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Biomedical subjects

N C Smith

Publications and source records attributed to N C Smith.

At least 19 recordsLinked to original sources
PubMed2000

Histamine H(3)-receptors: a new frontier in myocardial ischemia.

In protracted myocardial ischemia, sympathetic nerve endings undergo ATP depletion, hypoxia and pH(i) reduction. Consequently, norepinephrine (NE) accumulates in the axoplasm, because it is no longer stored in synaptic vesicles, and intraneuronal Na(+) concentration increases, as the Na(+)/H(+) exchanger (NHE) is activated. This forces the reversal of the Na(+)- and Cl(-)-dependent NE transporter, triggering a massive carrier-mediated release of NE and thus, arrhythmias. Indeed, NE overflow in myocardial ischemia directly correlates with the severity of arrhythmias. Histamine H(3)-receptors (H(3)R) have been identified as inhibitory heteroreceptors in adrenergic nerve endings of the heart. In addition to inhibiting NE exocytosis from sympathetic nerve endings, selective H(3)R agonists attenuate carrier-mediated release of NE in both animal and human models of protracted myocardial ischemia. Whereas H(3)R-mediated attenuation of exocytotic NE release involves an inhibition of N-type Ca(2+)-channels, H(3)R-mediated reduction of carrier-mediated NE release is associated with diminished NHE activity. In addition to inhibiting NE release, H(3)R stimulation significantly attenuates the incidence and duration of ventricular fibrillation. Although other presynaptic receptors also modulate NE release from sympathetic nerve endings, H(3)R stimulation reduces both exocytotic and carrier-mediated NE release, whereas alpha(2)-adrenoceptor agonists attenuate NE exocytosis but enhance carrier-mediated NE release. Furthermore, unlike adenosine A(1)-receptors, whose activation reduces both exocytotic and carrier-mediated NE release, H(3)R stimulation is devoid of negative chronotropic and dromotropic effects (i.e., sinoatrial and atrioventricular nodal functions are unaffected). Because excess NE release can trigger severe arrhythmias and sudden cardiac death, negative modulation of NE release by H(3)R agonists may offer a novel therapeutic approach to myocardial ischemia.

Animals↗
PubMed1999

Cytokines, nitric oxide, heat shock proteins and virulence in Toxoplasma.

Elucidating the factors that play important roles in the expression of virulence by parasites is crucial to understanding disease pathogenesis and to developing control strategies rationally. Here, Kate Miller, Nick Smith and Alan Johnson, using Toxoplasma gondii as a model, argue that the interactions between the immune system and 70 kDa heat shock proteins of apicomplexan parasites profoundly influence parasite virulence.

Animals↗
PubMed1999

Metabolic effects of nitric oxide synthase inhibition during exercise in the horse.

The effect of nitric oxide synthase (NOS) inhibition during exercise on lactate production was investigated in five Thoroughbred horses. A standard exercise test (SET), consisting of three canters (approximately 55 per cent VO2max), with walking and trotting between each canter, was performed twice (control and test, in random order) by each horse. Nphi-nitro-L-arginine methyl ester (L-NAME; 20 mg kg-1), a competitive inhibitor of NOS, induced a significant increase (P < 0.05) in plasma lactate [5.7 (2.9) vs 11.8 (3.8) mmol L-1], which continued to increase despite administration of L-arginine, the substrate for NOS. There were no differences in cardiac output (Q) or the total body oxygen consumption (VO) between each SET. The results show that non-specific inhibition of NOS isoforms during exercise in the horse increases plasma lactate concentration, although the mechanism/s remain uncertain.

Animals↗
PubMed1999

A six year study of the antenatal detection of fetal abnormality in six Scottish health boards.

OBJECTIVE: To assess the sensitivity of prenatal diagnosis by ultrasound and biochemical methods, to evaluate the reasons for non-detection and to make appropriate recommendations. DESIGN: Six year observational study, during which biochemical screening for trisomy 21 was introduced and there was an increase in routine ultrasound scanning at 18-22 weeks. SETTING: Six health boards in Scotland. POPULATION: 264,481 pregnancies, of which 862 were terminated because of fetal abnormality, and 2123 delivered with prenatally detectable major fetal abnormalities. MAIN OUTCOME MEASURES: The prenatal detection of trisomies 13, 18 and 21, and 12 major structural abnormalities, which the average ultrasonographer with average skills using average equipment would be expected to detect. RESULTS: Serum biochemical screening improved detection of trisomy 21 from 33% to 57%. The detection rate for the major abnormalities was 62% (815/1320) and 73% (598/818) when the trisomies were excluded. 18-22 weeks scanning yielded a 92% detection rate. Of the 505 undetected cases, 15% declined prenatal screening, 46% were unscreened because they were ineligible for testing, unbooked, booked too late or scanned too early for a diagnosis to be made, 2% had findings suspicious of a chromosomal abnormality but testing was not undertaken and 37% had a negative scan at a gestation when the abnormality was potentially detectable. CONCLUSIONS: A policy of first trimester scanning followed by serum alpha-fetoprotein screening and additional scanning as clinically indicated is effective in detecting major structural abnormalities, but scanning at 18-22 weeks and serum biochemical screening for trisomy 21 improved the detection rates. Supervised training and adequate equipment are essential. Present prenatal diagnostic tests will not detect all abnormalities and patients must be made aware of this.

Biomarkers↗
PubMed1999

LLC-PK(1) cells stably expressing the human norepinephrine transporter: A functional model of carrier-mediated norepinephrine release in protracted myocardial ischemia.

In myocardial ischemia, adrenergic terminals undergo ATP depletion, hypoxia, and intracellular pH reduction, causing the accumulation of axoplasmic norepinephrine (NE) and intracellular Na(+) [via the Na(+)-H(+) exchanger (NHE)]. This forces the reversal of the Na(+)- and Cl(-)-dependent NE transporter (NET), triggering massive carrier-mediated NE release and, thus, arrhythmias. We have now developed a cellular model of carrier-mediated NE release using an LLC-PK(1) cell line stably transfected with human NET cDNA (LLC-NET). LLC-NET cells transported [(3)H]NE and [(3)H]N-methyl-4-phenylpyridinium ([(3)H]MPP(+)) in an inward direction. This uptake was abolished by the NET inhibitors desipramine (100 nM) and mazindol (300 nM) and by extracellular Na(+) removal. Na(+)-gradient reversal induced an efflux of (3)H-substrate from preloaded LLC-NET cells. Desipramine and mazindol blocked this efflux. Because of its greater intracellular stability and higher sensitivity to Na(+)-gradient reversal, [(3)H]MPP(+) proved preferable to [(3)H]NE as an NET substrate; therefore, only [(3)H]MPP(+) was used for subsequent studies. The K(+)/H(+) ionophore nigericin (10 microM) evoked a large efflux of [(3)H]MPP(+). This efflux was potentiated by the Na(+),K(+)-ATPase inhibitor ouabain (100 microM), was sensitive to desipramine, and was blocked by the NHE inhibitor 5-(N-ethyl-N-isopropyl)-amiloride (EIPA; 10 microM). In contrast, EIPA failed to inhibit the [(3)H]MPP(+) efflux elicited by the Na(+) ionophore gramicidin (10 microM). Furthermore, [(3)H]MPP(+) efflux induced by the NHE-stimulant proprionate (25 mM) was negatively modulated by imidazoline receptor activation. Our findings suggest that LLC-NET cells are a sensitive model for studying transductional processes of carrier-mediated NE release associated with myocardial ischemia.

1-Methyl-4-phenylpyridinium↗
PubMed1998

Nuchal thickening in Jacobsen syndrome.

A routine detailed ultrasound examination performed at 20 weeks' gestation demonstrated the presence of nuchal thickening as an apparently isolated finding. The concentration of maternal alpha-fetoprotein was normal and the risk of Down's syndrome was 1 in 6800. Amniocentesis was performed and chromosome analysis showed the karyotype 46,XY, del(11)(q23) found in Jacobsen syndrome. Fetal autopsy performed following medical termination at 23 weeks confirmed the phenotype and internal abnormalities found in Jacobsen syndrome.

Abnormalities, Multiple↗
PubMed1997

Relaxation of the ovine isolated iris sphincter by adenosine receptor agonists: lack of effect of adenosine A1 and A2 receptor antagonists.

The effects of adenosine receptor ligands on the tone of the ovine isolated iris sphincter were investigated, and adenosine analogues were found to relax the carbachol-contracted tissue in a concentration-dependent manner with an order of potency of 5'-N-ethylcarboxamidoadenosine > or = 2-(p-(2-carboxyethyl)phenylethylamino)-5'-N-ethylcarboxamidoadenos ine (CGS 21680) > or = N6-cyclopentyladenosine > adenosine, consistent with activation of an adenosine A2A receptor. However, these responses were not inhibited by the non-selective adenosine A1/A2 receptor antagonist 8-p-sulphophenyltheophylline (50 microM), the selective adenosine A2A/A1 receptor antagonist N-[2-(dimethylamino)ethyl]-N-methyl-4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3- dipropyl-1H-purin-8-yl)benzenesulphonamide (PD 115,199) (0.1 microM) or the non-xanthine adenosine A2A receptor antagonist (4-(2-[7-amino-2-(2-furyl) [1,2,4]-triazolo[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol) (ZM 241385) (0.1 microM). The relaxations cannot therefore be mediated by activation of adenosine A1, A2A or A2B receptors.

Adenosine↗
PubMed1997

The spleen, IgG antibody subsets and immunity to Plasmodium berghei in rats.

The development of IgG subclass-specific antibody responses to Plasmodium berghei in spleen-chimeric rats were monitored to determine if there was any relationship between IgG subset profiles and resistance. Strongly immune eusplenic rats respond to challenge with P. berghei by producing high levels of parasite-specific IgG2a, IgG2b and IgG2c but only modest levels of IgG1. Splenectomy profoundly affects the antibody response to infection. Thus, in splenectomized immunized rats, which harbour a chronic parasitaemia of 1%, the IgG2a, IgG2b and IgG2c responses peak 1 week later than in eusplenic immunized rats although the size of the peak is similar. More marked effects are apparent in the IgG1 response, the magnitude of which is far greater in splenectomized immunized rats than eusplenic immunized rats. Similar antibody profiles are seen in splenectomized immunized rats transplanted with a naive spleen. In contrast, splenectomized naive rats receiving either a transplant of a spleen from an immune rat or a transfer of immune spleen cells have high levels of IgG2a, IgG2b and IgG2c but modest levels of IgG1. However, only the former group of rats completely clears the parasite, the latter maintaining a chronic 1% parasitaemia. Thus, although complete resistance to P. berghei is always associated with high levels of parasite-specific IgG2a, IgG2b and IgG2c plus modest levels of IgG1, this is not a sufficient set of conditions to guarantee complete immunity. The IgG subset profile may be related to cytokine production; IFN-gamma was detected in the sera of rats receiving spleens from rats immune to P. berghei (modest IgG1 responses) but not in rats receiving spleens from naive animals (pronounced IgG1 responses).

Adoptive Transfer↗
PubMed1997

Nitric oxide and thermoregulation during exercise in the horse.

The effect of inhibition of nitric oxide production on sweating rate (SR) and on core, rectal, and tail skin temperatures was measured in five Thoroughbred horses during exercise of variable intensity on a high-speed treadmill. A standard exercise test consisting of three canters [approximately 55% maximum O2 uptake (VO2max)], with walking (approximately 9% VO2max) and trotting (approximately 22% VO2max) between each canter, was performed twice (control or test), in random order, by each horse. N(G)-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg), a competitive inhibitor of nitric oxide synthase, was infused into the central circulation and induced a significant reduction in the SR measured on the neck (31.6 +/- 6.4 vs. 9.7 +/- 4.2 g x min(1) x m(-2); 69%) and rump (14.7 +/- 5.2 vs. 4.8 +/- 1.6 g x min(-1) x m(-2); 67%) of the horses during canter (P < 0.05). Significant increases in core, rectal, and tail skin temperatures were also measured (P < 0.05). L-Arginine (200 mg/kg iv) partially reversed the inhibitory effects of L-NAME on SR, but core, rectal, and tail skin temperatures continued to increase (P < 0.05), suggesting a cumulation of body heat. The results support the contention that nitric oxide synthase inhibition diminishes SR, resulting in elevated core and peripheral temperatures leading to deranged thermoregulation during exercise. The inhibition of sweating by L-NAME may be related to peripheral vasoconstriction but may also involve the neurogenic control of sweating.

Animals↗
PubMed1996

Nitric oxide and exercise in the horse.

1. The effects of exercise on the production rate of nitric oxide (NO) in exhaled air (VNO) and the effects of inhaled NO (80 p.p.m.) on cardiovascular and respiratory parameters were investigated in five Throughbred horses. 2. The concentration of NO ([NO]) in exhaled air collected from within the nasal opening was lower when collected at a high flow rate of 80 l min-1 than at a low flow rate of 20 l min-1: when trotting at 3.7 m s-1 the values were 0.78 +/- 0.15 and 1.23 +/- 9.14 p.p.b., respectively, and when cantering at 9 m s-1 the values were 1.69 +/- 0.31 and 2.25 +/- 0.32 p.p.b., respectively. 3. Nebulized methoxamine (40 mg ml-1 for 60 s), an alpha 1-adrenergic agonist, further reduced [NO] during the 9 m s-1 canter to 1.05 +/- 0.14 and 1.99 +/- 0.41 p.p.b. when collected at 80 and 20 l min-1, respectively, and induced cyclical changes in the breathing pattern. 4. Exercise induced a linear increase in VNO with work intensity to a maximum (428.1 +/- 31.6 pmol min-1 kg-1) which coincided with the maximal oxygen uptake for the horses (138.3 +/- 11.7 ml min-1 kg-1), although a further increase in VNO (779.3 +/- 38.4 pmol min-1 kg-1) occurred immediately after exercise. The changes in VNO correlated well with the tidal volume (r = 0.968; P < 0.01) and the haematocrit (r = 0.855; P < 0.01). 5. In the first 2 min of high intensity exercise, inhaled NO (80 p.p.m.) significantly (P < 0.05) reduced the pulmonary artery pressure: during the first minute, pulmonary artery pressure was 83.1 +/- 7.6 mmHg compared with a control value of 94.4 +/- 6.3 mmHg, and during the second minute, 84.2 +/- 7.1 mmHg compared with a control value of 98.4 +/- 4.7 mmHg. There were no other significant changes in cardiovascular or respiratory indices, including cardiac output, measured during exercise between control and inhaled NO tests. 6. The results show that exhaled NO is released from the airways of the horse and may contribute to the regulation of pulmonary vascular tone during exercise.

Adrenergic alpha-Agonists↗
PubMed1996

Effects of exercise intensity and environmental stress on indices of oxidative stress and iron homeostasis during exercise in the horse.

The effects of prolonged variable-intensity and short-term high-intensity exercise on indices of oxidative stress and iron homeostasis were compared in six fit horses under cool [20 degrees C, 40% relative humidity (RH)] or hot/humid (30 degrees C, 80% RH) environmental conditions. The exercise protocols were designed to simulate equine competition, including racing (intense exercise) or the speed and endurance phase of a 3-day event (prolonged exercise). Increased plasma concentrations of lipid hydroperoxides and haemolysate concentrations of oxidised glutathione (GSSG) were measured within 30 min of the completion of exercise, indicating production of reactive oxygen species (ROS) and lipid membrane peroxidation. The horses were unable to complete the prolonged exercise protocol at high temperature and humidity. This coincided with higher maximal values of lipid hydroperoxides [138.2 (17.7) microM and GSSG [110.6 (18.2) microM], compared to high-intensity [105.2 (14.9) microM and 63.6 (8.6) microM, respectively] or prolonged [100.7 (18.7) microM and 86.2 (9.1) microM, respectively] exercise performed under cooler environmental conditions. Significant correlations were found between the duration of the final stage of exercise during hot/humid environmental conditions and increased levels of lipid hydroperoxides (r = 0.85), GSSG (r = 0.94), xanthine (r = 0.92) and uric acid (r = 0.96). Exercise also decreased the iron (Fe)-binding antioxidant activity of the plasma and increased the total plasma Fe levels, although this was only significant for prolonged exercise in ambient conditions. There was no detectable free Fe in the plasma at any stage of exercise. Other changes in biochemical parameters had returned to pre-exercise levels within 24 h after exercise. The results show that exercise can induce changes in biochemical parameters that are indicative of oxidative stress in the fit horse and that this was, exacerbated during exercise at high temperature and humidity.

Animals↗
PubMed1996

The effect of BCG, zymosan and Coxiella burnetti extract on Eimeria infections.

Infection of animals with species of Eimeria induces a hyper-reactivity to endotoxin as manifest by a greatly increased capacity of infected animals to produce TNF in response to LPS in vivo compared with uninfected animals. This finding indicates priming for hyperactivation of macrophages by Eimeria infection and raises the possibility that non-specific triggering of macrophages by agents such as Bacille Calmette-Guerin (BCG), zymosan or Coxiella burnetti extract may be a simple means of control for coccidiosis. However, all of these agents enhanced oocyst excretion in mice, rats or chickens infected with Eimeria vermiformis, Eimeria nieschulzi or Eimeria tenella, respectively, without affecting the patent period.

Animals↗