Inhibition of nitric oxide production by aminoguanidine influences the number of Trichinella spiralis parasites in infected “low responders” (C57BL/6) and “high responders” (BALB/c) mice

The influence of nitric oxide (NO) on the development of adults and larvae Trichinella spiralis was examined in two strains of mice: C57BL/6 and BALB/c. The influence of aminoguanidine (AG)-inhibitor of inducible nitric oxide synthase (iNOS) administered in the first days after T. spiralis infection (1–5 dpi) on the number of adult parasites, as well as the influence of AG administered at the beginning of muscle phase of the T. spiralis infection (16–29 dpi) on the number of muscle larvae, was studied. In mice that were treated with AG from the 1st to the 5th day post infection (dpi), the numbers of adult T. spiralis were counted in intestines at 6, 9, 15, and 20 dpi. In this experiment, the impact of AG expressed as diminution of adult worms at 9, 15, and 20 dpi in BALB/c mice. The opposite effect of AG was demonstrated in C57BL/6 mice at 6 and 9 dpi. In mice in which AG was applied from the 16th to the 29th dpi T. spiralis larvae were counted at 30, 35, and 41 dpi. This experiment demonstrated that treating mice with AG at the beginning of muscle phase of the infection inhibits the reduction of muscle larvae number in mice of both strains.     

Inducible nitric oxide synthase inhibition influenced granuloma formation with suppressed collagen expression in myositis caused by <Emphasis Type="Italic">Toxocara canis</Emphasis> in mice

The role of nitric oxide (NO) in granuloma pathology is largely unclear to date. We investigated the role of NO in fibrotic granuloma development in the musculature of mice infected with Toxocara canis from 1 day (dpi) to 8 weeks post-infection (wpi) using the NO synthase (NOS) inhibitors, L-NIL (l-N ⁶-1-iminoethyl lysine). In infected mice, elevated serum NO concentrations were seen at 1 dpi (204.1 ± 0.2 μM) and 1 wpi (145.1 ± 0.2 μM); it declined drastically from 4 wpi onwards (57.0 ± 0.1 μM). In L-NIL-treated mice, the NO concentration was drastically reduced from 15% during 1 wpi; thereafter, it was restored to almost half that in infected mice. Inducible NOS expression was enhanced in infected and L-NIL-treated mice at 4 wpi but declined at 8 wpi as assessed by immunohistochemistry. L-NIL treatment resulted in large, irregularly shaped granulomas with suppressed collagen contents at 4 wpi but not at 8 wpi. The suppressed collagen contents might have been related to decreased serum NO and Th2-type cytokine of interleukin-4 but not Th1-type cytokine of interferon-γ expression.     

Nitric oxide involvement in experimental Trypanosoma cruzi infection in Calomys callosus and Swiss mice

Nitric oxide (NO) production by peritoneal macrophages was evaluated in Calomys callosus and Swiss mice during the course of infection with two strains of Trypanosomacruzi. In C. callosus, no NO production was detected throughout the period of observation in animals infected with either parasite strain, except for a very low amount measured on day 40 in animals infected with strain M226 and on the 28th day in animals infected with strain F after in vitro stimulation with interferon gamma (IFN-γ). Macrophages of Swiss mice produced large amounts of NO, the highest values being observed on the 40th day in mice infected with the F strain. Induced nitrogen oxide synthase (iNOS) was not detected in macrophages of infected C. callosus but was detected in mice. The i.p. inoculation of thioglycolate, bacille Calmette-Guérin (BCG) and periodate, nonspecific macrophage activators, did not induce NO production in C. callosus, but high levels were observed in Swiss mice after secondary in vitro IFN-γ plus lipopolysaccharide (LPS) stimulation. However, H₂O₂ release was induced in macrophages stimulated with phorbol myristate acetate (PMA) in both experimental models. Serum NO_x(NO₂ + NO₃) levels were low in C. callosus infected with strain M226, which was originally isolated from this animal species. Strain-F-infected animals had higher serum NO_x levels in the initial period of infection, which dropped to noninfected control values on the 40th day. In Swiss mice, both strains induced the production of higher levels of NO_x throughout the period of observation, with the increase being more pronounced in mice infected with the F strain. Daily treatment of F-strain-infected C. callosus with the arginine analogue L-nitro-arginine drastically reduced NO_x levels, with no influence on parasitemia or mortality being observed. The results obtained suggest that C. callosus shows a distinct behavior with regard to resistance to T. cruzi infection. Received: 26 February 1997 / Accepted: 10 April 1997     

Growth-inhibitory effects of interferon-γ on Neospora caninum in murine macrophages by a nitric oxide mechanism

To clarify the effector pathway of Neospora caninum growth-inhibitory activity induced by interferon-γ (IFN-γ) in murine macrophages we examined the relationship between IFN-γ and nitric oxide (NO). Production of NO was enhanced in cultures of macrophages supplemented with IFN-γ, and dose-dependent growth inhibition was observed. These findings suggest that the inhibitory activity induced in macrophages by IFN-γ is mediated NO molecules. A competitive inhibitor of the L-arginine-dependent effector pathway, N ^G-monomethyl-L-arginine, virtually abolished the inhibitory effects induced by IFN-γ. From this finding it appears that the inhibitory effects induced by IFN-γ in macrophages may be mediated by an L-arginine-dependent effector pathway that involves NO production. In vivo, mice with a targeted disruption of the inducible NO synthase gene (iNOS^−/−) were more susceptible than wild-type mice to N. caninum. Therefore, the production of NO in macrophages induced by IFN-γ is an important mechanism for the killing of intracellular N. caninum. Received: 28 February 2000 / Accepted: 20 March 2000     

Major histocompatibility complex class I- and II-deficient knock-out mice are resistant to primary but susceptible to secondary Eimeria papillata infections

Two distinct mechanisms seem to function in reducing oocyst output during Eimeria papillata infections in mice. For naive mice, immunity was afforded␣by␣a T-cell-independent gamma-interferon (IFN-γ) response mediated by natural killer (NK) cells. On reinfection, resistance was associated with T-cells and, to a lesser extent, perforin. To determine if antigen presentation with major histocompatibility complex␣(MHC) molecules was required to control oocyst production by NK cells during primary infection or by T-cells during secondary infection, mutant mice that lacked H2-IAβb (Aβb^−/−) or β₂-microglobulin (β2m^−/−) were used. Since MHC molecules are required for the maturation of αβ T-cells, Aβb^−/− and β2m^−/− mutant mice are also deficient in functional αβ⁺CD4⁺ or αβ⁺CD8⁺ T-cells, respectively. As compared with wild-type control mice, oocyst output by mutant mice was not significantly affected during primary infection, suggesting that the ability of NK cells to control parasite replication is not dependent on the expression of MHC molecules. On reinfection, differences were observed for mutant mice as compared with controls. Aβb^−/− mice were found to be more susceptible than β2m^−/− mice, suggesting that the αβ⁺CD4⁺ T-cell subset plays a greater role in resistance to reinfection than does the αβ⁺CD8⁺ T-cell subset. The mechanism of resistance depends on the immune status of the host and requires the coordinated interaction of both αβ⁺ T-cell subsets for optimal parasite control during subsequent infections. Received: 6 August 1997 / Accepted: 24 October 1997     

In vitro and in vivo activity of lignan lactones derivatives against <Emphasis Type="Italic">Trypanosoma cruzi</Emphasis>

The trypanocidal effect of six lignan lactones, (−)-cubebin (1), (−)-O-methyl cubebin (2), (−)-O-benzyl cubebin (3), (−)-6,6′-dinitrohinokinin (4), (−)-hinokinin (5) and dimethoxymorelensin (6), previously synthesized by our research group, was evaluated in vitro and in vivo. The compounds with higher anti-epimastigote activity were screened against intracellular amastigote of Trypanosoma cruzi. Among these, compound 5 was selected to be assayed in vivo. It was observed that compounds 5, 6 and 2 showed higher trypanocidal activity against epimastigote forms of T. cruzi, displaying inhibitory concentration (IC₅₀) values of 0.67, 3.89 and 31.35 μM, respectively. These compounds were also evaluated against intracellular amastigote forms of T. cruzi, with five displaying similar activity to benznidazole. In vivo assays showed significant reduction of parasitaemia after administration of five in mice infected.     

Immune response of mice with alveolar echinococcosis to therapy with transfer factor, alone and in combination with albendazole

The effect of dialysable leucocyte extract (transfer factor TF) on immune response of mice infected with Echinococcus multilocularis and treated with albendazole (ABZ) was observed. TF administration increased the parasite-suppressed proliferative response of T and B lymphocytes of infected mice from weeks 8 to 12 or 14 post infection (p.i.), respectively, with the most stimulative effect after TF+ABZ therapy. The CD4 T cell presence in the spleen of infected mice with TF or TF+ABZ therapy was increased from weeks 6 to 12 or 14 p.i., respectively. The production of IFN-γ (Th1 cytokine) after TF or TF+ABZ therapy was significantly higher from weeks 6 to 12 p.i., and during this time, the significantly inhibited IL-5 synthesis (Th2 cytokine) was detected, particularly after TF+ABZ therapy. The superoxide anion (O₂⁻) production in peritoneal macrophages of infected mice treated with TF or TF+ABZ was stimulated from weeks 8 to 18 p.i. The immunomodulative effect of TF reduced the growth of larval cysts till week 14 p.i. with a comparable intensity to the anthelmintic drug ABZ. Combined therapy TF+ABZ resulted in the greatest parasite restriction and reduced the cyst development till the end of the experiment.     

Effect of O2 availability on neuroendocrine variables at rest and during exercise: O2 breathing increases plasma prolactin

Neuroendrocrine and substrate responses were investigated in eight male athletes during inhalation of either 100% O₂ (HE), 14% O₂ (HO) or normoxic gas (NO) before, during and after 60 min of cycle ergometry at the same absolute work rate. Concentrations of prolactin (PRL), growth hormone (GH), testosterone (T), adrenocorticotropic hormone (ACTH), cortisol (COR), adrenalin (A), noradrenalin (NA), insulin (INS), ammonia (NH₃), free fatty acids, serotonin (5-HT), total protein, branched-chain amino acids (BCAA) and free tryptophan (free TRP) were determined in venous blood and lactate concentration [LA⁻], partial pressure of oxygen (PO₂), oxygen saturation (SO₂), partial pressure of carbon dioxide and pH in capillary blood. ThePO₂ andSO₂ were augmented in HE and decreased in HO (P ≤ 0.01). In HO and NO no significant changes were found for any other parameter during 30 min of rest prior to exercise. In HE, PRL increased by about 400% during this time, while NA declined (P ≤ 0.01). Heart rate (HR) and [LA⁻] were higher during exercise in HO (P ≤ 0.01). In all trials, NH₃, NA, A, T, GH and ACTH increased during exercise (P ≤ 0.01), while BCAA and INS declined. In comparison to NO and HE, increases of NA, A, GH, COR and ACTH were higher in HO (P < 0.01). The PRL in NO and COR in NO and HE did not change significantly. In HE, after the initial increase at rest, PRL declined during exercise but remained higher than in HO. Higher values for NA, A, GH, COR and ACTH in HO were likely to have reflected an augmented relative exercise intensity. Our results showed that PRL but no other hormone increased during acute exposure to hyperoxia. This PRL release was independent of exercise stress and greater than PRL augmentation during hypoxia, which was related to a higher relative exercise intensity as indicated by [LA⁻] and HR. Responses of plasma NH₃, BCAA, free TRP and 5-HT could not explain PRL augmentation induced by the increment in bloodSO₂ during hyperoxia. Deceased     

Interaction between the severity of the infection by the nematode <Emphasis Type="Italic">Anguillicola crassus</Emphasis> and the tolerance to hypoxia in the European eel <Emphasis Type="Italic">Anguilla anguilla</Emphasis>

An experiment was conducted to test the effect of the infection by the swimbladder nematode Anguillicola crassus on the survival of the European eel Anguilla anguilla when exposed to hypoxic conditions. Forty-four wild caught and naturally infected eels were placed in an aquarium filled with water from the fishing site (Vaccarès Lagoon, French Mediterranean coast). In this confined environment (271), under decreasing oxygen resources, the first eel death occurred after 45 h (O₂ = 0.98 mg l⁻¹) and the last one after 96 h (O₂ = 0.48 mg l⁻¹). After dissection and parasite examination, analyses revealed significant negative correlations between the time to death and various parameters of parasite pressure (e.g., number of lumen worms, parasite mass, health state of the infected organ). It was shown that the severity of damage to the swimbladder rather than the count of living parasites was the major contributing factor in explaining the variation in time to death. These semi-experimental data demonstrating an increased eel mortality rate under severe oxygen stress are discussed for their relevance under field conditions, especially during hot summer months.     

Prediction of <Emphasis Type="Italic">V</Emphasis>O<Subscript>2max</Subscript> with daily step counts for Japanese adult women

The purpose of the study was to develop a new non-exercise VO_2max prediction model using a physical activity (PA) variable determined by pedometer-determined step counts (SC, steps day⁻¹) in Japanese women aged 20–69 years old. Eighty-seven and 102 subjects were used to develop the prediction model, and to validate the new model, respectively. VO_2max was measured using a maximal incremental test on a bicycle ergometer. SC was significantly related to VO_2max (partial correlation coefficient r = 0.40, P < 0.001) after adjusting for BMI (kg m⁻²) and age (years). When the new prediction equation developed by multiple regression to estimate VO_2max from age, BMI, and SC (R = 0.71, SEE = 5.3 ml kg⁻¹ min⁻¹, P < 0.001) was applied to the Validation group, predicted VO_2max correlated well with measured VO_2max (r = 0.81, P < 0.001), suggesting that SC is a useful PA variable for non-exercise prediction of VO_2max in Japanese women.     

TNF controls the infiltration of dendritic cells into the site of <Emphasis Type="Italic">Leishmania major</Emphasis> infection

TNF-negative C57BL/6 (B6.TNF^−/−) mice are highly susceptible to Leishmania (L.) major infection and succumb rapidly to fatal leishmaniasis. A T helper type 1 (Th1) cell-mediated immune response is central for protective anti-leishmanial immunity. Therefore, the observed susceptibility of B6.TNF^−/− mice to L. major parasites could be caused by a deficiency in mounting a Th1 response. Analysis of infected footpads revealed, that B6.TNF^−/− mice exhibited a substantially diminished formation of DCs at the site of infection. Furthermore, Th1 cytokines such as IFN-γ were reduced in footpads of infected B6.TNF^−/− mice. Cutaneous reconstitution of B6.TNF^−/− mice with either bone marrow derived DCs (BM-DCs) or recombinant TNF simultaneous to infection resulted in an increased expression of cytokines such as IFN-γ and in an enhanced presence of Leishmania-antigen in skin draining lymph nodes. In addition, the individual time of survival was doubled. In conclusion we demonstrate that the expression of dermal TNF is necessary to provide an environment that initiates a local inflammatory response, but is not sufficient to induce protective immunity.     

The <Emphasis Type="Italic">Campylobacter jejuni</Emphasis> NCTC11168 capsule prevents excessive cytokine production by dendritic cells

Campylobacter jejuni is the leading cause of human bacterial gastroenteritis worldwide, mainly caused by handling and consumption of contaminated poultry. However, the immune response to infection is poorly understood. Here, the impact of the C. jejuni capsule, flagella and the N-linked glycosylation system on cytokine production by dendritic cells was investigated. Bone marrow-derived murine dendritic cells (BMDCs) infected with C. jejuni lacking the N-linked glycosylation system produced similar amounts of cytokines compared to cells infected with C. jejuni 11168H wild-type (WT) cultures. C. jejuni flagellin FlaA mutants elicited reduced IL-6 and IL-10 production in BMDCs compared to C. jejuni WT and this reduction was more pronounced in TLR4^−/− BMDCs. An acapsular C. jejuni mutant as well as a mutant lacking the O-methyl phosphoramidate modification of the capsule elicited a higher cytokine response in BMDCs. Experiments with TLR4^−/− BMDCs revealed that this increased cytokine production was not solely dependent on signalling through TLR4. Therefore, the C. jejuni capsule is important to prevent excessive cytokine production by BMDCs and even minor changes in capsule composition such as the lack of the O-methyl phosphoramidate modification can lead to increased cytokine production.     

Gaseous messengers in oxygen sensing

The carotid body is a sensory organ that detects acute changes in arterial blood oxygen (O₂) levels and reflexly mediates systemic cardiac, vascular, and respiratory responses to hypoxia. This article provides a brief update of the roles of gas messengers as well as redox homeostasis by hypoxia-inducible factors (HIFs) in hypoxic sensing by the carotid body. Carbon monoxide (CO) and nitric oxide (NO), generated by heme oxygenase-2 (HO-2) and neuronal nitric oxide synthase (nNOS), respectively, inhibit carotid body activity. Molecular O₂ is a required substrate for the enzymatic activities of HO-2 and nNOS. Stimulation of carotid body activity by hypoxia may reflect reduced formation of CO and NO. Glomus cells, the site of O₂ sensing in the carotid body, express cystathionine γ-lyase (CSE), an H₂S generating enzyme. Cth ^−/− mice, which lack CSE, exhibit severely impaired hypoxia-induced H₂S generation, sensory excitation, and stimulation of breathing in response to low O₂. Hypoxia-evoked H₂S generation in the carotid body requires the interaction of CSE with HO-2, which generates CO. Carotid bodies from Hif1a ^+/− mice with partial HIF-1α deficiency do not respond to hypoxia, whereas carotid bodies from mice with partial HIF-2α deficiency are hyper-responsive to hypoxia. The opposing roles of HIF-1α and HIF-2α in the carotid body have provided novel insight into molecular mechanisms of redox homeostasis and its role in hypoxia sensing. Heightened carotid body activity has been implicated in the pathogenesis of autonomic morbidities associated with sleep-disordered breathing, congestive heart failure, and essential hypertension. The enzymes that generate gas messengers and redox regulation by HIFs represent potential therapeutic targets for normalizing carotid body function and downstream autonomic output in these disease states.     

Beneficial Effect of Eucommia Polysaccharides on Systemic Lupus Erythematosus-like Syndrome Induced by Campylobacter jejuni in BALB/c Mice

The stem bark of Eucommia ulmoides Oliv. is commonly used for the treatment of hypertension, rheumatoid arthritis, lumbago, and ischialgia in traditional Chinese medicine. This study was to determine whether the crude polysaccharides (EUPs) isolated from the stem bark of E. ulmoides had beneficial effects on lupus-like syndrome in mice. BALB/c mice were immunized with CJ-S₁₃₁ in Freund’s complete adjuvant on day 0, and then boosted on day 14. EUPs 15 or 30 mg kg⁻¹·day⁻¹, or prednisone 5 mg kg⁻¹·day⁻¹ was given to BALB/c mice intragastrically from day 0 to 34. Treatment with EUPs 15 or 30 mg kg⁻¹·day⁻¹ for 35 days protected kidney from glomerular injury with reduced immunoglobulin deposition and lowered proteinuria. The increased production of serum autoantibodies and total immunoglobulin G (IgG) was also inhibited. These findings suggested that Eucommia polysaccharides had a beneficial effect on systemic lupus erythematosus-like syndrome induced by CJ-S₁₃₁ in BALB/c mice.     

Influence of recovery manipulation after hyperlactemia induction on the lactate minimum intensity

This study analyzed the influence of recovery phase manipulation after hyperlactemia induction on the lactate minimum intensity during treadmill running. Twelve male runners (24.6 ± 6.3 years; 172 ± 8.0 cm and 62.6 ± 6.1 kg) performed three lactate minimum tests involving passive (LMT_P) and active recoveries at 30%vVO_2max (LMT_A30) and 50%vVO_2max (LMT_A50) in the 8-min period following initial sprints. During subsequent graded exercise, lactate minimum speed and VO₂ in LMT_A50 (12.8 ± 1.5 km h⁻¹ and 40.3 ± 5.1 ml kg⁻¹ min⁻¹) were significantly lower (P < 0.05) than those in LMT_A30 (13.3 ± 1.6 km h⁻¹ and 42.9 ± 5.3 ml kg⁻¹ min⁻¹) and LMT_P (13.8 ± 1.6 km h⁻¹ and 43.6 ± 6.1 ml kg⁻¹ min⁻¹). In addition, lactate minimum speed in LMT_A30 was significantly lower (P < 0.05) than that in LMT_P. These results suggest that lactate minimum intensity is lowered by active recovery after hyperlactemia induction in an intensity-dependent manner compared to passive recovery.     

The role of nitric oxide in cellular response to hyperbaric conditions

Nitric oxide (NO) acts as a regulator in cell proliferation and expression of growth factors and forms peroxynitrite (ONOO⁻) in oxidative conditions. The aim of the study was to investigate the role of NO in cellular response to hyperbaric oxygen (HBO). NO and nitrotyrosine (NT), biochemical marker for ONOO⁻, cell proliferation and growth factors, were ex-vivo studied in cell cultures under HBO and normobaric (NOR) conditions. A549 (epithelial), L929 (fibroblast) and SVEC (endothelial) were exposed to 100% O₂, at P = 280 kPa for t = 60 min, once daily for five sessions. Cell proliferation was determined as the incorporation of bromodeoxyuridine (BrdU) into cells and NO as nitrates/nitrites (NO₃ ⁻/ NO₂ ⁻) Gries reaction product in cell culture supernatant (CCSP). NT, vascular endothelial growth factor (VEGF) and transforming growth factor-beta 1 (TGFb1) were measured with enzyme-inked immunosorbent assay (ELISA) in CCSP. The time course of total NO was opposite to that of cell proliferation in HBO conditions, peaking after the second HBO session, while cell proliferation showed a reverse trend, minimizing at the same time, suggesting a reverse and transient anti-proliferative effect. Released growth factors were significantly increased in late HBO sessions. NT peaked after second treatment, indicating the formation of ONOO⁻. In control cultures (NOR), proliferation rate was downward and no significant differences were found for the other parameters. In conclusion, the data suggested a key role for NO in the beneficial HBO action, depending on its concentration, which fluctuated with the time of HBO exposure and the activation of oxidant–antioxidant (REDOX) mechanisms, regardless of cell type.     

Endothelial function in aorta segments of apolipoprotein E-deficient mice before development of atherosclerotic lesions

Acetylcholine (ACh)-induced relaxation declines in apolipoprotein E-deficient (apoE^−/−) mouse aortas, but only after atherosclerotic plaque formation. This study investigated intracellular calcium concentrations [Ca²⁺]_i and changes in phenylephrine-induced contractions as index of baseline nitric oxide (NO) bioavailability before plaque development. Isometric contractions of thoracic aorta rings of young (4 months) apoE^−/− and C57BL/6J (WT) mice were evoked by phenylephrine (3 × 10⁻⁹–3 × 10⁻⁵ M) in the presence and absence of endothelial cells (ECs) or NO synthase (NOS) inhibitors. [Ca²⁺]_i (Fura-2 AM) and endothelium-dependent relaxation were measured at baseline and after ACh stimulation. Segments of apoE^−/− mice were significantly more sensitive and developed more tension than WT segments in response to phenylephrine. The differences disappeared after NOS inhibition or EC removal or upon increasing [Ca²⁺]_i in apoE^−/− strips with 10⁻⁶ M cyclopiazonic acid or 10⁻⁷ M Ca²⁺-ionophore A23187. Expression of endothelial NOS (eNOS) mRNA was similar in apoE^−/− and WT aorta segments. Basal [Ca²⁺]_i was significantly lower in apoE^−/− than in WT strips. Relaxation by ACh (3 × 10⁻⁹–10⁻⁵ M) was time- and dose-dependently related to [Ca²⁺]_i, but neither ACh-induced relaxation nor Ca²⁺ mobilization were diminished in apoE^−/− strips. In conclusion, basal, but not ACh-induced NO bioavailability, was compromised in lesion-free aorta of apoE^−/− mice. Decreased basal NO bioavailability was not related to lower eNOS expression, but most likely related to lower basal [Ca²⁺]_i. These findings further point to important differences between basal and stimulated eNOS activity.     

The influence of either no fluid or carbohydrate-electrolyte fluid ingestion and the environment (thermoneutral versus hot and humid) on running economy after prolonged, high-intensity exercise

This study investigated the effects on running economy (RE) of ingesting either no fluid or an electrolyte solution with or without 6% carbohydrate (counterbalanced design) during 60-min running bouts at 80% maximal oxygen consumption (V˙O_2max). Tests were undertaken in either a thermoneutral (22–23°C; 56–62% relative humidity, RH) or a hot and humid natural environment (Singapore: 25–35°C; 66–77% RH). The subjects were 15 young adult male Singaporeans [V˙O_2max = 55.5 (4.4 SD) ml kg⁻¹ min⁻¹]. The RE was measured at 3 m s⁻¹ [65 (6)% V˙O_2max] before (RE1) and after each prolonged run (RE2). Fluids were administered every 2 min, at an individual rate determined from prior tests, to maintain body mass (group mean = 17.4 ml min⁻¹). The V˙O₂ during RE2 was higher (P < 0.05) than that during the RE1 test for all treatments, with no differences between treatments (ANOVA). The mean increase in V˙O₂ from RE1 to RE2 ranged from 3.4 to 4.7 ml kg⁻¹ min⁻¹ across treatments. In conclusion, the deterioration in RE at 3 m s⁻¹ (65% V˙O_2max) after 60 min of running at 80% V˙O_2max appears to occur independently of whether fluid is ingested and regardless of whether the fluid contains carbohydrates or electrolytes, in both a thermoneutral and in a hot, humid environment. Accepted: 30 October 1997     

Role of nitric oxide in regulation of systemic vascular resistance during and after cardiopulmonary bypass

Cardiopulmonary bypass (CPB) is known to result in the abnormal production of vasoactive substances contributing to the changes in hemodynamics such as systemic vascular resistance (SVR) during and after CPB. Nitric oxide (NO) is an inflammation-mediated vasoactive substance that plays a role in the whole-body inflammatory response induced by CPB. We evaluated the role of NO in the regulation of SVR during and after CPB. Fifteen patients underwent open-heart surgery for valvular heart disease. The perfusate blood temperature of CPB was set to 34°C. The plasma levels of NO metabolites (NO ₂ ⁻ +NO ₃ ⁻ ), prostaglandin E₂ (PGE₂), bradykinin (BK), and systemic vascular resistance index (SVRI) were measured before CPB and 0, 12, and 24 h after CPB. The plasma level of NO metabolites increased gradually after CPB (pre-CPB, 26.3 ±4.4; 0h, 33.7±6.5; 12 h, 49.8±11.1; 24 h, 43.1±7.5 μM). SVRI decreased gradually after CPB (pre-CPB, 2361±364; 0h, 2048±216; 12 h, 1590±308; 24 h, 1727±435 dyne·s·cm⁻⁵·m²). There was a significant inverse correlation between SVRI and the plasma level of NO metabolites as a whole (r=−0.674,P<0.0001). No significant correlations were observed between SVRI and the other vasoactive substances PGE₂ and BK. These findings demonstrated that NO production increased gradually during and after CPB in association with the decrease in SVR. Part of this study was presented at the 2nd annual meeting of the Japan Society for Adaptation Medicine on February 27, 1998     

<Emphasis Type="Italic">V</Emphasis>O<Subscript>2</Subscript>max during successive maximal efforts

The concept of VO₂max has been a defining paradigm in exercise physiology for >75 years. Within the last decade, this concept has been both challenged and defended. The purpose of this study was to test the concept of VO₂max by comparing VO₂ during a second exercise bout following a preliminary maximal effort exercise bout. The study had two parts. In Study #1, physically active non-athletes performed incremental cycle exercise. After 1-min recovery, a second bout was performed at a higher power output. In Study #2, competitive runners performed incremental treadmill exercise and, after 3-min recovery, a second bout at a higher speed. In Study #1 the highest VO₂ (bout 1 vs. bout 2) was not significantly different (3.95 ± 0.75 vs. 4.06 ± 0.75 l min⁻¹). Maximal heart rate was not different (179 ± 14 vs. 180 ± 13 bpm) although maximal V _E was higher in the second bout (141 ± 36 vs. 151 ± 34 l min⁻¹). In Study #2 the highest VO₂ (bout 1 vs. bout 2) was not significantly different (4.09 ± 0.97 vs. 4.03 ± 1.16 l min⁻¹), nor was maximal heart rate (184 + 6 vs. 181 ± 10 bpm) or maximal V _E (126 ± 29 vs. 126 ± 34 l min⁻¹). The results support the concept that the highest VO₂ during a maximal incremental exercise bout is unlikely to change during a subsequent exercise bout, despite higher muscular power output. As such, the results support the “classical” view of VO₂max.