Skeletal muscle lactate accumulation and creatine phosphate depletion during heavy exercise in congestive heart failure. Cause of limited exercise capacity?

OBJECTIVE: To study the mechanisms of limited exercise capacity and skeletal muscle energy production in male patients with congestive heart failure. DESIGN: Muscle biopsy study. PATIENTS: Skeletal muscle metabolic response to maximal bicycle exercise was studied in 10 patients with chronic congestive heart failure (ejection fraction 0.22 +/- 0.05; peak oxygen consumption, VO2 15.1 +/- 4.9 ml.min-1.kg-1) and in nine healthy subjects (peak VO2 33.5 +/- 6.7 ml.min-1.kg-1). Activities of skeletal muscle enzymes were measured from the vastus lateralis muscle of 48 patients (ejection fraction 0.24 +/- 0.06, peak VO2 17.4 +/- 5.4 ml.min-1.kg-1) and 36 healthy subjects (peak VO2 38.3 +/- 8.4 ml.min-1.kg-1). RESULTS: Although blood lactate levels were lower in patients than in healthy subjects (2.2 +/- 0.3 vs 5.2 +/- 0.6 mmol.l-1; P < 0.001) at peak exercise (96 +/- 11 W for patients and 273 +/- 14 W for controls), skeletal muscle lactate was similarly elevated (25.6 +/- 3.2 vs 22.7 +/- 2.7 mmol.kg-1) and creatine phosphate was equally depressed (P < 0.02) to low levels (7.0 +/- 1.9 vs 6.7 +/- 0.9 mmol.kg-1). The muscle ATP decreased by 21% (P < 0.05) and 8% (P < 0.01) in the patients and controls, respectively. Activities of rate limiting enzymes of the citric acid cycle (alpha-ketoglutarate dehydrogenase) and oxidation of free fatty acids (carnitine palmitoyltransferase II) were 48% and 21% lower than in controls, but the mean phosphofructokinase activity was unchanged in congestive heart failure. CONCLUSIONS: It seems that the main limiting factor of exercise performance during heavy exercise is the same in congestive heart failure and healthy subjects, a high rate of skeletal muscle lactate accumulation and high-energy phosphate depletion. In congestive heart failure, the low activity of aerobic enzymes is likely to impair energy production and lead to lactate acidosis at low workloads.     

Flight energetics of sphinx moths: power input during hovering flight

The energetic cost of hovering flight was measured in sphinx moths from five species. Mean power input per unit mass (Pi/M) varied from 237-2 W kg-1 in Manduca sexta (Subfamily:Sphinginae), mean body mass 1-2 X 10(-3) kg, to 327-9 W kg-1 in Deilephila elpenor (Subfamily: Macroglossinae) mean body mass 7-3 X 10(-4) kg. Mean Pi/M for the five species was inversely proportional to mean body mass and directly proportional to mean wing loading. For any given body mass, Pi/M was greater in Hyles lineata than in M. sexta. This difference is correlated with higher wing loading at any given mass in H. lineata. Energy expenditure per unit mass of thorax was 1018 W kg-1 in H. lineata and 694 W kg-1 in M. sexta. Within each of these species, Pi per unit mass of thorax does not vary with body mass. Power input data are compared with calculated power requirements based on momentum theory and blade-element theory of helicopter aerodynamics. Absolute efficiency, the ratio between calculated power requirements and measured energy expenditure, appears to vary directly with body mass. These data provide an energetic basis for observed correlates between thoracic temperature and flight effort in flying sphinx moths.     

Modulation of whole body protein metabolism, during and after exercise, by variation of dietary protein

The aim of this study was to investigate dietary protein-induced changes in whole body leucine turnover and oxidation and in skeletal muscle branched chain 2-oxo acid dehydrogenase (BCOADH) activity, at rest and during exercise. Postabsorptive subjects received a primed constant infusion of L-[1-13C,15N]leucine for 6 h, after previous consumption of a high- (HP; 1.8 g . kg-1 . day-1, n = 8) or a low-protein diet (LP; 0.7 g . kg-1 . day-1, n = 8) for 7 days. The subjects were studied at rest for 2 h, during 2-h exercise at 60% maximum oxygen consumption, then again for 2 h at rest. Exercise induced a doubling of both leucine oxidation from 20 micromol . kg-1 . h-1 and BCOADH percent activation from 7% in all subjects. Leucine oxidation was greater before (+46%) and during (+40%, P < 0.05) the first hour of exercise in subjects consuming the HP rather than the LP diet, but there was no additional change in muscle BCOADH activity. The results suggest that leucine oxidation was increased by previous ingestion of an HP diet, attributable to an increase in leucine availability rather than to a stimulation of the skeletal muscle BCOADH activity.     

Exploring the nature of informed consent in coronary care practice

A study has been carried out of the RF field strength around a total of 17 patients undergoing radio-frequency endometrial ablation in three hospital centres. The mean equivalent power density at the position of the surgeon exceeded 10 W m-2, which is the derived investigation level for exposure to electromagnetic fields. This value is derived from a basic restriction in the average specific absorption rate in the body to 0.4 W kg-1. This limit applies to general population as well as occupational exposure and is well below that which has been shown to be hazardous to health. Also, the working conditions did not place physical stress on the surgeon. The maximum value of the specific energy absorption rate in the head or trunk should not exceed 10 W kg-1. Measured values on the field strength suggest that this organ dose limit was not exceeded. It is concluded that staff exposure to stray RF radiation during radio-frequency endometrial ablation is not considered to be hazardous to health.     

Relationship between structure and inhibitory effect of arginine analogues on neuronal nitric oxide synthase activity

2,3,5-Trimethyl-6-(3-pyridylmethyl)1,4-benzoquinone (CV-6504), an inhibitor of 5-lipoxygenase and thromboxane A2 synthase and a scavenger of active oxygen species, has been shown to exhibit profound anti-tumour activity against three established murine adenocarcinomas (MACs) that are generally refractory to standard cytotoxic agents. For the cachexia-inducing MAC16 tumour, optimal anti-tumour activity was seen at dose levels of 10 and 25 mg kg-1 day-1, together with a reversal of cachexia and a doubling of the time to sacrifice of the animals through cachexia from 8 days to 17 days. The remaining tumour fragments showed extensive necrosis in regions distal from the blood supply. Growth of the MAC13 tumour was also effectively suppressed at dose levels between 5 and 50 mg kg-1 day-1, resulting in a specific growth delay between 1.0 and 1.2. Growth of the MAC26 tumour was also inhibited a concentration-related manner, with doses of 25-50 mg kg-1 day-1 being optimal. Anti-tumour activity towards all three tumours at low dose levels of CV-6504 was effectively suppressed by concurrent administration of linoleic acid (1 g kg-1 day-1), suggesting that inhibition of linoleate metabolism was responsible for the anti-tumour effect. Tumour sensitivity may be correlated with increased DT-diaphorase that are required to metabolise CV-6504 to the active hydroquinone, which inhibits 5-lipoxygenase activity.     

Role of 5-HT4 receptors in the mouse passive avoidance test

The effects of the administration of different 5-HT4 receptor antagonists (SDZ 205557, GR 125487) and 5-HT4 receptor agonists (BIMU 1, BIMU 8) on memory processes were evaluated in the mouse passive avoidance test. The administration of SDZ 205557 (10 mg kg-1 i.p.) and GR 125487 (10 mg kg-1 i.p.) immediately after termination of the training session produced an amnesic effect. BIMU 1 (20 mg kg-1 i.p.) and BIMU 8 (30 mg kg-1 i.p.), administered 20 min before the training session, prevented the 5-HT4 receptor antagonist-induced amnesia. In the same experimental conditions BIMU 1 (10 mg kg-1 i.p.; 25 microgram/mouse intracerebroventricularly) and BIMU 8 (30 mg kg-1 i.p.; 30 microgram per mouse intracerebroventricularly) prevented scopolamine (1 mg kg-1 i.p.) and dicyclomine (2 mg kg-1 i.p.) amnesia and, at the dose of 10 and 30 mg kg-1 i.p. respectively, prevented amnesia induced by exposure to a hypoxic environment. At the highest effective doses, none of the drugs impaired motor coordination, as revealed by the rota rod test, or modified spontaneous motility and inspection activity, as revealed by the hole board and Animex tests. The 5-HT3 antagonist ondansetron (0.1-1 mg kg-1 i.p.) was unable to prevent scopolamine-, 5-HT4 antagonist- and hypoxia-induced amnesia. These results suggest that the modulation of 5-HT4 receptors plays an important role in the regulation of memory processes. On these bases, the 5-HT4 receptor agonists could be useful in the treatment of cognitive deficits although 5-HT4 receptor antagonists may represent pharmacological tools for investigation of new potential antiamnesic drugs.     

Phenylalanine requirements determined by using L-[1-14C]phenylalanine in neonatal piglets receiving total parenteral nutrition supplemented with tyrosine

The definition of amino acid requirements for neonates receiving total parenteral nutrition (TPN) is critical for the further improvement of this nutritional regimen. In the present study we investigated the kinetics and requirements of phenylalanine and tyrosine in neonatal piglets receiving TPN. Twenty-four 3-d-old male Yorkshire piglets were fitted with external jugular and femoral catheters and maintained on identical TPN formulations for 5 d. Total amino acid, phenylalanine, tyrosine, and energy intakes were 15, 0.61, and 0.51 g. kg-1 . d-1 and 1.1 MJ . kg-1 . d-1, respectively. On day 5, piglets (three per level) were randomly assigned to receive one of eight phenylalanine intakes: 0.2. 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 1.2 g. kg-1 . d-1. On day 6, phenylalanine kinetics were measured during a 4-h primed, continuous infusion of L-[1-14C]phenylalanine. Plasma phenylalanine and phenylalanine oxidation were statistically similar for the three lowest phenylalanine intakes and increased thereafter. Crossover regression analysis yielded estimates for the mean requirement and safe phenylalanine intake of 0.45 and 0.48 g . kg-1 . d-1, respectively (equivalent to 30 and 32 mg/g amino acids, respectively), in the presence of excess tyrosine. An inability of piglets to maintain a linear oxidative response at phenylalanine intakes > 0.8 g . kg-1 . d-1 (equivalent to 53 mg/g amino acids) was found. These data represent the first direct estimates of phenylalanine requirements in neonates receiving TPN and demonstrate the use of oxidation techniques for the estimation of amino acid requirements during parenteral nutrition.     

Bepridil reducing levothyroxine-induced enhancement of mitochondria Ca2+ Mg(2+)-ATPase activity in rat cerebrum

AIM: To study if bepridil (Bep) could affect the enhancement of activity of cerebral mitochondria Ca2+ Mg(2+)-ATPase caused by levothyroxine (Lev) in relation to ischemic overload calcium cerebrum injury. METHODS: The experimental hyperthyroidism model with ischemic cerebrum was developed in rats by ig Lev 1 mg.kg-1.d-1 for 7 d. Ca2+ Mg(2+)-ATPase activity and its kinetic parameters were assayed. RESULTS: The activity, Vmax and Km of cerebral mitochondria Ca2+ Mg(2+)-ATPase in control rats were 3.1 +/- 0.8, 5.1 +/- 2.3 mmol.P(i).h-1/g protein and 0.81 +/- 0.08 mmol.L-1 (ATP) respectively, whereas those of hyperthyroid rats were significantly altered to 4.6 +/- 0.5, 8.5 +/- 1.9 mmol.P(i).h-1/g protein and 0.49 +/- 0.11 mmol.L-1 (ATP) respectively. After treated with Bep 10 or 20 mg.kg-1.d-1 ig for 3 d, allabove 3 parameters of the enzyme were very significantly reduced vs those of either control or hyperthyroid. CONCLUSION: Bep, via decreasing Ca2+ Mg(2+)-ATPase activity and increasing the affinity of Ca2+ Mg(2+)-ATPase to ATP, could prevent rat cerebrum from ATP depletion and ischemic overload calcium injury.     

Importance of substrate changes in the decrease of hepatic glucose cycling during insulin infusion and declining glycemia in the depancreatized dog

We wished to determine whether the elevated glucose cycling (GC) between glucose and glucose-6-phosphate (G<-->G6P) in diabetes can be reversed with acute insulin treatment. In six insulin-deprived, anesthetized, depancreatized dogs, insulin was infused for 6-9 h at a starting dose of 45-150 pmol.kg-1.min-1 to normalize plasma glucose from 23.9 +/- 1.4 to 5.0 +/- 0.4 mmol/l and gradually decreased to and maintained at a basal rate (1.7 +/- 1.0 pmol.kg-1.min-1) during the last 3 h. GC, measured with [2-3H]- and [6-3H]glucose, fell markedly from 15.3 +/- 2.7 and normalized at 1.3 +/- 0.6 mumol.kg-1.min-1 (P < 0.001). This occurred because total hepatic glucose output fell much more (from 41.2 +/- 3.1 to 11.6 +/- 1.2) than did glucose production (from 25.9 +/- 1.9 to 10.3 +/- 1.0 mumol.kg-1.min-1) (both P < 0.01). Freeze-clamped liver biopsies were taken at timed intervals for measurements of hepatic enzymes and substrates. The elevated hepatic hexose-6-phosphate levels decreased with insulin infusion (151 +/- 24 vs. 71 +/- 13 nmol/g, P < 0.01). Maximal activities of glucose-6-phosphatase (G6Pase) (from 17.6 +/- 0.8 to 19.6 +/- 2.6 U/g) and glucokinase (from 1.1 +/- 0.2 to 1.0 +/- 0.2 U/g) did not change. Insulin infusion resulted in a threefold increase (P < 0.05) in the activity of glycogen synthase (active form), but had no effect on hepatic glycogen content.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of hemin in treating hemorrhagic anemia and toxicity

AIM: To study the effect of hemin in treating hemorrhagic anemia and toxicity. METHODS: Fifty rats with hemorrhagic anemia were randomly divided into 5 groups with different dosage of hemin (93, 168, 300 mg.kg-1.d-1), ferrous gluconate (FG 300 mg.kg-1.d-1), and water, ig for 7 d. Twenty mice fed with hemin (6.0 g.kg-1.d-1) in 24 h for observing acute toxicity effects. Long-term toxicity were observed in 80 rats given hemin (0.65, 1.3, 2.6 g.kg-1.d-1) in 3 months. RESULTS: Hb of the rats of corresponding groups were 66-->121, 71-->141, 66-->148, 69-->140, and 67-->112 g.L-1. There were no adverse effects observed on acute toxicity test. No abnormalitis were found in hemogram, liver renal function test, and autopsy. CONCLUSION: Hemin had a better effect than FG and no adverse effect was found in hemin.     

Six-month physical activity and fitness changes in Project Active, a randomized trial

PURPOSE: Project Active is a randomized clinical trial (N = 235) comparing a lifestyle physical activity program with a structured exercise program in changing physical activity (total energy expenditure [kcal.kg-1.d-1]) and cardiorespiratory fitness (VO2peak in mL.kg-1.min-1). METHODS: Sedentary but healthy adults (N = 235) aged 35-60 years received 6 months of intensive intervention. RESULTS: Analysis of covariance (ANCOVA), adjusting for baseline measure, age, gender, body mass index (BMI), cohort, and ethnicity, showed that at 6 months both lifestyle and structured groups significantly increased energy expenditure over baseline (P < 0.001). The mean increases +/- SE, 1.53 +/- 0.19 kcal.kg-1.d-1 for the lifestyle group and 1.34 +/- 0.20 kcal.kg-1 d-1 for the structured group, were not significantly different between groups (P = 0.49). For cardiorespiratory fitness, both groups had significant increases from baseline (P < 0.001). Mean increases +/- SE were 1.58 +/- 0.33 mL.kg-1.min-1 and 3.64 +/- 0.33 mL.kg-1.min-1 for the lifestyle and structured groups, respectively. This was significantly greater in the structured group (P < 0.001). We also studied changes in intensity of physical activity. Both groups significantly increased moderate intensity activity from baseline, but the increase was significantly greater in the lifestyle group than the structured group (P = 0.02). In contrast, the structured group increased its hard activity more than the lifestyle group, but the difference was not significantly different (P = 0.02). In contrast, the structured group increased its hard increased (P < 0.01) for both groups by 0.25 kcal.kg-1.d-1. CONCLUSION: Both intervention approaches are effective for increasing physical activity and fitness over a 6-month period in initially sedentary men and women.     

Toxocara canis infection in the paratenic host: a study on the chemosusceptibility of the somatic larvae in mice

A research on formulation and dosage strategies of anthelmintics have been conducted in mice experimentally infected with eggs of Toxocara canis. Multidose treatments commenced at days 2, 14, 81, 87 and 123 postinfection. Results indicated no detectable difference in the chemosusceptibility of the migrating early infection larvae and the resting hypobiotic chronic infection larvae. Application of medicated dry food (pellets) may be a simple way of improving efficacy of treatment compared to oral drenching. The larvicidal potential of fenbendazole (FBZ), albendazole (ABZ), flubendazole (FUBZ), oxibendazole (OBZ) and ivermectin was assessed. Reductions of 84.2 to 99.7 or 88.8 to 100% of group mean larval counts were recorded after 20-30-day courses of feeding pellets containing FBZ at 6 g kg-1 or ABZ at 1.6 g kg-1 food, respectively. Efficacies of 57.8 to 88.2 or 81.1 to 32.0% were achieved by 20-day courses of feeding pellets medicated with FUBZ and OBZ at 1.6 g kg-1 or 6.0 g kg-1 food, respectively. Ivermectin at various dosing regimens showed only moderate larvicidal potential. Efficacy rates were not closely correlated with the amount of drug taken by the animals. The blood-brain barrier is permeable for the anthelmintics tested, and the brain of mice does not provide a site promoting survival of larvae.     

5-Hydroxytryptamine induces forestomach hypomotility in sheep through 5-HT4 receptors

The effects evoked by 5-hydroxytryptamine (5-HT; serotonin) on forestomach myoelectric activity were investigated in conscious sheep. Myoelectric signals were recorded with electrodes chronically implanted in the reticulum, rumen (dorsal sac) and omasal body, and were analysed by a computer-based method. The 5-HT receptors and the neuronal pathways involved in these actions were studied. The intravenous (i.v.) infusion of 5-HT (8 micrograms kg-1 min-1 for 5 min) evoked an inhibition of activity of the whole forestomach. Methiothepin, injected i.v. at 0.1 mg kg-1, inhibited rumen secondary contractions and omasum activity. However, forestomach activity remained unchanged after the administration of 0.2 mg kg-1 of ketanserin, ondansetron, tropisetron, GR-113808, phentolamine, propranolol, domperidone and naloxone. Atropine (0.2 mg kg-1), hexamethonium (2 mg kg-1) or haloperidol (0.1 mg kg-1) abolished rumen secondary cycles and inhibited omasum activity. In addition, atropine also suppressed primary cycles. GR-113808 blocked all 5-HT-induced effects. Furthermore, atropine or hexamethonium prevented the 5-HT-evoked inhibition of reticulorumen primary cycles. In contrast, the remaining antagonists did not alter the 5-HT-evoked forestomach hypomotility. In conclusion, 5-HT induces inhibition of forestomach myoelectric activity through 5-HT4 receptors, these actions being mediated by cholinergic neural pathways involving muscarinic and nicotinic receptors. However, adrenergic, dopaminergic or opiate pathways are not implicated.     

Altered growth and metabolism of an estuarine shrimp (Palaemonetes pugio) during and after metamorphosis onto fenvalerate-laden sediment

Dry weight (W), carbon (C), nitrogen (N), and energy (E) (calculated) accumulation were measured in the estuarine grass shrimp, Palaemonetes pugio, throughout larval development and during the first 2 weeks as postlarvae in seawater over sediment containing the pyrethroid insecticide fenvalerate (SCF; nominal concentrations of 1, 10, and 100 microgram fenvalerate kg-1 sediment). The influence of fenvalerate-laden sediment on shrimp growth and utilization patterns of C, N, and E was dependent on fenvalerate concentration, age of shrimp, and whether shrimp were premetamorphic or postmetamorphic in development. The fenvalerate concentration in the sediment, which ultimately inhibited larval metamorphosis (100 microgram fenvalerate kg-1 sediment), significantly reduced W accumulation in developing larvae and in postlarvae growing on the sediment for an equivalent time. Accumulation of C, N, and E varied not only with concentration of SCF, but differed between pelagic larvae developing in water above SCF and newly settled postlarvae growing in direct contact with SCF. Larvae developing above >/=10 microgram kg-1 SCF contained significantly less N, while postlarval shrimp settling onto >/=10 microgram kg-1 SCF accumulated significantly less C and E. Measurable variations in growth and energy reserves of toxicant-sensitive life stages in response to environmentally realistic insecticide exposures have a direct link to ecological consequences of toxic stress and may be useful as biomarkers to diagnose early damage in estuarine populations.     

A comprehensive appraisal of 241Am in soils around Rocky Flats, Colorado

Soils east of Rocky Flats Plant (RFETS) near Golden, Colorado, were contaminated with actinides because of accidental release of oils laden with plutonium isotopes. Consequently, these soils were contaminated by 241Am due to radioactive decay of 241Pu (t1/2 = 14.4 y). A spatial analysis of 241Am activity in soils east of RFETS was conducted to elucidate the magnitude and the mode of 241Am dispersion in the soil environment. 241Am activity of 178 soil samples ranged from 0.037 Bq kg-1 to 10,004 Bq kg-1 with a mean of 214 Bq kg-1, median of 7.28 Bq kg-1, standard deviation of 942 Bq kg-1, and a coefficient of variation of 4.3. Spatial analysis of 241Am in soils around RFETS was conducted using indicator kriging, which is a nonparametric technique especially suitable to model a conditional cumulative distribution function (ccdf) of highly skewed environmental data such as 241Am. The ccdf was used to generate an E-type (mean of the conditional cdf) surface. The resulted surfaces were consistent with the hypothesis that the westerly winds were the dominant mechanism of americium dispersal. The spatial distribution and dispersal mechanisms of 241Am were similar to those of 239+240Pu. The ccdf was also used to construct probability of exceedence maps of 241Am in soils. For the purpose of this report two threshold values for the probability maps were selected: (1) the mean measured background activity of 241Am (0.4 Bq kg-1), and (2) the programmatic preliminary remediation goal for residential occupancy scenario (87.7 Bq kg-1). The probability-of-exceedance maps provide estimates of spatial uncertainty associated with each threshold. The E-type maps in conjunction with the probability-of-exceedance maps provide a robust framework for future cleanup options and land use decisions.     

Lhermitte-Duclos disease: first report in Taiwan

Nutritional support is important in critically ill patients, with variable energy and nitrogen requirements (e.g., sepsis, trauma, postsurgical state) in this population. This study investigates how age, severity of illness, and mechanical ventilation are related to resting energy expenditure (REE) and nitrogen balance. Nineteen critically ill children (mean age, 8 +/- 6 [SD] y and range 0.4-17.0 y) receiving total parenteral nutrition (TPN) were enrolled. We used indirect calorimetry to measure REE. Expected energy requirements (EER) were obtained from Talbot tables. Pediatric Risk of Mortality (PRISM) and Therapeutic Intervention Scoring System (TISS) score were calculated. Total urinary nitrogen was measured using the Kjeldahl method. PRISM and TISS scores were 9 +/- 5 and 31 +/- 6 points, respectively. REE was 62 +/- 25 kcal.kg-1.d-1, EER was 42 +/- 11 kcal.kg-1. d-1, and caloric intake was 49 +/- 22 kcal.kg-1.d-1. Nitrogen intake was 279 +/- 125 mg.kg-1.d-1, total urinary nitrogen was 324 +/- 133 mg.kg-1.d-1, and nitrogen balance was -120 +/- 153 mg.kg-1.d-1. The protein requirement in this population was approximately 2.8 g.kg-1.d-1. These critically ill children were hypermetabolic, with REE 48% higher (20 kcal.kg-1.d-1) than expected. Nitrogen balance significantly correlated with caloric and protein intake, urinary nitrogen, and age, but not with severity of illness scores or ventilatory parameters.     

Involvement of hydroxyl radicals in neurogenic airway plasma exudation and bronchoconstriction in guinea-pigs in vivo

1. Cigarette smoke induces plasma exudation in the airways of rodents by activation of capsaicin-sensitive 'sensory-efferent' nerves. The response is mediated predominantly by substance P (SP) and the magnitude of exudation is regulated by neutral endopeptidase (NEP). The component(s) of the smoke responsible for the activation of the nerves may be reactive oxygen radicals. We investigated the effect of the hydroxyl radical scavenger dimethylthiourea (DMTU), a regulator of superoxide anion, superoxide dismutase (SOD), and a regulator of hydrogen peroxide, catalase, on plasma exudation (measured using Evans blue dye) induced by cigarette smoke in guinea-pig main bronchi in vivo. The effect of DMTU on plasma exudation and non-cholinergic bronchoconstriction (measured as pulmonary insufflation pressure, PIP) induced by electrical stimulation of the vagus nerves was also assessed. Interaction between hydroxyl radicals and NEP was assessed with the NEP inhibitor phosphoramidon. 2. In each of the experiments, cigarette smoke increased plasma exudation by approximately 200% above air-exposed controls. Acute administration of DMTU (1.5 g kg-1, i.v. for 20 min) significantly reduced cigarette smoke-induced plasma exudation by 69%. In contrast, neither SOD (240,000 u kg-1, i.v.) nor catalase (400,000 u kg-1, i.v.) significantly affected the exudative response. 3. Chronic pretreatment with DMTU (1.25 g kg-1 over 4 days) significantly reduced bronchial plasma exudation induced by cigarette smoke by 72%. Phosphoramidon (1.5 mg kg-1, i.v.) completely reversed the inhibition by DMTU of cigarette smoke-induced plasma exudation. 4. Vagal stimulation increased plasma exudation by approximately 200% and PIP by approximately 250%. Acute treatment with DMTU had no significant inhibitory effect on these responses, whereas chronic pretreatment inhibited them by approximately 80%. Phosphoramidon reversed the inhibition by chronic DMTU. 5. SP (1 nmol kg-1) increased plasma exudation by approximately 250%, a response which was not inhibited by either acute or chronic DMTU. 6. We conclude that hydroxyl radicals, rather than superoxide anion or hydrogen peroxide, are involved in the induction of neurogenic plasma exudation and bronchoconstriction induced by cigarette smoke or by electrical stimulation of the vagus nerves. These radicals also affect the activity of NEP. Acute DMTU may affect directly the neural actions of hydroxyl radicals contained in the cigarette smoke. Chronic pretreatment with DMTU may inhibit the neurogenic airway responses by effects on tachykinin biosynthesis and/or axonal transport.     

Role of nitric oxide in the development of tolerance and sensitization to behavioural effects of phencyclidine in mice

1. To determine whether nitric oxide (NO) was involved in tolerance and sensitization to the effects of phencyclidine (PCP), we examined NO synthase activity and the number of NADPH-diaphorase (NADPH-d)-positive cells in discrete brain regions of saline-, acute PCP- and repeated PCP-treated mice. We also investigated the effects of a NO synthase inhibitor, NG-nitro-L- arginine methyl ester (L-NAME), on the behavioural changes induced by repeated PCP treatment in mice. 2. Acute PCP (1, 3, and 10 mg kg-1, s.c.) treatment induced dose-dependent hyperlocomotion, motor incoordination and stereotyped behaviours, consisting of sniffing, head movement and ataxia in mice. 3. In mice treated repeatedly with PCP (1, 3, and 10 mg kg-1 day-1), s.c., once a day for 14 days), the sniffing, head movement, ataxia and motor incoordination induced by PCP were attenuated (indicating the development of tolerance to these behaviours), whereas the hyperlocomotion induced by PCP was potentiated (indicating the development of sensitization to hyperlocomotion). The development of tolerance and sensitization to PCP-induced behaviours in the repeated PCP-treated mice was more marked at the dose of 10 mg kg-1 day-1) than at other doses. 4. NO synthase activity in the cerebral cortex and cerebellum, but not in the striatum and hippocampus, was significantly decreased by acute PCP (10 mg kg-1) treatment in comparison with saline treatment, and such changes in activity in the cerebral cortex and cerebellum were reversed by repeated PCP treatment (10 mg kg-1 day-1). 5. The number of neurones containing NADPH-d reactivity in the cerebral cortex, nucleus accumbens, and striatum of acute and repeated PCP-treated mice showed no change in comparison with saline-treated mice. 6. Tolerance to PCP (10 mg kg-1 day-1)-induced ataxia and motor incoordination was significantly attenuated by combined treatment with L-NAME (50 mg kg-1 day-1 i.p.). 7. Sensitization to PCP-induced hyperlocomotion was further enhanced by combined treatment with L-NAME (50 mg kg-1 day-1). However, NG-nitro-D-arginine methyl ester (D-NAME, 50 mg kg-1 day-1, i.p.), a less active enantiomer of L-NAME, had no effect, suggesting a stereospecific mechanism. 8. The PCP-induced behaviours in animals that had exhibited tolerance and sensitization to PCP (10 mg kg-1 day-1) were not influenced by acute L-NAME (5 and 50 mg kg-1, i.p.) or D-NAME (50 mg kg-1, i.p.) treatment. 9. These results suggest that NO may play an important role in the development, but not in the maintenance, of tolerance and sensitization to the effect of PCP in mice.     

Effects of 3 days of carbohydrate supplementation on muscle glycogen content and utilisation during a 1-h cycling performance

This study compared the effects of supplementing the normal diets of six trained cyclists [maximal oxygen uptake (VO2max) 4.5 (0.36) l.min-1; values are mean (SD)] with additional carbohydrate (CHO) on muscle glycogen utilisation during a 1-h cycle time-trial (TT). Using a randomised crossover design, subjects consumed either their normal diet (NORM) for 3 days, which consisted of 426 (137) g.day-1 CHO [5.9 (1.4) g. kg-1 body mass (BM)], or additional CHO (SUPP) to increase their intake to 661 (76) g.day-1 [9.3 (0.7) g. kg-1 BM]. The SUPP diet elevated muscle glycogen content from 459 (83) to 565 (62) mmol.kg-1 dry weight (d.w.) (P < 0.05). However, despite the increased pre-exercise muscle glycogen stores, there was no difference in the distance cycled during the TT [40.41 (1.44) vs 40.18 (1.76) km for NORM and SUPP, respectively]. With NORM, muscle glycogen declined from 459 (83) to 175 (64) mmol.kg-1 d.w., whereas with SUPP the corresponding values were 565 (62) and 292 (113) mmol.kg-1 d.w. Accordingly, both muscle glycogen utilisation [277 (64) vs 273 (114) mmol.kg-1 d.w.] and total CHO oxidation [169 (20) vs 165 (30) g.h-1 for NORM and SUPP, respectively] were similar. Neither were there any differences in plasma glucose or lactate concentrations during the two experimental trials. Plasma glucose concentration averaged 5.5 (0.5) and 5.6 (0.6) mmol.l-1, while plasma lactate concentration averaged 4.4 (1.9) and 4.4 (2.3) mmol.l-1 for NORM and SUPP, respectively. The results of this study show that when well-trained subjects increase the CHO content of their diet for 3 days from 6 to 9 g.kg-1 BM there is only a modest increase in muscle glycogen content. Since supplementary CHO did not improve TT performance, we conclude that additional CHO provides no benefit to performance for athletes who compete in intense, continuous events lasting 1 h. Furthermore, the substantial muscle CHO reserves observed at the termination of exercise indicate that whole-muscle glycogen depletion does not determine fatigue at this exercise intensity and duration.     

Gabapentin (neurontin) and S-(+)-3-isobutylgaba represent a novel class of selective antihyperalgesic agents

1. Gabapentin (neurontin) is a novel antiepileptic agent that binds to the alpha 2 delta subunit of voltage-dependent calcium channels. The only other compound known to possess affinity for this recognition site is the (S)-(+)-enantiomer of 3-isobutylgaba. However, the corresponding (R)-(-)-enantiomer is 10 fold weaker. The present study evaluates the activity of gabapentin and the two enantiomers of 3-isobutylgaba in formalin and carrageenan-induced inflammatory pain models. 2. In the rat formalin test, S-(+)-3-isobutylgaba (1-100 mg kg-1) and gabapentin (10-300 mg kg-1) dose-dependently inhibited the late phase of the nociceptive response with respective minimum effective doses (MED) of 10 and 30 mg kg-1, s.c. This antihyperalgesic action of gabapentin was insensitive to naloxone (0.1-10.0 mg kg-1, s.c.). In contrast, the R-(-)-enantiomer of 3-isobutylgaba (1-100 mg kg-1) produced a modest inhibition of the late phase at the highest dose of 100 mg kg-1. However, none of the compounds showed any effect during the early phase of the response. 3. The s.c. administration of either S-(+)-3-isobutylgaba (1-30 mg kg-1) or gabapentin (10-100 mg kg-1), after the development of peak carrageenan-induced thermal hyperalgesia, dose-dependently antagonized the maintenance of this response with MED of 3 and 30 mg kg-1, respectively. Similar administration of the two compounds also blocked maintenance of carrageenan-induced mechanical hyperalgesia with MED of 3 and 10 mg kg-1, respectively. In contrast, R-(-)-3-isobutylgaba failed to show any effect in the two hyperalgesia models. 4. The intrathecal administration of gabapentin dose-dependently (1-100 micrograms/animal) blocked carrageenan-induced mechanical hyperalgesia. In contrast, administration of similar doses of gabapentin into the inflamed paw was ineffective at blocking this response. 5. Unlike morphine, the repeated administration of gabapentin (100 mg kg-1 at start and culminating to 400 mg kg-1) over 6 days did not lead to the induction of tolerance to its antihyperalgesic action in the formalin test. Furthermore, the morphine tolerance did not cross generalize to gabapentin. The s.c. administration of gabapentin (10-300 mg kg-1), R-(-) (3-100 mg kg-1) or S-(+)-3-isobutylgaba (3-100 mg kg-1) failed to inhibit gastrointestinal motility, as measured by the charcoal meal test in the rat. Moreover, the three compounds (1-100 mg kg-1, s.c.) did not generalize to the morphine discriminative stimulus. Gabapentin (30-300 mg kg-1) and S-(+)-isobutylgaba (1-100 mg kg-1) showed sedative/ataxic properties only at the highest dose tested in the rota-rod apparatus. 6. Gabapentin (30-300 mg kg-1, s.c.) failed to show an antinociceptive action in transient pain models. It is concluded that gabapentin represents a novel class of antihyperalgesic agents.