating the physiological relevance for EDHF in mediating nucleotide dilatation. Dilatory responses were examined after pre‐contraction with noradrenaline in the presence of 10 mM indomethacin. Adenosine‐5′‐O‐thiodiphosphate (ADPβS), adenosine triphosphate (ATP) and uridine triphosphate (UTP) induced vasodilatation (pEC50=6.5–7 and Emax=40–70%), while uridine diphosphate (UDP) was ineffective. Endothelium‐derived hyperpolarizing factor was studied in the presence of 0.5 mM Nϖ‐nitro‐L‐arginine (L‐NOARG). ADPβS and UTP induced strong and potent EDHF‐dilatations, while ATP only had a weak effect (Emax=25%). After P2X1 receptor desensitization with 10 μMαβ‐methylene‐adenosine triphosphate, the ATP response was significantly increased (Emax=65%). Putatively, this could be because of simultaneous activation of both endothelial P2Y receptors and P2X1 receptors on smooth muscle cells, which resulted in the release of EDHF and subsequent hyperpolarization, and depolarization, respectively. Nitric oxide (NO) was studied in the presence of 60 mM K+. ADPβS, ATP and UTP induced weak NO dilatations, suggesting a minor role for NO as compared with EDHF. In conclusion, extracellular nucleotides stimulate dilatation by activating P2Y1 and P2Y2/P2Y4 receptors, but not P2Y6 receptors. The dilatory responses are mediated primarily by EDHF in the peripheral vascular bed.
Adaptive stress response of glutathione and uric acid metabolism in man following controlled exercise and diet
Authors: Svensson M. B. , Ekblom B. , Cotgreave I. A. , Norman B. , Sjöberg B. , Ekblom Ö , Sjödin B. , Sjödin A.
Published: March 2003

Ergometer cycling performance as well as acute exercise‐induced changes in the metabolism of energy‐intermediates and glutathione (GSH) were investigated in skeletal muscle (SM) of 15 healthy young male subjects (VO2max∼54.7 mL kg−1 min−1, age ∼25 years), before and after 3 days of controlled ‘ìoverload‐training’ in combination with either high (62% of energy intake) or low (26% of energy intake) dietary intake of carbohydrates. The intake of a carbohydrate‐rich diet clearly reduced the depletion of SM glycogen following the short‐term training period, paralleled with a positive effect on the endurance performance, but not on high‐intensity work‐performance. An ‘delayed over‐reaching effect’, defined as impaired work‐performance, was observed after 2.5 days of recovery from the short‐term training period, irrespective of the carbohydrate content of the diet and basal glycogen level in SM. Taken together, the main and novel findings of present investigation are: (1) an acute decrease of reduced GSH content and altered thiol‐redox homeostasis in SM induced by strenuous high‐intensity exercise; (2) an adaptive elevation of basal GSH level following the short‐term training period; (3) an adaptive decrease of basal GSH level following 2.5 days recovery from training; (4) evidence of a relationship between the SM fibre type, physical performance capacity and GSH turnover during acute bouts of exercise; and (5) no evident effect of the level of carbohydrate intake on metabolism of GSH or energy intermediates. Furthermore, the induction of acute oxidative stress in exercising human SM and the adaptive responses to training are suggested to provide a protective antioxidant phenotype to the exercising SM during periods with repeated intense intermittent training.
Effects of oestrogen and exercise on caspase‐3 activity in primary and secondary lymphoid compartments in ovariectomized mice
Authors: Patel H. , Hoffman‐Goetz L.
Published: March 2003

This study investigated the effect of oestrogen exposure and exercise on caspase‐3 activity, a measure of apoptosis, in lymphocytes from the thymus, spleen, and lymph nodes in ovariectomized mice. Fifty‐nine female B6D2F1 mice were randomized to hormone and exercise conditions. Hormone treatment consisted of implantation with oestradiol pellets (0.72 mg oestradiol) or placebo pellets (0 mg) for 21 days following bilateral ovariectomy (OVX). Exercise consisted of a single treadmill exercise bout (26 m min−1, 6° slope, 90‐min) or sedentary condition. Mice were killed and the thymus, spleen and lymph nodes were removed for the determination of caspase‐3 expression by enzyme‐linked immunosorbent assay (ELISA), serum oestrogen levels by RIA, and tissue weights. Body weights were monitored throughout the study. In the thymus, oestrogen exposure, exercise and both treatments together were associated with higher caspase‐3 activity (P < 0.05) and lower thymus weights (P < 0.05). In contrast, oestrogen exposure and exercise treatment were not associated with greater caspase‐3 activity or change in tissue weight in secondary lymphoid tissues (spleen, lymph nodes). Oestrogen‐replaced OVX mice had a higher concentration of plasma oestradiol than placebo OVX mice (P < 0.05). Conclusion: The results suggest that oestrogen and treadmill exercise are associated with greater apoptosis, as measured by caspase‐3 activity, in the thymus but not in the spleen or lymph nodes. Clinical studies will be necessary to determine if women who take oestrogen have higher rates of apoptosis in primary lymphoid tissues and the significance of thymocyte apoptosis for maintenance of cellular immune function during the post‐menopausal years.
A rat resistance exercise regimen attenuates losses of musculoskeletal mass during hindlimb suspension
Authors: Fluckey J. D. , Dupont‐Versteegden E. E. , Montague D. C. , Knox M. , Tesch P. , Peterson C. A. , Gaddy‐Kurten D.
Published: March 2003

Exposure to microgravity and/or spaceflight causes dramatic losses in both muscle and bone mass. In normal gravity, resistance exercise has been effectively used to increase muscle and bone mass. We tested a novel form of resistance exercise training using flywheel technology as a countermeasure to offset the loss of musculoskeletal mass during 4 weeks of adult rat hindlimb suspension (HS), an unloading model of microgravity. Male, Sprague–Dawley rats (6‐month old) were operantly conditioned to perform resistance exercise, and then randomly assigned to groups of sedentary control (CON), HS, and HS with resistance exercise training (HSRT; 2 sets of ∼21 repetitions, 3 days week−1 for 4 weeks during suspension). In soleus, HS resulted in lower (P < 0.05) muscle mass to body mass ratio (∼50% of controls) and rates of protein synthesis. HSRT significantly attenuated the loss of muscle mass in soleus muscle, and rates of protein synthesis for soleus were similar for HSRT and controls. There were no differences among groups for mass or rates of protein synthesis in extensor digitorum longus. In cancellous regions of the distal femur, HS resulted in significant reductions of bone mineral density (BMD), but this was restored to control levels with HSRT. Cortical regions of the femur were not different among HS, HSRT or control groups. Together, these data suggest that resistance training using flywheel technology may be a promising tool to attenuate losses of the musculoskeletal system during periods of hindlimb unloading.
Enzyme activities in the tibialis anterior muscle of young moderately active men and women: relationship with body composition, muscle cross‐sectional area and fibre type composition
Authors: Jaworowski Å. , Porter M. M. , Holmbäck A. M. , Downham D. , Lexell J.
Published: March 2003

The aims of this study were (i) to assess the differences between men and women in maximal activities of selected enzymes of aerobic and anaerobic pathways involved in skeletal muscle energy production, and (ii) to assess the relationships between maximal enzyme activities, body composition, muscle cross‐sectional area (CSA) and fibre type composition. Muscle biopsies were obtained from the tibialis anterior (TA) muscle of 15 men and 15 women (age 20–31 years) with comparable physical activity levels. The muscle CSA was determined by magnetic resonance imaging (MRI). Maximal activities of lactate dehydrogenase (LDH), phosphofructokinase (PFK),β‐hydroxyacyl‐coenzyme A dehydrogenase (HAD), succinate dehydrogenase (SDH) and citrate synthase (CS), were assayed spectrophotometrically. The proportion, mean area and relative area (proportion × area) of type 1 and type 2 fibres were determined from muscle biopsies prepared for enzyme histochemistry [myofibrillar adenosine triphosphatase (mATPase)]. The men were significantly taller (+6.6%;P < 0.001) and heavier (+19.1%;P < 0.001), had significantly larger muscle CSA (+19.0%;P < 0.001) and significantly larger areas and relative areas of both type 1 and type 2 fibres (+20.5–31.4%;P = 0.007 toP < 0.001). The men had significantly higher maximal enzyme activities than women for LDH (+27.6%;P = 0.007) and PFK (+25.5%;P = 0.003). There were no significant differences between the men and the women in the activities of HAD (+3.6%; ns), CS (+21.1%;P = 0.084) and SDH (+7.6%; ns). There were significant relationships between height and LDH (r = 0.41;P = 0.023), height and PFK (r = 0.41;P = 0.025), weight and LDH (r = 0.45;P = 0.013), and weight and PFK (r = 0.39;P = 0.032). The relationships were significant between the muscle CSA and the activities of LDH (r = 0.61;P < 0.001) and PFK (r = 0.56;P = 0.001), and between the relative area of type 2 fibres and the activities of LDH (r = 0.49;P = 0.006) and PFK (r = 0.42;P = 0.023). There were no significant relationships between HAD, CS and SDH, and height, weight, muscle CSA and fibre type composition, respectively. These data indicate that the higher maximal activities of LDH and PFK in men are related to the height, weight, muscle CSA and the relative area of type 2 fibres, which are all significantly larger in men than women.
Paraventricular nucleus of the hypothalamus and elevated sympathetic activity in heart failure: the altered inhibitory mechanisms
Authors: Li Y.‐F. , Patel K. P.
Published: March 2003

Abstract Aim:  There is a characteristic neurohumoral activation in heart failure (HF). However, few studies have been performed to examine the role of the central nervous system in the activation of sympathetic outflow during HF. In this paper we review some of our studies, with particular emphasis on examining the role of the paraventricular nucleus (PVN) in the exaggerated sympathetic outflow commonly observed in HF.

Results:  Our studies have revealed that the inhibitory mechanisms regulating sympathetic outflow are mediated by nitric oxide (NO) and γ‐aminobutyric acid (GABA) within the PVN and are attenuated in HF. These alterations are associated with elevated sympathetic activity. Furthermore, these studies have indicated that the interactions among excitatory (angiotensin II and glutamate) and inhibitory (NO and GABA) neurotransmitters/mediators within the PVN significantly influence sympathetic outflow.

Conclusion:  Reduced inhibitory actions of NO and/or GABA within the PVN may exaggerate an increase in the actions of excitatory neurotransmitters such as glutamate and angiotensin II within the PVN and this may contribute to the overall sympatho‐excitation commonly observed in HF.
Transmitter characteristics of cutaneous, renal and skeletal muscle small arteries in the rat
Authors: Tarasova O. , Sjöblom‐Widfeldt N. , Nilsson H.
Published: March 2003

Aim:  We studied transmitter characteristics of proximal and distal arteries supplying skin (saphenous artery and its medial tarsal branch), kidneys (terminal branches of renal artery and interlobar arteries) and skeletal muscle (proximal and distal sections of external sural artery).

Methods:  Artery segments were mounted in an isometric myograph and intramural nerves were activated by electrical field stimulation. Adrenergic and purinergic components of the neurogenic response were blocked using phenoxybenzamine and α,β‐methylene adenosine triphosphate (mATP), respectively.

Results:  Arteries from skin or kidney developed rapid and prominent neurogenic contractile responses, with half‐maximal amplitude reached within 5–15 s; responses in proximal vessels were greater than in distal vessels. Arteries from skeletal muscle responded to sympathetic stimulation with a moderate contraction developing over 1 min or more, the response of distal segments was greater than that of proximal segments. In skeletal muscle vessels the sympathetically evoked contraction was completely blocked by phenoxybenzamine, whereas in skin and renal vessels it was the combined effect of noradrenaline and adenosine triphosphate (ATP). Given alone, mATP did not change the magnitude of the response to nerve stimulation, but increased its latency and also potentiated the response to exogenous noradrenaline. In all vascular beds, distal vessels were more sensitive to noradrenaline and mATP.

Conclusion:  It thus appears that the noradrenaline/ATP ratio of the sympathetic vasoconstrictor response differs between vascular beds in a way that is consistent with known differences in the selective regulation of regional vascular resistance by the sympathetic nervous system.