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Biomedical subjects

G D Thomas

Publications and source records attributed to G D Thomas.

At least 19 recordsLinked to original sources
PubMed2000

Metabolic modulation of sympathetic vasoconstriction in exercising skeletal muscle.

The tight coupling of oxygen supply and utilization in exercising skeletal muscle is the result of complex interactions between local mechanisms that control muscle blood flow and substrate utilization and systemic mechanisms that control cardiac output and arterial pressure. The role of the sympathetic nervous system in the integration of these responses, specifically the interaction between sympathetic activation and local vasodilator mechanisms in exercising muscle, has been an active area of research for many years yet remains incompletely understood. The functional consequence of sympathetic activation in exercising skeletal muscle has been the subject of considerable debate. Previous studies in animals and humans have suggested that sympathetic vasoconstricton in active muscle is (a) well maintained and serves to limit active hyperaemia, thereby preventing muscle blood flow from outstripping cardiac output in order to preserve blood pressure and vital organ perfusion or (b) greatly attenuated in order to optimize muscle perfusion, a concept that has been termed 'functional sympatholysis'. Studies performed over the past 70 years have provided conflicting evidence regarding the relative importance of sympathetic vasoconstriction vs. functional sympatholysis in exercising skeletal muscle. The focus of this review is mainly on recent studies in anaesthetized animal preparations and in conscious humans that have provided evidence for the metabolic modulation of sympathetic vasoconstriction in contracting skeletal muscle and have identified a number of key underlying mechanisms that extend the initial concept of sympatholysis.

Animals↗
PubMed1999

Magnetic resonance imaging and invasive evaluation of development of heart failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha.

BACKGROUND: Transgenic mice expressing tumor necrosis factor-alpha (TNF-alpha) in cardiac myocytes develop dilated cardiomyopathy, but the temporal progression to cardiac dysfunction is not well characterized. We asked (1) Does magnetic resonance imaging (MRI) provide a reproducible assessment of cardiac output in mice that correlates with invasive measurements obtained with thermodilution? (2) What is the time course of left ventricular (LV) remodeling in transgenic mice with myocardial expression of TNF-alpha? METHODS AND RESULTS: Transgenic mice from 2 different lineages with differing amounts of myocardial TNF-alpha expression [lineage 1 (L1) and lineage 2 (L2)] and littermate controls (LC) were studied. In protocol 1, cardiac output (CO) and stroke volume (SV) were measured by MRI and thermodilution (TD) in 15 mice (3 L1, 4 L2, 8 LC). In protocol 2, 23 mice (7 L1, 8 L2, 8 LC) were scanned at 1 month of life and every 4 weeks thereafter. In both protocols, cine-MRI was performed with the use of a 1.5-T clinical system (1.5-mm slices, 195x195 microm in-plane resolution). MRI CO and SV correlated well with TD [COTD (mL/min)=0.94*COMRI+0.72, r=0.84; SVTD( microL)=1. 01*SVMRI-1.07, r=0.94]. Serial MRI studies showed significant increase in LV mass and volumes over time and a significant decrease in ejection fraction in transgenic mice when compared with littermate controls. Compared with lineage 2, lineage 1 showed significantly larger LV mass and volumes and significantly lower ejection fraction. CONCLUSIONS: MRI assessment of cardiac function in mice correlates well with invasive measurements. Serial MRI studies in the TNF-alpha mouse model demonstrate that the rate of progression and severity of LV dysfunction are dependent on the degree of TNF-alpha overexpression.

Animals↗
PubMed1999

Exercise-induced attenuation of alpha-adrenoceptor mediated vasoconstriction in humans: evidence from phase-contrast MRI.

OBJECTIVE: We recently provided evidence for contraction-induced attenuation of reflex sympathetic vasoconstriction in human skeletal muscle microcirculation. We now asked whether contraction-induced modulation of alpha-adrenoceptor mediated vasoconstriction in the human forearm (a) is evident in a large artery supplying the contracting skeletal muscle and (b) implicates a post-junctional site of action. METHODS AND RESULTS: To address these questions in humans, we used phase-contrast magnetic resonance imaging to measure blood flow velocity and cross-sectional area of the brachial artery during brachial-artery infusion of the alpha-adrenoceptor agonist norepinephrine (NE) (1.1 g/min for 5 min) at rest and during mild ipsilateral rhythmic handgrip (20% of maximum). At rest, brachial artery conductance decreased progressively during the entire 5 min period of infusion (baseline to first half to second half of infusion: 0.421 +/- 0.157 to 0.255 +/- 0.187 to 0.012 +/- 0.014 ml/min/mmHg, P < 0.05). When NE was superimposed on handgrip, conductance at first decreased sharply (1.205 +/- 0.127 to 0.330 +/- 0.097 ml/min/mmHg, P < 0.05). However, during the second half of the infusion, conductance did not decrease further but rather returned progressively toward baseline (0.476 +/- 0.199 ml/min/mmHg at the end of the exercise, P < 0.05 vs. NE alone). CONCLUSION: These data provide new evidence in humans that alpha-adrenoceptor mediated vasoconstriction is sensitive to modulation by skeletal muscle contraction. Such modulation is evident at the level of a large conduit artery and it involves a post-junctional mechanism of action.

Adrenergic alpha-Agonists↗
PubMed1998

Impaired metabolic modulation of alpha-adrenergic vasoconstriction in dystrophin-deficient skeletal muscle.

The neuronal isoform of nitric oxide synthase (nNOS) is highly expressed in mammalian skeletal muscle, but its functional role has not been defined. NO has been implicated in the local metabolic regulation of blood flow in contracting skeletal muscle in part by antagonizing sympathetic vasoconstriction. We therefore hypothesized that nNOS in skeletal muscle is the source of the NO mediating the inhibition of sympathetic vasoconstriction in contracting muscle. In the mdx mouse, a model of Duchenne muscular dystrophy in which dystrophin deficiency results in greatly reduced expression of nNOS in skeletal muscle, we found that the normal ability of skeletal muscle contraction to attenuate alpha-adrenergic vasoconstriction is defective. Similar results were obtained in mutant mice that lack the gene encoding nNOS. Together these data suggest a specific role for nNOS in the local metabolic inhibition of alpha-adrenergic vasoconstriction in active skeletal muscle.

Animals↗
PubMed1998

Nitric oxide mediates contraction-induced attenuation of sympathetic vasoconstriction in rat skeletal muscle.

1. Sympathetic vasoconstriction is attenuated by metabolic events in contracting rat skeletal muscle, in part by activation of ATP-sensitive potassium (KATP) channels. However, the specific metabolites in contracting muscle that open KATP channels are not known. We therefore asked if contraction-induced attenuation of sympathetic vasoconstriction is mediated by the endogenous vasodilators nitric oxide (NO), adenosine, or prostaglandins PGI2 or PGF2, all of which are putative KATP channel openers. 2. In anaesthetized rats, hindlimb contraction alone significantly attenuated the vasoconstrictor responses to lumbar sympathetic nerve stimulation. Inhibition of NO synthase with N-nitro-L-arginine methyl ester (L-NAME, 5 mg kg-1, i.v.) partially reversed this effect of contraction, resulting in enhanced sympathetic vasoconstriction in contracting hindlimb. Subsequent treatment with the KATP channel blocker glibenclamide (20 mg kg-1, i.v.) had no further effect on sympathetic vasoconstriction in contracting hindlimb. 3. This effect of L-NAME to partially reverse contraction-induced attenuation of sympathetic vasoconstriction was not replicated by D-NAME (5 mg kg-1, i.v.) or angiotensin II (12.5 ng kg-1 min-1, i.v.), the latter used as a hypertensive control. 4. Adenosine receptor blockade with 8-(p-sulphophenyl)theophylline (10 mg kg-1, i.v.) or cyclooxygenase inhibition with indomethacin (5 mg kg-1, i.v.) had no effect on contraction-induced attenuation of sympathetic vasoconstriction. 5. These results suggest that NO plays an important role in the precise regulation of blood flow in exercising skeletal muscles by opposing sympathetic vasoconstriction. Although the underlying mechanism is not known, it may involve NO-induced activation of vascular KATP channels.

Adenosine↗
PubMed1997

ATP-sensitive potassium channels mediate contraction-induced attenuation of sympathetic vasoconstriction in rat skeletal muscle.

Sympathetic vasoconstriction is sensitive to inhibition by metabolic events in contracting rat and human skeletal muscle, but the underlying cellular mechanisms are unknown. In rats, this inhibition involves mainly alpha2-adrenergic vasoconstriction, which relies heavily on Ca2+ influx through voltage-dependent Ca2+ channels. We therefore hypothesized that contraction-induced inhibition of sympathetic vasoconstriction is mediated by ATP-sensitive potassium (KATP) channels, a hyperpolarizing vasodilator mechanism that could be activated by some metabolic product(s) of skeletal muscle contraction. We tested this hypothesis in anesthetized rats by measuring femoral artery blood flow responses to lumbar sympathetic nerve stimulation or intraarterial hindlimb infusion of the specific alpha2-adrenergic agonist UK 14,304 during KATP channel activation with diazoxide in resting hindlimb and during KATP channel block with glibenclamide in contracting hindlimb. The major new findings are twofold. First, like muscle contraction, pharmacologic activation of KATP channels with diazoxide in resting hindlimb dose dependently attenuated the vasoconstrictor responses to either sympathetic nerve stimulation or intraarterial UK 14,304. Second, the large contraction-induced attenuation in sympathetic vasoconstriction elicited by nerve stimulation or UK 14,304 was partially reversed when the physiologic activation of KATP channels produced by muscle contraction was prevented with glibenclamide. We conclude that contraction-induced activation of KATP channels is a major mechanism underlying metabolic inhibition of sympathetic vasoconstriction in exercising skeletal muscle.

Adrenergic alpha-Agonists↗
PubMed1997

Differential modulation of cortical synaptic activity by calcineurin (phosphatase 2B) versus phosphatases 1 and 2A.

Reversible protein phosphorylation is thought to play an important regulatory role in synaptic neurotransmission. We recently have shown in cultured rat cortical neurons that inhibition of the Ca2+/calmodulin-dependent phosphatase calcineurin (phosphatase 2B) increases the frequency, but not the amplitude, of postsynaptic glutamatergic currents, implicating a presynaptic site of action for calcineurin. The specific presynaptic phosphoprotein substrates for calcineurin are unknown, however, calcineurin has been implicated in the control of the Ca2+-independent phosphatases, phosphatases 1 and 2A. To determine whether calcineurin's effects on synaptic transmission are direct or are mediated by changes in phosphatase 1 and/or 2A activities, we used whole-cell voltage clamp to record spontaneous and miniature excitatory postsynaptic currents in the presence of calyculin A (1 microM in bath solution), a membrane permeant inhibitor of phosphatases 1 and 2A which has no effect on calcineurin. Calyculin increased postsynaptic current amplitude without changing current frequency. In these same neurons, subsequent inhibition of calcineurin with cyclosporine A or FK506 had no further effect on current amplitude, but increased current frequency. The increased current amplitude seen with calyculin involved a postsynaptic mechanism, since the effect was reproduced by microcystin (10 microM in pipette solution), which is a membrane-impermeant inhibitor of phosphatases 1 and 2A. Thus, in rat cortical neurons, glutamatergic neurotransmission appears to be frequency-modulated through a presynaptic mechanism by calcineurin, and amplitude-modulated through a postsynaptic mechanism by phosphatases 1 and 2A.

Amino Acid Sequence↗
PubMed1997

Calculating economic injury levels for stable flies (Diptera:Muscidae) on feeder heifers.

A procedure for calculating the economic injury levels for stable flies, Stomoxys calcitrans (L.), on feeder heifers was developed from reduction of average daily weight gain-stable fly population level data in 8 independent replicated experiments over 17 yr. A negative exponential was fitted to the data using nonlinear regression. Regression coefficients were then used to derive a simple predictive equation for calculating the economic injury level in relation to cost of controlling stable flies in the feedlot, and the market value of heifers. Examples for calculating the economic injury level under practical feedlot situations are presented. Also included are recommendations for a simple random sampling design for stable flies in feedlots.

Animal Husbandry↗
PubMed1997

Susceptibility of stable flies (Diptera:Muscidae) from southeastern Nebraska beef cattle feedlots to selected insecticides and comparison of 3 bioassay techniques.

Insecticide susceptibility of field populations of stable flies, Stomoxys calcitrans (L.), was assayed using 3 exposure techniques: treated filter papers, treated glass petri dishes, and topical applications. Both topical applications and residual exposure to treated glass surfaces were suitable for testing susceptibility of stable flies to permethrin, stirofos, or methoxychlor. Residues on filter papers yielded inconsistent results with stirofos and methoxychlor. Significant concentration-mortality regression lines were generated with permethrin residues on filter papers, but approximately 1,000 times more insecticide was required to produce a toxic response when compared with permethrin residues on glass. Because of higher variability in response and the greater amount of insecticide required, residues on filter papers do not appear appropriate to test insecticide susceptibility in stable flies. Paired comparisons of field (F) and susceptible (S) stable flies resulted in field to susceptible ratios significantly > 1.0 only when the flies were treated topically, which suggests that topical application is more sensitive than residues on glass for the insecticides tested. Topical treatment with permethrin resulted in one FS(LD90) of 1.8-fold. Topical treatment with methoxychlor resulted in one FS(LD90) of 3.4-fold. However, the magnitude of these ratios is not larger than the significant differences observed within the susceptible laboratory colony from one generation to another. Intense exposure to insecticides is not known to have occurred in these field populations, indicating that the observed differences are the result of natural variation among stable fly populations and unrelated to prior selection with insecticides.

Animals↗
PubMed1997

Oxidation of lactate and acetate in rat skeletal muscle: analysis by 13C-nuclear magnetic resonance spectroscopy.

The balance between carbohydrate and fatty acid utilization in skeletal muscle previously has been studied in vivo by using a variety of methods such as arteriovenous concentration differences and radioactive isotope tracer techniques. However, these methodologies provide only indirect estimates of substrate oxidation. We used 13C-nuclear magnetic resonance (NMR) spectroscopy and non-steady-state isotopomer analysis to directly quantify the relative oxidation of two competing exogenous substrates in rat skeletal muscles. We infused [1,2-13C]acetate and [3-13C]lactate intravenously in anesthetized rats during the final 30 min of 35 (n = 10) or 95 (n = 10) min of intense, unilateral, rhythmic hindlimb contractions. 13C-NMR spectroscopy and isotopomer analysis were performed on extracts of gastrocnemius and soleus muscles from both the contracting and contralateral resting hindlimbs. We found that 1) [13C]lactate and [13C]acetate were taken up and oxidized by both resting and contracting skeletal muscles; and 2) high-intensity muscle contractions altered the pattern of substrate utilization such that the relative oxidation of acetate decreased while that of lactate remained unchanged or increased. Based on these findings, we propose that 13C-NMR spectroscopy in combination with isotopomer analysis can be used to study the general dynamics of substrate competition between carbohydrates and fats in rat skeletal muscle.

Acetates↗
PubMed1996

Differential sympathetic neural control of oxygenation in resting and exercising human skeletal muscle.

Metabolic products of skeletal muscle contraction activate metaboreceptor muscle afferents that reflexively increase sympathetic nerve activity (SNA) targeted to both resting and exercising skeletal muscle. To determine effects of the increased sympathetic vasoconstrictor drive on muscle oxygenation, we measured changes in tissue oxygen stores and mitochondrial cytochrome a,a3 redox state in rhythmically contracting human forearm muscles with near infrared spectroscopy while simultaneously measuring muscle SNA with microelectrodes. The major new finding is that the ability of reflex-sympathetic activation to decrease muscle oxygenation is abolished when the muscle is exercised at an intensity > 10% of maximal voluntary contraction (MVC). During high intensity handgrip, (45% MVC), contraction-induced decreases in muscle oxygenation remained stable despite progressive metaboreceptor-mediated reflex increases in SNA. During mild to moderate handgrips (20-33% MVC) that do not evoke reflex-sympathetic activation, experimentally induced increases in muscle SNA had no effect on oxygenation in exercising muscles but produced robust decreases in oxygenation in resting muscles. The latter decreases were evident even during maximal metabolic vasodilation accompanying reactive hyperemia. We conclude that in humans sympathetic neural control of skeletal muscle oxygenation is sensitive to modulation by metabolic events in the contracting muscles. These events are different from those involved in either metaboreceptor muscle afferent activation or reactive hyperemia.

Adult↗
PubMed1996

Sympathetic neural mechanisms of cyclosporine-induced hypertension.

The immunosuppressant drug cyclosporine A (CsA) has emerged as an important new cause of hypertension in both organ transplant recipients and patients with autoimmune diseases. Despite the clinical importance of this hypertension, the underlying mechanisms have been enigmatic. This article presents a conceptual framework for understanding the pathophysiologic basis of CsA-induced hypertension and focuses on the hypothesis that a common molecular mechanism is involved in mediating the immunosuppressive and the hypertensive effects of CsA. This mechanism involves the binding of CsA to a newly discovered class of cytoplasmic receptors (termed "immunophilins") not only in T lymphocytes but also in the kidney, vascular smooth muscle, and central nervous system, which are the main target tissues mediating CsA-induced hypertension. Binding of CsA to its receptor leads to inhibition of calcineurin, the Ca2+/calmodulin-dependent protein phosphatase. Evidence is reviewed to support the hypothesis that calcineurin inhibition plays a pivotal role in mediating both CsA-induced immunosuppression and hypertension, the latter being produced at least in part by sympathetic neural activation. The elucidation of novel CsA-sensitive cellular signaling pathways has lead to the search for the ideal immunosuppressant drug, one which retains CsA's immunosuppressive efficacy but without its toxicity.

Amino Acid Isomerases↗
PubMed1996

The Yorkshire slide exchange external quality assessment (EQA) scheme.

A slide circulation scheme measuring cervical screening performance of individual cytologists in 15 laboratories in Yorkshire Regional Health Authority is described. The advantages and disadvantages are compared with the current National Proficiency Testing (NPT) scheme. The results indicate that a slide circulation scheme can be successfully used in cervical cytology external quality assessment (EQA). Levels of participation are better than those currently achieved by regional variations of the NPT scheme, and the use of laboratory consensus in the selection of scoring slides appears to be no less valid than the use of a pre-selected slide pool assembled by an expert panel. The volume of data accumulated in one round is considerably greater than that achieved by proficiency testing and the educational value is regarded as high. However, the scheme is very time consuming for participants and consequently expensive for laboratories. The lack of external supervision increases the risk of unfair practices within individual laboratories. Because of these problems, Yorkshire has now switched to an NPT scheme.

Cytodiagnosis↗
PubMed1996

Scheduled sanitation to reduce stable fly (Diptera: Muscidae) populations in beef cattle feedlots.

Sanitation has been long recommended as a means of reducing stable fly, Stomoxys calcitrans (L.), populations at cattle feedlots, but there is little published research to support this recommendation. In each of the 2 yr of this study, 4 feedlots received complete sanitation and 4 feedlots received no cleaning. The objective was to have the initial cleaning done before 1 June and then to reclean as needed every 2 wk thereafter. The feedlots that were cleaned had significantly fewer flies than the uncleaned feedlots, with 50.9% fewer stable flies during the 1st yr and 36.2% fewer flies in the 2nd yr. These reductions were realized even though initial cleaning was not done by 1 June in either year: bad weather delayed completion until 20 June the 1st yr and 29 June the 2nd yr. Sanitation at cattle feedlots significantly reduces stable fly populations and sanitation may have been more effective if initial cleaning was done by 1 June.

Animals↗
PubMed1996

Comparison of core sampling and pupal traps for monitoring immature stable flies and house flies (Diptera: Muscidae) in beef feedlot pens.

Core samples and cylindrical pupal traps were used to monitor immature stages of the stable fly, Stomoxys calcitrans (L.), and house fly, Musca domestica L., from 5 sample areas in beef feedlot pens: the feed apron-soil interface, the back fence, the side (pen dividing) fence, the mound, and the general lot. One feedlot was sampled during 1986, two feedlots were sampled in 1987, and three samples were taken at random from each sample area on each sample date. Core samples showed that both populations were highest from the feed apron sample area. Pupal traps tended to show the same result but differences between sample areas were not significant for immature stable flies. Both sampling methods generally indicated similar population trends of the 2 fly species over the season; correlation coefficients between the 2 sampling methods were generally significant but few correlations were strong and large divergences between population trends were present. Only approximately 69% of the total number of pupal traps placed were recovered; the loss of traps could have contributed to differences between the 2 sampling methods. Core sampling would be preferred if lower variance of samples is important; if collecting pupae of known age is important, then pupal traps may be useful if they are protected from trampling by cattle.

Animals↗
PubMed1995

Presynaptic modulation of cortical synaptic activity by calcineurin.

Synaptic plasticity is modulated by Ca(2+)-induced alterations in the balance between phosphorylation and dephosphorylation. Recent evidence suggests that calcineurin, the Ca(2+)-calmodulin-dependent phosphatase (2B), modulates the activity of postsynaptic glutamate receptors. However, in rat cortex, calcineurin is enriched mainly in presynaptic, not postsynaptic, fractions. To determine if calcineurin modulates glutamatergic neurotransmission through a presynaptic mechanism, we used whole-cell patch clamp experiments to test effects of two specific calcineurin inhibitors, cyclosporin A (CsA) and FK506, on synaptic activity in fetal rat cortical neurons. The rate of spontaneous action-potential firing was markedly increased by either CsA or FK506 but was unaffected by rapamycin, a structural analog of FK506 which has no effect on calcineurin. In voltage-clamp experiments, CsA increased the rate but not the amplitude of glutamate receptor-mediated, excitatory postsynaptic currents, suggesting an increased rate of glutamate release. CsA had no effect on the amplitude of currents evoked by brief bath application of selective glutamate receptor agonists, providing further evidence for a pre- rather than postsynaptic site of action. In conclusion, these data indicate that calcineurin modulates glutamatergic neurotransmission in rat cortical neurons through a presynaptic mechanism.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1994

Overwintering of the stable fly (Diptera: Muscidae) in southeastern Nebraska.

Adult stable flies, Stomoxys calcitrans (L.), were monitored during three winters at two, four, and 13 locations with Alsynite fiberglass traps and by examination of the interiors of buildings. No stable flies were found inside buildings during the winter. Adult stable flies were consistently caught on Alsynite traps at one location during two winters and at two other locations during one winter. Distribution and physiological age of these flies indicate that they emerged from pupae that had developed at or near the location where they were captured. Potential breeding sites were examined. A few third instars were found in silage in midwinter, but silage should not be considered a major source for overwintering stable flies.

Animals↗