bluuebunny/crossref_metadata_2025 huggingface dataset:
ARSENIC‐INDUCED OXIDATIVE STRESS AND ITS REVERSIBILITY FOLLOWING COMBINED ADMINISTRATION OF N‐ACETYLCYSTEINE AND MESO 2,3–DIMERCAPTOSUCCINIC ACID IN RATS
Authors: Flora Swaran Js
Published: March 2003

1. The present study examined whether arsenic induces oxidative stress in liver, brain and erythrocytes (RBC) based on the investigation of certain selected parameters. It also explored the possibility that combined administration of N‐acetylcysteine (NAC) and meso 2,3‐dimercaptosuccinic acid (DMSA) was capable of achieving better reversibility in the parameters indicative of arsenic‐induced oxidative stress than individual treatment with either of these drugs.

2. Male rats were exposed to 100 p.p.m. sodium arsenite in their drinking water for 12 weeks (equivalent to 12 mg/kg As). The arsenic was then removed and rats were given NAC (1 mmol/kg per day), DMSA (1 mmol/kg per day) or a combination of the two, orally, once daily for 5 days. Animals not given arsenic and those given arsenic but not NAC or DMSA served as negative and positive controls, respectively.

3. Twelve weeks of arsenic exposure was found to deplete glutathione (GSH) levels, increase oxidized glutathione (GSSG) and promote malondialdehyde (MDA) production in both liver and brain samples. In addition to a significant reduction in RBC δ‐aminolevulinic acid dehydratase (ALAD) activity and GSH levels, a marked elevation in MDA production may also contribute to arsenic‐induced oxidative stress.

4. Treatment with either NAC or DMSA alone partially reversed arsenic‐induced alterations in hepatic GSH and MDA, while only brain MDA levels responded favourably to these drugs. Only DMSA appeared to restore blood ALAD, while RBC MDA levels responded favourably to both drugs. Treatment with DMSA also produced an effective depletion of blood and hepatic arsenic concentrations. In the liver, most of these parameters were more effectively reversed by combined treatment with NAC and DMSA compared with the effects of either drug alone.

5. These results provide in vivo evidence of arsenic‐induced oxidative stress in liver, brain and RBC and indicate that these effects can be mitigated by pharmacological intervention that encompasses combined treatment with NAC and DMSA.
EFFECTS OF PYRUVATE ON INTRACELLULAR Ca2+ REGULATION IN CARDIAC MYOCYTES FROM NORMAL AND DIABETIC RATS
Authors: Mellors Linda J , Kotsanas George , Wendt Igor R
Published: March 2003

1. Pyruvate has been shown to enhance the contractile performance of cardiac muscle when provided as an alternative substrate to glucose. The aims of the present study were to determine whether the inotropic effects of pyruvate are due to increased mobilization of intracellular Ca2+ ([Ca2+]i) and to compare the effects of pyruvate on [Ca2+]i levels in myocytes from normal and diabetic animals.

2. Fura‐2 was used to monitor [Ca2+]i in ventricular myocytes isolated from control and streptozotocin‐treated male Wistar rats. The experiments were performed at 25°C, with an extracellular [Ca2+] of 1.5 mmol/L and either 10 mmol/L glucose or 10 mmol/L pyruvate as the substrate.

3. In myocytes from both control and diabetic rats, increasing the stimulus frequency from 0.33 to 2.0 Hz resulted in significant increases in resting and peak [Ca2+]i as well as in the amplitude of the [Ca2+]i transient, irrespective of substrate. Compared with glucose, pyruvate significantly increased resting and peak [Ca2+]i and the amplitude of the [Ca2+]i transient at each stimulus frequency in myocytes from both control and diabetic animals. However, the extent of potentiation of the [Ca2+]i transient amplitude produced by pyruvate was significantly less in myocytes from the diabetic rats.

4. The rate of restitution of the [Ca2+]i transient was used as an index of the rate of Ca2+ cycling by the sarcoplasmic reticulum (SR). Pyruvate enhanced the rate of restitution in control but not diabetic rat cells.

5. The time course of decay of the [Ca2+]i transient was analysed as a measure of the rate of removal of Ca2+ from the cytosol. Pyruvate tended to increase the rate of decay in cells from control but not diabetic animals. The rate of decay was slower in cells from diabetic animals compared with controls.

6. The data reveal that pyruvate increases SR Ca2+ cycling, leading to greater Ca2+ release and an increase in the amplitude of the [Ca2+]i transient. Therefore, it seems highly likely that increased [Ca2+]i mobilization is responsible for the previously reported positive inotropic actions of pyruvate. These effects of pyruvate are attenuated in diabetic rat cells, which may reflect an impaired capacity of mitochondria in diabetic hearts to oxidize pyruvate, thus limiting potential energetic benefits.
Pattern Formation And Rhythm Generation In The Ventral Respiratory Group
Authors: McCrimmon Donald R , Monnier Armelle , Hayashi Fumiaki , Zuperku Edward J
Published: March 2003

1. There is increasing evidence that the kernel of the rhythm‐generating circuitry for breathing is located within a discrete subregion of a column of respiratory neurons within the ventrolateral medulla referred to as the ventral respiratory group (VRG). It is less clear how this rhythm is transformed into the precise patterns appearing on the varied motor outflows.

2. Two different approaches were used to test whether subregions of the VRG have distinct roles in rhythm or pattern generation. In one, clusters of VRG neurons were activated or inactivated by pressure injection of small volumes of neuroactive agents to activate or inactivate groups of respiratory neurons and the resulting effects on respiratory rhythm and pattern were determined. The underlying assumption was that if rhythm and pattern are generated by neurons in different VRG subregions, then we should be able to identify regions where activation of neurons predominantly alters rhythm with little effect on pattern and other regions where pattern is altered with little effect on rhythm.

3. Based on the pattern of phrenic nerve responses to injection of an excitatory amino acid (DL‐homocysteate), the VRG was divided into four subdivisions arranged along the rostrocaudal axis. Injections into the three rostral regions elicited changes in both respiratory rhythm and pattern. From rostral to caudal the regions included: (i) a rostral bradypnoea region, roughly associated with the Bötzinger complex; (ii) a dysrhythmia/tachypnoea area, roughly associated with the pre‐Bötzinger complex (PBC); (iii) a second caudal bradypnoea area; and, most caudally, (iv) a region from which no detectable change in respiratory motor output was elicited.

4. In a second approach, the effect of unilateral lesions of one subregion, the PBC, on the Breuer–Hering reflex changes in rhythm were determined. Activation of this reflex by lung inflation shortens inspiration and lengthens expiration (TE).

5. Unilateral lesions in the PBC attenuated the reflex lengthening of TE, but did not change baseline respiratory rhythm.

6. These findings are consistent with the concept that the VRG is not functionally homogeneous, but consists of rostrocaudally arranged subregions. Neurons within the so‐called PBC appear to have a dominant role in rhythm generation. Nevertheless, neurons within other subregions contribute to both rhythm and pattern generation. Thus, at least at an anatomical level resolvable by pressure injection, there appears to be a significant overlap in the circuitry generating respiratory rhythm and pattern.
Development Of An Experimental Model Of Liver Cirrhosis In Rabbits
Authors: Brandão CG , Ferreira HHA , Piovesana H , Polimeno NC , Ferraz JGP , De Nucci G , Pedrazzoli J
Published: March 2003

1. The aim of the present study was to develop an experimental model of liver cirrhosis in rabbits using CCl4 and phenobarbital.

2. Liver cirrhosis was induced in male New Zealand white rabbits (n = 10) by intragastric administration of CCl4 once weekly starting 14 days after the addition of phenobarbital to the drinking water (50 mg/day). Controls received phenobarbital only (n = 7). Alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ‐glutamyl transpeptidase (GGT), albumin and bilirubin levels were determined throughout CCl4 treatment. The initial dose of CCl4 was 20 μg and subsequent doses were calculated to maintain AST and ALT levels between 400 and 800 IU/L for the duration of treatment (16 weeks). Indocyanine green (ICG) clearance was performed before and at the end of CCl4 treatment. Animals were killed at 16 weeks and three fragments of each liver lobe were processed for histological examination. A semiquantitative score was used to evaluate the development of fibrosis.

3. Cirrhosis developed in 80% of rabbits treated with CCl4. These animals did not gain weight compared with controls (P < 0.05). A significant reduction of ICG clearance was observed in CCl4‐treated rabbits compared with controls (P < 0.05). The AST, ALT, bilirubin and γ‐GGT levels were elevated in CCl4‐treated rabbits.

4. In conclusion, this model is successful in producing liver cirrhosis and may be useful in studies investigating metabolic, immunological or biochemical changes during the evolution of chronic liver disease.
Acute But Not Chronic Caffeine Impairs Functional Responses To Ischaemia–Reperfusion In Rat Isolated Perfused Heart
Authors: Rose'Meyer Roselyn B , Headrick John P , Peart Jason N , Harrison Glenn J , Garnham Bronwyn G , Willis Roger J
Published: March 2003

1. The effect of acute (50 μmol/L) and chronic (0.06% in drinking water for 14 days) caffeine on the response to ischaemia–reperfusion was studied in Wistar rat isolated perfused hearts.

2. Neither acute nor chronic caffeine modified normoxic heart rate or left ventricular pressures. However, acute caffeine decreased coronary flow by up to 20%, while chronic caffeine consumption increased coronary flow by approximately 15% and abolished the vasoconstrictor effect of acute caffeine (P < 0.05).

3. After 15 min global ischaemia, chronic caffeine treatment did not alter the recovery of left ventricular diastolic pressure (LVDP), end‐diastolic pressure (EDP) or heart rate during reperfusion, but did enhance coronary flow rate (P < 0.05). Acute caffeine inhibited the recovery of LVDP and elevated postischaemic EDP in both caffeine‐naïve and chronic caffeine‐treated groups. Acute caffeine also significantly inhibited coronary reflow in naïve but not chronic caffeine‐treated groups and produced a transient tachycardia during reperfusion in hearts from chronic caffeine‐treated rats.

4. The incidence of arrhythmias was unaltered by chronic caffeine treatment, but was increased by acute caffeine in both naïve and chronic caffeine hearts.

5. In conclusion, chronic caffeine intake alone has no detrimental effects on recovery from ischaemia; however, acute caffeine worsens postischaemic contractile function in hearts from naïve and chronic caffeine‐treated rats.
Acute Opioid Receptor Desensitization And Tolerance: Is There A Link?
Authors: Borgland Stephanie L
Published: March 2003

1. Morphine, used long‐term for the treatment of pain, results in drug tolerance. The therapeutic benefits, as well as side effects, of morphine are mediated predominantly via activation of μ‐opioid receptors. Although the underlying mechanisms for opioid tolerance remains unclear, early adaptive processes, such as acute receptor desensitization and receptor downregulation, have been suggested to be crucial to the development of opioid tolerance.

2. Other neuroadaptations resulting from chronic opioid use include upregulation of the cAMP pathway, an increase in the cAMP response element‐binding protein and Fos‐related antigens. However, the connection between upregulation of these cellular elements and the mechanism behind the behavioural phenomenon remains unclear.

3. Acute receptor desensitization is thought to occur via uncoupling of the receptor and G‐protein, which is followed by internalization of the receptor from the cell membrane. This process occurs after a few minutes of agonist exposure. Receptor–G‐protein uncoupling is mediated via phosphorylation of putative sites on the intracellular loops of activated receptors.

4. Acute desensitization and downregulation of receptors both result in a reduction of agonist efficacy. These events occur early in the cascade of cellular adaptation; however, it is uncertain whether these processes contribute to the long‐term changes in receptor sensitivity that occur after repeated exposure to opioids.

5. Acute desensitization may, in fact, be a protective mechanism whereby cells adapt to avoid the development of physiological drug tolerance by rapidly attenuating receptor‐mediated signalling. Those drugs that do not cause receptor internalization, such as morphine, may have higher propensities to develop tolerance.
KRH‐594, A New Angiotensin At1 Receptor Antagonist, Prevents End‐Organ Damage In Stroke‐Prone Spontaneously Hypertensive/Izm Rats
Authors: Inada Yoichi , Tazawa Shigeki , Murakami Makoto , Akahane Masuo
Published: March 2003

1. In the present study, we examined whether KRH‐594, a new angiotensin AT1 receptor antagonist, would stop the progression of renal failure and end‐organ damage and improve the survival rate in salt‐loaded stroke‐prone spontaneously hypertensive rats (SHRSP/Izm).

2. Oral administration of KRH‐594 (3 and 10 mg/kg per day) for 11 weeks significantly reduced systolic blood pressure, urinary total protein, blood urea nitrogen, serum creatinine and urinary N‐acetyl glucosaminidase and increased creatinine clearance in SHRSP/Izm.

3. In a histological study, KRH‐594 (3 and 10 mg/kg per day) significantly improved the glomerulosclerosis, basophilic change and hyalin cast of tubules, proliferation of afferent arterioles and interlobular artery wall scores of the kidney and the cardiac fibrosis scores of the heart in SHRSP/Izm. KRH‐594 (3 and 10 mg/kg per day) also significantly inhibited cardiac hypertrophy.

4. KRH‐594 (3 and 10 mg/kg per day) prevented death in SHRSP/Izm during the examination period.

5. These results suggest that KRH‐594 improves hypertensive complications, such as renal failure, cardiac hypertrophy and thickening of the artery wall, and prevents death in salt‐loaded SHRSP/Izm.
Suppressive Effects Of Oxcarbazepine On Tooth Pulp‐Evoked Potentials Recorded At The Trigeminal Spinal Tract Nucleus In Cats
Authors: Kiguchi Sumiyoshi , Ichikawa Kiyoshi , Kojima Masami
Published: March 2003

1. The purpose of the present study was to evaluate the antinociceptive effect of oxcarbazepine, a keto derivertive of carbamazepine (an anticonvulsant), in an animal model. To evoke a nociceptive response, we electrically stimulated the maxillary canine tooth pulp (MCTP) in anaesthetized (allobarbital–urethane), spontaneously breathing cats.

2. The evoked potentials were recorded from the superficial layers of the caudal part of the trigeminal spinal tract nucleus (5ST). We examined a slow component with a large amplitude (the P3 component) in evoked compound potentials; its mean conduction velocity was 1.7 m/s, suggesting a response mediated by C‐fibres.

3. To confirm that the P3 component was related to pain sensation, we used morphine, a most efficacious antinociceptive agent, in the present study. The P3 component was significantly suppressed by intravenous administration of morphine (3 mg/kg) and was also suppressed by microinjection of morphine (2 μg) into the recording site of the 5ST. These results suggest that the P3 component is involved in the transmission of nociceptive information.

4. We compared the effect of oxcarbazepine with mexiletine; both are known to block neuronal Na+ channels. Intravenous administration of mexiletine suppressed the P3 component at a dose of 5 mg/kg. Microinjection of mexiletine (10 μg) into the recording site of the 5ST tended to suppress the P3 component, but this effect was not significant.

5. Intravenous administration of oxcarbazepine (1–10 mg/kg) caused a dose‐dependent inhibition of the P3 component, which was significantly suppressed at 10 mg/kg oxcarbazepine. Intravenous administration of 10,11‐dihydro‐10‐hydroxy‐ 5H‐dibenz[b,f]azepine‐5‐carboxamide (MHD), a metabolite of oxcarbazepine, at doses of 3–30 mg/kg caused a dose‐dependent inhibition of the P3 component. Oxcarbazepine was not available for the microinjection study because it is not water soluble. We used MHD for the microinjection study instead of oxcarbazepine, because MHD can be dissolved in water up to 3 mg/mL. Microinjections of MHD (6 μg) into the recording site of the 5ST suppressed the P3 component. These results indicate that oxcarbazepine has an antinociceptive action.
An Electrophysiological Study Of The Effects Of Propofol On Native Neuronal Ligand‐Gated Ion Channels
Authors: Patten Debra , Foxon Graham R , Martin Keith F , Halliwell Robert F
Published: March 2003

1. Pharmacological evidence suggests that some of the clinical actions of propofol may be mediated, at least in part, by positive modulation of the GABAA receptor chloride channel. The effect of propofol at other native neuronal ligand‐gated ion channels is unclear.

2. To gain some insight into the effects of propofol at a range of native neuronal receptors, the present study has used an extracellular recording technique and determined its effects at GABAA, 5‐HT3, P2X and nicotinic acetylcholine (nACh) receptors of the rat isolated vagus nerve and the GABAA and strychnine‐sensitive glycine receptor of the rat isolated optic nerve. In addition, we have used patch‐clamp recording techniques to further investigate the effects of propofol at the GABAA and strychnine‐sensitive glycine receptors in rat cultured hippocampal neurons.

3. Propofol (0.3–100 μmol/L) concentration‐dependently potentiated submaximal GABA‐evoked responses in the vagus nerve and shifted the GABA concentration–response curve to the left. In contrast, propofol at concentrations ranging from 1 to 10 μmol/L had little or no effect on 5‐HT3, P2X or nACh receptor‐mediated responses in the vagus nerve but, at 100 μmol/L, propofol inhibited these responses to approximately 50% of control. In the optic nerve, EC20 GABA‐evoked responses were also potentiated by propofol (10 μmol/L), while EC20 glycine‐evoked responses were minimally enhanced.

4. Further investigations using cultured hippocampal neurons showed that submaximal (10 μmol/L) GABA‐evoked currents were potentiated by propofol (1–10 μmol/L), in a non‐voltage‐dependent manner, whereas submaximal (100 μmol/L) glycine‐evoked currents were unaffected.

5. These data suggest that propofol, at therapeutic concentrations, exerts its principle pharmacological actions at GABAA receptors with relatively little effect at other neuronal ligand‐gated ion channels.
Proceedings of the Australian Physiological and Pharmacological Society Symposium: New Frontiers in Muscle Research Gene transfer: manipulating and monitoring function in cells and tissues
Authors: Panchal Rekha G , Williams David A , Kitchener Peter D , Reilly Angela M , Khan Jameel , Bowser David N , Petrou Steven
Published: March 2003

1. The ectopic expression of genes has proven to be an extremely valuable tool for biologists. The most widely used systems involve electrically or chemically mediated transfer of genes to immortalized cell lines and, at the other end of the spectrum, transgenic animal models. As would be expected, there are compromises to be made when using either of these broad approaches. Immortalized cell lines have limited ‘physiological relevance’ and transgenic approaches are costly and out of the reach of many laboratories. There is also significant time required for the de novo generation of a transgenic animal.

2. As a viable alternative to these approaches, we describe the use of recombinant adenovirus and Sindbis virus to deliver genes to cells and tissues.

3. We exemplify this approach with studies from our laboratories: (i) an investigation of Ca2+ handling deficits in cardiac myocytes of hypertrophied hearts using infection with recombinant adenovirus encoding either green fluorescent protein (GFP) or the sarcoplasmic/endoplasmic reticulum calcium‐ATPase (Serca2a); (ii) a study of the mechanism of macrophage/microglial migration by infection of embryonic phagocytes with a GFP‐encoding virus and coculture with brain slices to then track the movement of labelled cells; and (iii) we are also exploiting the natural tropism of the Sindbis virus to label neurons in hippocampal brain slices in culture to resolve high‐resolution structure and to map neuronal connectivity.

4. Further development of these approaches should open new avenues of investigation for the study of physiology in a range of cells and tissues.
Troglitazone Enhances Glucose Uptake Induced By α‐Adrenoceptor Stimulation Via Phosphatidylinositol 3‐Kinase In Rat Heart
Authors: Yoshioka Jun , Kusuoka Hideo , Imahashi Kenichi , Hashimoto Katsuji , Hori Masatsugu , Terakawa Taichiro , Nishimura Tsunehiko
Published: March 2003

1. Thiazolidinedione‐derived agents have been reported to act as insulin sensitizers by augmenting insulin‐dependent stimulation of phosphatidylinositol 3‐kinase (PI3K) activity in a specific manner. It has been suggested that α‐adrenoceptor stimulation mediates glucose uptake through PI3K in the heart.

2. To elucidate whether the thiazolidinedione‐derived agent troglitazone (TRO) affects glucose uptake induced by α‐adrenoceptor stimulation through PI3K, the rate of glucose uptake was quantified from the rate of accumulation of sugar phosphate (d[SP]/dt) using [31P] nuclear magnetic resonance spectroscopy after substitution of glucose with 2‐deoxyglucose in rat perfused heart. Hearts were stimulated with 100 μmol/L phenylephrine plus 10 μmol/L propranolol (α‐adrenoceptor stimulation), or 1 μmol/L isoproterenol plus 10 μmol/L phentolamine (β‐adrenoceptor stimulation).

3. The d[SP]/dt in the α‐ and β‐adrenoceptor‐stimulated groups (0.45 ± 0.06 and 0.42 ± 0.04 μmol/min per g, respectively) was higher than that of the control group (0.27 ± 0.02 μmol/min per g; P < 0.01). The addition of 2 μg/mL troglitazone to α‐adrenoceptor stimulation augmented d[SP]/dt (0.72 ± 0.08 μmol/min per g; P < 0.05 vs the α‐adrenoceptor‐stimulated group), which was effectively blocked by 3 μmol/L wortmannin (0.35 ± 0.06 μmol/min per g; P < 0.01 vs troglitazone + α‐adrenoceptor stimulation group). However, addition of troglitazone to β‐adrenoceptor stimulation did not alter d[SP]/dt (0.33 ± 0.02 μmol/min per g; P = NS vs the β‐adrenoceptor‐stimulated group).

4. These results indicate that troglitazone acutely enhances α‐adrenoceptor stimulation on glucose uptake through a PI3K‐dependent pathway, thus possibly improving glucose utilization in a catecholamine‐released state.
Time Of Day And Access To Food Alter Water Intake In Rats After Water Deprivation
Authors: Ang Kooi K , McKitrick Douglas J , Phillips Paddy A , Arnolda Leonard F
Published: March 2003

1. Drinking behaviour after water deprivation is one of the standard tests used to study thirst in humans and animals. Diurnal cycle and food availability are known to influence water intake, but have not been considered in previous studies of thirst after water deprivation. In the present study, we examined the effects of diurnal variation and food availability on water intake after 24 h water deprivation in rats.

2. All rats cycled through four treatments in varying order. These treatments were: (i) 24 h water deprivation with free access to food from 1900 h one day to 1900 h the next day, followed by free access to both food and water (Night‐with‐Food); (ii) 24 h water deprivation with free access to food from from 1900 h one day to 1900 h the next day, followed by free access to water but not food (Night‐without‐Food); (iii) 24 h water deprivation with free access to food from 0700 h one day to 0700 h the next day, followed by free access to both food and water (Day‐with‐Food); or (iv) 24 h water deprivation with free access to food from 0700 h one day to 0700 h the next day, followed by free access to water but not food (Day‐ without‐Food). The amount of water consumed during the first 6 h, post‐24 h water deprivation, was examined under each condition.

3. There was a significant diurnal effect (P < 0.001) and a significant food availability effect (P = 0.007) on the water consumed in the 6 h period after water deprivation. Most water was consumed by the Night‐with‐Food group and the least amount of water was consumed by the Day‐without‐Food group. These effects persisted after correction for water intake during 6 h periods from 0700 and 1900 h with and without food but without previous water deprivation. The diurnal and food availability effects on water consumption were independent (P = 0.5).

4. The coefficient of variability for each group suggests that the most sensitive measurements of water intake are obtained during the day in the absence of food.

5. We conclude that both the time of day and access to food independently alter water intake in rats subjected to a previous 24 h water deprivation. Our study also supports the validity of performing water intake measurements in thirst studies in rats during the day.
Monocyte Integrin Expression And Monocyte–Platelet Complex Formation In Humans With Coronary Restenosis
Authors: Arefieva Tatiana I , Provatorov Sergey I , Samko Anatoly N , Krasnikova Tatiana L , Resink Therese J , Erne Paul , Tkachuk Vsevolod A , Chazov Eugeniy I
Published: March 2003

1. In the present study, we sought to determine whether patients with restenosis after coronary stenting possess increased monocyte reactivity, as manifested by a higher level of adhesion molecule expression and an enhanced propensity to form monocyte–platelet aggregates after activation in vitro.

2. Anti‐coagulated peripheral venous blood from 24 patients, 10 with and 14 without angiographically verified restenosis, was obtained. Leucocyte antigen expression and the number of leucocyte–platelet complexes were measured by flow cytometry after activation in whole blood.

3. Surface integrin Mac‐1 (CD11b/CD18) and VLA‐4 (CD49d/ CD29) expression on monocytes and the relative number of monocyte–platelet complexes after in vitro activation were significantly elevated in patients with restenosis compared with patients without restenosis (fluorescence intensities of 1425 ± 76 vs 1195 ± 71, 87 ± 7 vs 65 ± 6 and 47 ± 4 vs 29 ± 3% for for Mac‐1, VLA‐4 and monocyte–platelet complexes, respectively; P < 0.05 for each parameter).

4. The results suggest that restenosis is associated with increased monocyte VLA‐4 and Mac‐1 integrin expression and monocyte–platelet complex formation, which can be revealed after activation in vitro.
Investigation Of AM‐36: A Novel Neuroprotective Agent
Authors: Callaway Jk
Published: March 2003

1. The neurochemical sequelae following cerebral ischaemia are complex, involving excess release of excitatory amino acids, particularly glutamate, disruption of ionic homeostasis due to Na+ and Ca2+ influx and generation of toxic free radicals, ultimately leading to cell death by both necrosis and apoptosis.

2. Drugs that block components of this biochemical cascade, such as glutamate receptor antagonists, sodium channel blockers and free radical scavengers, have been investigated as putative neuroprotective agents. The knowledge that multiple mechanisms contribute to neuronal injury in ischaemia have led to the general recognition that a single drug treatment is unlikely to be beneficial in the treatment of cerebral ischaemia.

3. AM‐36 [1‐(2‐(4‐chlorophenyl)‐2‐hydroxy)ethyl‐4‐(3,5‐bis(1,1‐dimethyl)‐4‐hydroxyphenyl)methylpiperazine] is one of a series of hybrid molecules designed to incorporate multiple neuroprotective mechanisms within the one structure. Primary screening tests demonstrated that AM‐36 inhibited binding to the polyamine site of glutamate receptors, blocked neuronal sodium channels and had potent anti‐oxidant activity. In neuronal cell cultures, AM‐36 inhibited toxicity induced by N‐methyl‐D‐aspartate (NMDA) and the sodium channel opener veratridine and, in addition, inhibited veratridine‐induced apoptosis.

4. In a middle cerebral artery occlusion model of stroke in conscious rats, systemic administration of AM‐36 markedly reduced both cortical and striatal infarct volume and significantly improved functional outcome in motor performance, neurological deficit and sensorimotor neglect tests. AM‐36 was neuroprotective even when administration was delayed until 3 h systemically, or 5 h intravenously, after induction of stroke.

5. These studies indicate that AM‐36 is a unique neuroprotective agent with multiple modes of action, making it an attractive candidate for the treatment of acute stroke in humans.
Recent Developments Concerning Diet And Hypertension
Authors: Beilin Lawrie J , Burke Valerie , Puddey Ian B , Mori Trevor A , Hodgson Jonathan M
Published: March 2003

1. Recent data from randomized controlled dietary trials have shown blood pressure‐lowering effects of foodstuffs and dietary patterns to be of practical importance for both individual and population blood pressure control.

2. The salient studies include Dietary Approaches to Stop Hypertension (DASH) trials, on complex dietary patterns and of additive effects of salt restriction, Trial of Nonpharmacologic Interventions in the Elderly (TONE), on weight control and sodium restriction as substitutes for drug therapy, and two Australian trials showing additive effects of dietary fish and weight control and of dietary protein and fibre in treated hypertensives.

3. Regular coffee drinking raised blood pressure in older hypertensives, whereas potential antihypertensive effects of dietary anti‐oxidants require further scrutiny.
Different Aortic Reflection Wave Responses Following Long‐Term Angiotensin‐Converting Enzyme Inhibition And Beta‐Blocker In Essential Hypertension
Authors: Pannier Bruno M , Guerin Alain P , Marchais Sylvain J , London Gérard M
Published: March 2003

1. In arterial hypertension, aortic wave reflections contribute to determining central systolic and pulse pressures. The present study assessed the central pressure alterations at the level of the common carotid artery following 1 month treatment with perindopril or atenolol and investigated during the 8 h following drug intake.

2. Twenty patients suffering from permanent hypertension were included after a 4 week run‐in placebo period in a double‐blind, randomized cross‐over study comparing the angiotensin‐converting enzyme (ACE) inhibitor perindopril with the beta‐blocker atenolol during a 4 week treatment period.

3. Before and during the 8 h after drug intake, serial measurements included brachial artery systolic and diastolic blood pressures (SBP and DBP, respectively; mercury sphygmomanometer), carotid artery SBP and pulse pressure (PP; applanation tonometry), aortic pulse wave velocity (Complior; Colson, Les Lilas, France) and arterial wave reflections from the aorta (applanation tonometry; Sphygmocor; PWV Medical, Sydney, NSW, Australia).

4. Both treatments decreased brachial and carotid artery SBP, DBP and PP. Heart rate and pulse wave velocity decreased following atenolol (P < 0.001). Pulse wave velocity was reduced slightly following perindopril (NS). Arterial wave reflections were significantly (P < 0.001) decreased with perindopril in comparison with atenolol, but this effect on wave reflections was not associated with a larger decrease in carotid artery PP.

5. Thus, during chronic treatment, ACE inhibition and selective β1‐adrenoceptor blockade resulted in a similar decrease in brachial and carotid artery PP, but only atenolol reduced heart rate. Aortic pulse wave velocity was reduced with both drugs, but atenolol appeared more effective in improving aortic stiffness. Arterial wave reflections were decreased only following perindopril.

6. Central pulse pressure was improved following 1 month treatment with an ACE inhibitor or β‐adrenoceptor blockade following a decrease in arterial wave reflections with perindopril and a higher decrease in regional aortic stiffness with atenolol.
Vasculoprotective Effects Of Oestrogens
Authors: Arnal Jean‐François , Bayard Francis
Published: March 2003

1. The rationale for preclinical research on the atheroprotective effect of oestrogens is based on the epidemiological evidence that women are protected against the clinical complications of atherosclerosis until menopause. However, this protection, probably due to sex hormones, is progressively lost within the years following menopause.

2. In addition, numerous studies have clearly demonstrated the atheroprotective effect of oestrogens in all animal models.

3. In the present paper, we first summarize our understanding of the pathophysiology of atherosclerosis. We then focus on the recognized target of oestradiol (E2) in the vessel wall: the classical target, namely the endothelium, and a recently characterized target, namely cells of the inflammatory–immune system. Finally, we discuss how unknown mechanisms in atherosclerosis could be responsible for the absence of effect of hormone‐replacement therapy in the Heart and Estrogen/ progestin Replacement Study (HERS).
Effects Of Endomorphin‐1 And ‐2 On μ‐Opioid Receptors In Myenteric Neurons And In The Peristaltic Reflex In Rat Small Intestine
Authors: Storr Martin , Hahn Andreas , Gaffal Evelyn , Saur Dieter , Allescher Hans D
Published: March 2003

1. The aim of the present investigations was to characterize the effect of endomorphins on the function of rat small intestine smooth muscle and on the electrically induced ascending and descending reflex pathway of rat small intestine in vitro.

2. Endomorphin‐1 and ‐2 left the basal tonus and the pharmacologically stimulated smooth muscle unchanged. In contrast, electrically induced twitch contractions were significantly reduced by endomorphin‐1 and ‐2 and this reduction was reversed by the μ‐opioid receptor antagonist Cys‐Tyr‐Orn‐Pen‐amide (CTOP), suggesting a specific μ‐opioid receptor‐mediated effect on neural tissue.

3. In the reflex model, endomorphin‐1 caused a significant inhibition (IC50 2.3 × 10–8 mol/L) of the ascending contraction (10–8 mol/L: –28.3 ± 5.8%; 10–7 mol/L: –94.7 ± 0.2.8%; both P < 0.05; n = 7). Descending relaxation increased at a concentration of 10–8 mol/L endomorphin‐1 (+61.6 ± 24.5%; 10–7 mol/L: +237.0 ± 65.4%; both P < 0.05; n = 6).

4. Endomorphin‐1 caused a further significant increase in the latency of the ascending contraction (10–8 mol/L: +44.7 ± 20.5%; 10–7mol/L: +93.5 ± 16.1%; both P < 0.05; n = 7), whereas the latency of the descending relaxation was unaltered (n = 7). Similar results were observed for endomorphin‐2.

5. All effects could be reversed by a wash‐out afterwards and were blocked by pre‐incubation with CTOP (10–6 mol/L).

6. Reverse transcription–polymerase chain reaction demonstrated mRNA expression of μ‐opioid receptors in the rat ileum longitudinal muscle/myenteric plexus preparation, as well as in the oesophagus and stomach.

7. Endomorphin‐1 and ‐2 reduce the cholinergic‐induced contractile response of the rat ileal smooth muscle preparation via a presynaptic mechanism.

8. By a specific and reversible interaction with μ‐opioid receptors, the ascending excitatory and descending inhibitory reflex responses were attenuated or facilitated, respectively.

9. In conclusion, the endomorphins may be the physiological endogenous μ‐opioid receptor agonists in the rat small intestine.
Chronic Ethanol Consumption Alters Vascular Smooth Muscle Responses In Rats
Authors: Ladipo CO , Adigun SA , Nwaigwe CI , Adegunloye BJ
Published: March 2003

1. The effect of chronic ethanol (10%) consumption for 5 months on vascular smooth muscle (VSM) using aortic rings of both sexes of Sprague‐Dawley rats was studied.

2. Chronic ethanol consumption increased the sensitivity of VSM to noradrenaline (NA) in both male and female ethanol‐treated rats.

3. There was no significant difference in the contractile response of male and female ethanol‐treated rats to NA. Hence, the enhancement of vascular contractility to the agonist due to chronic ethanol consumption is independent of gender.

4. Vascular relaxation induced by acetylcholine showed similar responses in all experimental groups. Thus, chronic ethanol consumption seems to have no significant effect on the production of endothelium‐dependent relaxing factor.

5. However, the VSM sensitivity to potassium chloride was increased in female ethanol‐treated rats, whereas male ethanol‐treated rats had similar responses as controls.

6. The results suggest that the effect of chronic ethanol consumption on VSM varies with gender. Impairment of VSM in male ethanol‐treated rats is due partly to changes in the receptor‐operated channel, whereas in females it is due to changes in both receptor‐ and potential‐operated channels.
Dual nitric oxide mechanisms of cholestasis‐induced bradycardia in the rat
Authors: Mani Ali R , Nahavandi Arezo , Moosavi Maryam , Safarinejad Reza , Dehpour Ahmad R
Published: March 2003

1. Cholestatic liver disease is associated with nitric oxide (NO) overproduction and bradycardia. Nitric oxide has a dual effect on sinoatrial node and its effects depend on its concentration. Nitric oxide can increase heart rate by activating hyperpolarization‐activated pacemaker current (If) but, at high concentrations, it can potentially decrease heart rate by inhibition of L‐type calcium current. In the present study, the responsiveness of isolated atria to CsCl (an inhibitor of the If current) and acetylcholine (ACh; which decreases L‐type calcium current through a NO‐dependent pathway) were evaluated in bile duct‐ligated and sham‐operated control rats.

2. Bile duct ligation induced a significant decrease in the negative chronotropic effect of CsCl (0.2–5 mmol/L), but increased the responsiveness of isolated atria to ACh (10−8 to 10−3 mol/L). These effects were restored after incubation of the atria in the presence of the NO synthase inhibitor NG‐nitro‐l‐arginine methyl ester (0.1 mmol/L).

3. Anaesthetized bile duct‐ligated rats showed bradycardia and the plasma levels of NO2–/NO3– were significantly higher in bile duct‐ligated rats compared with sham‐operated animals.

4. Different and opposite responses of atria of cholestatic rats to CsCl and ACh can be explained by NO overproduction in bile duct‐ligated animals. A dual role of NO in the regulation of the sinoatrial node may be responsible for this opposite effect and may have a role in the pathophysiology of cholestasis‐induced bradycardia.
Actions of specific adenosine receptor A1 and A2 agonists and antagonists in recovery of phrenic motor output following upper cervical spinal cord injury in adult rats
Authors: Nantwi KD , Goshgarian HG
Published: March 2003

1. Previous studies from our laboratory have established that a latent respiratory motor pathway can be activated to restore function to a hemidiaphragm paralysed by upper cervical (C2) spinal cord hemisection during a reflex known as the ‘crossed phrenic phenomenon’. In addition, theophylline, a general adenosine A1 and A2 receptor antagonist, can activate the latent pathway by acting centrally through antagonism at adenosine receptors.

2. The present study was designed to assess the relative contributions of adenosine A1 and A2 receptors in inducing functional recovery in our model of spinal cord injury. Specific adenosine A1 and A2 agonists and antagonists were used in an electrophysiological study.

3. Our results demonstrate that, in hemisected rats, systemic administration of the adenosine A1 receptor‐specific antagonist 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX) restores, in a dose‐dependent manner, phrenic nerve respiratory related output that is lost following hemisection. Furthermore, DPCPX augments respiratory activity in non‐injured animals. The A2 receptor agonist CGS‐21680 mediates its effects by predominantly acting on peripheral rather than central nervous system (CNS) receptors. CGS‐21680 modulates respiratory related phrenic nerve activity in non‐injured animals by enhancing tonic activity, but does not induce recovery of phrenic nerve activity in hemisected animals in the majority of cases. When CGS‐21680 was administered prior to DPCPX in hemisected rats, the magnitude of recovery of respiratory function was significantly greater than that elicited by DPCPX alone. However, when the A2 receptor agonist was administered after DPCPX, the magnitude of recovery was virtually unchanged, whereas activity in the right phrenic nerve was significantly enhanced. The A1 receptor agonist N6‐cyclohexyladenosine depressed respiratory activity in non‐injured, as well as hemisected, rats. The A2 receptor antagonist 3,7‐dimethyl‐1‐propargylxanthine did not affect respiratory activity.

4. We conclude that while antagonism at central adenosine A1 receptors mediates functional restitution in hemisected animals, activation of A2 receptors located outside of the CNS subserves the A1 receptor‐mediated respiratory recovery.
Effect of an intrathoracic injection of sodium hyaluronic acid on the prevention of pleural thickening in excess fluid of tuberculous thoracic cavity
Authors: Zhou Ailian , Guo Lanping , Tang Liangchun
Published: March 2003

1. The aim of the present study was to evaluate the effect of a hyaluronate‐based gel (HAbg) on the prevention of pleural thickening and adhesion in tuberculous pleural effusions (TPE).

2. Fifty‐two patients who had accumulated a medium or large volume of tuberculous thoracic fluid, fluid being bound by fibre tissues and a pleura thickened more than 2 mm were divided randomly into two groups. All patients were all given standard treatments with antituberculous drugs. The HAbg was injected into the thoracic cavity in the treatment group (n = 27 patients), whereas normal saline was introduced into the thoracic cavity in the control group (n = 25 patients). Before and after HAbg injection, routine thoracic fluid examiniations (including qualitative protein analysis, cell counts and classification of cell types) and protein quantification were performed. A chest radiograph and B‐ultrasound were performned and pulmonary function was tested after 2 weeks and 3 months of thoracic fluid absorption.

3. The results show that patients who were treated with the HAbg had a significantly thinner pleura, a lower protein concentration and white blood cell count in the thoracic fluid and a higher forced expiratory volume in 1 s and forced vital capacity compared with patients in the control group.

4. Intrathoracic HAbg can prevent pleural thickening and improve lung function in patients who have a large amount of TPE.
Ketanserin stabilizes blood pressure in conscious spontaneously hypertensive rats
Authors: Miao Chao‐Yu , Xie He‐Hui , Yu Hui , Chu Zheng‐Xu , Su Ding‐Feng
Published: March 2003

1. It has been demonstrated that blood pressure variability (BPV) is increased in hypertension and related to organ damage. It will be important to lower BPV in the treatment of hypertension. The present study was designed to investigate the effect of ketanserin, a 5‐HT2A receptor antagonist with a weak α1‐adrenoceptor blocking effect, on BPV in conscious spontaneously hypertensive rats (SHR).

2. It was found that ketanserin decreased blood pressure (BP) and BPV in SHR when administered intravenously (3 mg/kg, i.v.). Ketanserin decreased BPV, but not the BP level, when administered intracerebroventricularly (50 µg/rat, i.c.v.).

3. Prazosin, an α1‐adrenoceptor antagonist, lowered BP but did not affect BPV when given either i.v. (0.5 mg/kg) or i.c.v. (30 ug/rat). Ritanserin (0.625 mg/kg, i.v.; 40 'ug/rat, i.c.v.), a 5‐HT2A receptor antagonist, decreased BPV only when administered i.c.v. and did not modify the BP level.

4. Ketanserin enhanced arterial baroreflex function in SHR when given either i.v. or i.c.v.

5. The stabilizing effect of ketanserin on BP was persistent when administered intragastrically. This administration route is similar to oral administration clinically.

6. It is concluded that ketanserin is an antihypertensive agent with an effect of reducing BPV. This effect is mainly mediated by central 5‐HT2A receptors and is probably attributable to the restoration of arterial baroreflex function.
Resting energy expenditure among Japanese
Authors: Hosoya N , Mitsuhashi F , Sugiyama M
Published: March 2003

1. Resting energy expenditure (REE) provides appropriate basic data for the calculation of energy requirements.

2. The REE of 6498 subjects according to sex and age (1 year stratification), with a minimum of 10 subjects per group, was measured systematically using the easy portable calorimeter (Metavine; Vine, Tokyo, Japan).

3. The REE or the REE/kg according to age and sex was observed to obtain the amount of standard deviation (20–25%).

4. The REE/kg for male and female subjects was maintained at a steady level after the age of 15 years and was estimated to be around 29 kcal/kg.
Cytochalasin B inhibits morphogenetic movement and muscle differentiation of activin‐treated ectoderm in Xenopus
Authors: Tamai Keiko , Yokota Chika , Ariizumi Takashi , Asashima Makoto
Published: March 2003

Xenopus ectodermal explants (animal caps) begin to elongate after treatment with the mesoderm inducing factor activin A. This phenomenon mimics the convergent extension of dorsal mesoderm during gastrulation. To analyze the relationship between elongation movement and muscle differentiation, animal caps were treated with colchicine, taxol, cytochalasin B and hydroxyurea (HUA)/aphidicolin following activin treatment. Cytochalasin B disrupted the organization of actin filaments and inhibited the elongation of the activin‐treated explants. Muscle differentiation was also inhibited in these explants at the histologic and molecular levels. Colchicine and taxol, which are known to affect microtubule organization, had little effect on elongation of the activin‐treated explants. Co‐treatment with HUA and aphidicolin caused serious damage on the explants and they did not undergo elongation. These results suggest that actin filaments play an important role in the elongation movement that leads to muscle differentiation of activin‐treated explants.
Proteins with tandemly arranged repeats of a highly charged 16‐amino‐acid motif encoded by the Dhmst101 gene family are structural components of the outer sheath of the extremely elongated sperm tails of Drosophila hydei
Authors: Neesen Jürgen , Heinlein Uwe A. O. , Glätzer Karl Heinz , Bünemann Hans
Published: March 2003

Fruit fly species of the genus Drosophila show a remarkable variation in sperm length. Some of them produce gigantic sperm several times the total male body length. Sperm of Drosophila hydei, for example, are more than 20 mm long. Little is known about the advantage of such elongated sperm or about the proteins that stabilize their thin flagellar tails. Recently, two members of a novel gene family Dhmst101(1) and Dhmst101(2), whose gene products are associated with the sperm tail, were isolated and characterized. Here a third member of this gene family, Dhmst101(3), is described. It was previously demonstrated that all three genes are located in a single small cluster on chromosome 5 of D. hydei. They are located within 15 kb of genomic DNA, oriented in the same direction and transcribed testis‐specifically. The encoded sperm tail‐specific proteins are mainly composed of tandemly arranged repeats of a highly charged, cysteine‐containing motif of 16 amino acids with the consensus sequence KKKCA/EEAAKKEKEAAE. Experiments with synthetic repeat monomers and dimers have demonstrated a tendency for α‐helical rod formation, which increased strongly with an increase in repeat number. Therefore, Dhmst101 proteins with 7–60 repeats with regularly spaced cystein‐residues are thus expected to form long α‐helical rods cross‐linked by numerous Cys‐Cys bridges. Here we apply immuno‐ electron microscopy and monospecific antibodies, α‐mst101, raised against the KKKCAEAAKKEKEAAE‐motif to investigate the distribution of Dhmst101 proteins within the sperm tail of D. hydei. We show that Dhmst101 proteins are part of the outer sheath of the sperm tail where they presumably help to provide a tight but elastic envelope for the extremely extended spermatozoa of D. hydei.