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Biomedical subjects

G Edwards

Publications and source records attributed to G Edwards.

At least 37 records · Page 2Linked to original sources
PubMed2002

Characterization of an apamin-sensitive small-conductance Ca(2+)-activated K(+) channel in porcine coronary artery endothelium: relevance to EDHF.

1. The apamin-sensitive small-conductance Ca(2+)-activated K(+) channel (SK(Ca)) was characterized in porcine coronary arteries. 2. In intact arteries, 100 nM substance P and 600 microM 1-ethyl-2-benzimidazolinone (1-EBIO) produced endothelial cell hyperpolarizations (27.8 +/- 0.8 mV and 24.1 +/- 1.0 mV, respectively). Charybdotoxin (100 nM) abolished the 1-EBIO response but substance P continued to induce a hyperpolarization (25.8 +/- 0.3 mV). 3. In freshly-isolated endothelial cells, outside-out patch recordings revealed a unitary K(+) conductance of 6.8 +/- 0.04 pS. The open-probability was increased by Ca(2+) and reduced by apamin (100 nM). Substance P activated an outward current under whole-cell perforated-patch conditions and a component of this current (38%) was inhibited by apamin. A second conductance of 2.7 +/- 0.03 pS inhibited by d-tubocurarine was observed infrequently. 4. Messenger RNA encoding the SK2 and SK3, but not the SK1, subunits of SK(Ca) was detected by RT - PCR in samples of endothelium. Western blotting indicated that SK3 protein was abundant in samples of endothelium compared to whole arteries. SK2 protein was present in whole artery nuclear fractions. 5. Immunofluorescent labelling confirmed that SK3 was highly expressed at the plasmalemma of endothelial cells and was not expressed in smooth muscle. SK2 was restricted to the peri-nuclear regions of both endothelial and smooth muscle cells. 6. In conclusion, the porcine coronary artery endothelium expresses an apamin-sensitive SK(Ca) containing the SK3 subunit. These channels are likely to confer all or part of the apamin-sensitive component of the endothelium-derived hyperpolarizing factor (EDHF) response.

Amino Acid Sequence↗
PubMed2002

K+-induced hyperpolarization in rat mesenteric artery: identification, localization and role of Na+/K+-ATPases.

1. Mechanisms underlying K(+)-induced hyperpolarizations in the presence and absence of phenylephrine were investigated in endothelium-denuded rat mesenteric arteries (for all mean values, n=4). 2. Myocyte resting membrane potential (m.p.) was -58.8+/-0.8 mV. Application of 5 mM KCl produced similar hyperpolarizations in the absence (17.6+/-0.7 mV) or presence (15.8+/-1.0 mV) of 500 nM ouabain. In the presence of ouabain +30 microM barium, hyperpolarization to 5 mM KCl was essentially abolished. 3. In the presence of 10 microM phenylephrine (m.p. -33.7+/-3 mV), repolarization to 5 mM KCl did not occur in the presence or absence of 4-aminopyridine but was restored (-26.9+/-1.8 mV) on addition of iberiotoxin (100 nM). Under these conditions the K+-induced repolarization was insensitive to barium (30 microM) but abolished by 500 nM ouabain alone. 4. In the presence of phenylephrine + iberiotoxin the hyperpolarization to 5 mM K(+) was inhibited in the additional presence of 300 nM levcromakalim, an action which was reversed by 10 microM glibenclamide. 5. RT-PCR, Western blotting and immunohistochemical techniques collectively showed the presence of alpha(1)-, alpha(2)- and alpha(3)-subunits of Na(+)/K(+)-ATPase in the myocytes. 6. In K(+)-free solution, re-introduction of K(+) (to 4.6 mM) hyperpolarized myocytes by 20.9+/-0.5 mV, an effect unchanged by 500 nM ouabain but abolished by 500 microM ouabain. 7. We conclude that under basal conditions, Na(+)/K(+)-ATPases containing alpha(2)- and/or alpha(3)-subunits are partially responsible for the observed K(+)-induced effects. The opening of myocyte K(+) channels (by levcromakalim or phenylephrine) creates a 'K(+) cloud' around the cells which fully activates Na(+)/K(+)-ATPase and thereby abolishes further responses to [K(+)](o) elevation.

Animals↗
PubMed2002

Pharmacokinetics and anticonvulsant effects of diazepam in children with severe falciparum malaria and convulsions.

AIMS: Convulsions are a common complication of severe malaria in children and are associated with poor outcome. Diazepam is used to terminate convulsions but its pharmacokinetics and pharmacodynamics have not been studied in this group. Accordingly, we carried out a comparative study of the pharmacokinetics of intravenous (i.v.) and rectal (p.r.) diazepam. METHODS: Twenty-five children with severe malaria and a convulsion lasting >5 min were studied. Sixteen children received diazepam intravenously (i.v.; 0.3 mg kg(-1)) and nine rectally (p.r.; 0.5 mg kg(-1)). Plasma diazepam concentrations were measured by reversed phase high-performance liquid chromatography. The duration of convulsions, depth of coma, respiratory and cardiovascular parameters were monitored. RESULTS: Median maximum plasma diazepam concentrations of 634 (range 402-1507) ng ml(-1) and 423 (range 112-1953) ng ml(-1) were achieved at 5 and 25 min following i.v. and p.r. administration, respectively. All patients except three (one i.v. and two p.r.) achieved plasma diazepam concentration >200 ng ml(-1) within 5 min. Following p.r. administration, plasma diazepam concentrations were more variable than i.v. administration. A single dose of i.v. diazepam terminated convulsions in all children but in only 6/9 after p.r. administration. However, nine children treated with i.v. and all those treated with p.r. diazepam had a recurrence of convulsions occurring at median plasma diazepam concentrations of 157 (range: 67-169) and 172 (range: 74-393) ng ml(-1) , respectively. All the children in the i.v. and four in the PR diazepam group who had recurrence of convulsions required treatment. None of the children developed respiratory depression or hypotension. CONCLUSIONS: Administration of diazepam i.v. or p.r. resulted in achievement of therapeutic concentrations of diazepam rapidly, without significant cardio-respiratory adverse effects. However, following p.r. administration, diazepam did not terminate all convulsions and plasma drug concentrations were more variable.

Administration, Rectal↗
PubMed2002

The use of porcine dermal implant in a minimally invasive pubovaginal sling procedure for genuine stress incontinence.

OBJECTIVE: To assess the outcome of a suburethral sling using a porcine dermal implant (Pelvicoltrade mark, Bard Urology, UK) in the surgical management of urinary stress incontinence. PATIENTS AND METHODS: Forty women with urodynamically confirmed genuine stress incontinence were recruited into the study and followed up at 6 weeks and at least 6 months (mean 12 months, range 6-18). The sling was inserted using a minimal-access technique, which allowed 23 women to be operated as day-cases. Outcome measures included continence rates, voiding dysfunction, satisfaction scores and whether the patients would recommend the operation to a friend or relative. RESULTS: The cure rate was 85%, with sustained benefit; a further 10% of the women were improved by surgery. Voiding dysfunction rates were low and satisfaction scores high. Most women would undergo the procedure again if they became incontinent in the future and would recommend the procedure to a friend or relative. CONCLUSION: A minimal access pubovaginal sling using Pelvicoltrade mark is effective in treating stress incontinence. The complication rate is low and the procedure can be performed as a day-case with no loss of efficacy.

Adult↗
PubMed2001

Differential effects of prostacyclin and iloprost in the isolated carotid artery of the guinea-pig.

The effects on membrane potential of prostacyclin and iloprost were compared in smooth muscle cells of the guinea pig carotid artery. Both prostacyclin and iloprost induced hyperpolarization of the smooth muscle cells. In the presence of (3R)-3-(4-fluorophenyl-sulfonamido)-1,2,3,4-tetrahydro-9-carbazolepropanoic acid (Bay U3405), an antagonist of TP receptors, the response to iloprost was unaffected while that to prostacyclin was increased. Iloprost-induced hyperpolarizations were abolished by glibenclamide while those to prostacyclin were either not affected, or converted to either depolarization or to rhythmic electrical activity. The latter effects of prostacyclin were abolished by Bay U3405. After removal of the endothelium, iloprost and prostacyclin produced hyperpolarizations similar to those observed in control blood vessels. However, in the presence of glibenclamide, prostacyclin produced only depolarizations inhibited by Bay U3405. These results suggest that iloprost activates IP receptors and K(ATP) channels in smooth muscle. In contrast, prostacyclin produces additional endothelium-dependent and -independent effects via activation of TP receptors.

Animals↗
PubMed2001

Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2.

IL-1 is of utmost importance in the host response to immunological challenges. We identified and functionally characterized two novel IL-1 ligands termed IL-1delta and IL-1epsilon. Northern blot analyses show that these IL-1s are highly abundant in embryonic tissue and tissues containing epithelial cells (i.e., skin, lung, and stomach). In extension, quantitative real-time PCR revealed that of human skin-derived cells, only keratinocytes but not fibroblasts, endothelial cells, or melanocytes express IL-1delta and epsilon. Levels of keratinocyte IL-1delta are approximately 10-fold higher than those of IL-1epsilon. In vitro stimulation of keratinocytes with IL-1beta/TNF-alpha significantly up-regulates the expression of IL-1epsilon mRNA, and to a lesser extent of IL-1delta mRNA. In NF-kappaB-luciferase reporter assays, we demonstrated that IL-1delta and epsilon proteins do not initiate a functional response via classical IL-1R pairs, which confer responsiveness to IL-1alpha and beta or IL-18. However, IL-1epsilon activates NF-kappaB through the orphan IL-1R-related protein 2 (IL-1Rrp2), whereas IL-1delta, which shows striking homology to IL-1 receptor antagonist, specifically and potently inhibits this IL-1epsilon response. In lesional psoriasis skin, characterized by chronic cutaneous inflammation, the mRNA expression of both IL-1 ligands as well as IL-1Rrp2 are increased relative to normal healthy skin. In total, IL-1delta and epsilon and IL-1Rrp2 may constitute an independent signaling system, analogous to IL-1alphabeta/receptor agonist and IL-1R1, that is present in epithelial barriers of our body and takes part in local inflammatory responses.

Amino Acid Sequence↗
PubMed2001

The role of glutathione in the neurotoxicity of artemisinin derivatives in vitro.

The role of antioxidants in the neurotoxicity of the antimalarial endoperoxides artemether and dihydroartemisinin was studied in vitro by quantitative image analysis of neurite outgrowth in the neuroblastoma cell line NB2a. Intracellular glutathione concentrations were measured by high performance liquid chromatography with fluorescence detection. Both dihydroartemisinin (1 microM) and a combination of artemether (0.3 microM) plus haemin (2 microM) significantly inhibited neurite outgrowth from differentiating NB2a cells to 11.5 +/- 11.0% (SD) and 19.6 +/- 15.2% of controls, respectively. The inhibition by artemether/haemin was prevented by the antioxidants superoxide dismutase (109.7 +/- 47.8% of control), catalase (107.0 +/- 29.3%) glutathione (123.8 +/- 12.4%), L-cysteine (88.0 +/- 6.3%), N-acetyl-L-cysteine (107.8 +/- 14.9%), and ascorbic acid (104.3 +/- 12.7%). Dihydroartemisinin-induced neurotoxicity was completely or partially prevented by L-cysteine (99.5 +/- 17.7% of control), glutathione (57.9 +/- 23.4% of control), and N-acetyl-L-cysteine (57.3 +/- 9.5%), but was not prevented by superoxide dismutase, catalase, or ascorbic acid. Buthionine sulphoximine, an inhibitor of gamma-glutamylcysteine synthetase, significantly increased the neurotoxic effect of non-toxic concentrations of artemether/haemin (0.1 microM/2 microM) and dihydroartemisinin (0.2 microM), suggesting that endogenous glutathione participates in the prevention of the neurotoxicity of artemether/haemin and dihydroartemisinin. Artemether/haemin completely depleted intracellular glutathione levels, whereas dihydroartemisinin had no effect. We conclude that although glutathione status is an important determinant in the neurotoxicity of endoperoxides, depletion of glutathione is not a prerequisite for their toxicity. This is consistent with their mechanisms of toxicity being free radical-mediated damage to redox-sensitive proteins essential for neurite outgrowth, or alteration of a redox-sensitive signalling system which regulates neurite outgrowth.

Animals↗
PubMed2001

Measurement of bladder volume following cesarean section using bladderscan.

Urinary dysfunction is common following delivery, especially after cesarean section. A large number of women may undergo catheterization to ascertain whether they are in retention, as ultrasound is not always available. The bladder volume in 50 women was estimated using a Bladderscan and compared to that measured by urethral catheterization. A close correlation was found (r = 0.807: P = 0.610). These results have resulted in the Bladderscan being used as an alternative to intermittent catheterization as a test of bladder overdistension following cesarean section in our unit.

Adolescent↗
PubMed2001

Executive functioning, temporal discounting, and sense of time in adolescents with attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD).

Clinic-referred teens (ages 12-19) with ADHD and ODD (N = 101) were compared to community control (CC) teens, equated for age and sex, (N = 39) on a variety of psychological tasks assessing executive functioning (EF), temporal reward discounting, and time estimation and reproduction. A factor analysis reduced the EF measures to three dimensions, representing CPF Inattention, Working Memory, and CPT Inhibition. Results indicated that the ADHD group had significantly more CPT Inattention than the CC group. No differences were found for Working Memory or CPT Inhibition. The ADHD group displayed significantly greater temporal discounting of delayed hypothetical monetary rewards relative to immediate ones and manifested more impaired time reproduction, but not time estimation, than did the CC group. Main effects for level of IQ were found only on the Working Memory factor and largely did not interact with the group factor otherwise. The group differences in CPT Inattention, temporal discounting, and time reproduction were not a function of level of comorbid oppositional defiant disorder, delinquency, or anxiety-depression. Results are reasonably consistent with past research on EF and sense of time in children with ADHD and extend these findings to the adolescent age group. Problems with working memory and CPT inhibition found in prior studies of children with ADHD, however, were not evident here, perhaps owing to age-related improvements or insufficient task difficulty.

Adolescent↗
PubMed2001

Parent-adolescent conflict in teenagers with ADHD and ODD.

Eighty-seven male teens (ages 12-18 years) with ADHD/ODD and their parents were compared to 32 male teens and their parents in a community control (CC) group on mother, father, and teen ratings of parent-teen conflict and communication quality, parental self-reports of psychological adjustment, and direct observations of parent-teen problem-solving interactions during a neutral and conflict discussion. Parents and teens in the ADHD/ODD group rated themselves as having significantly more issues involving parent-teen conflict, more anger during these conflict discussions, and more negative communication generally, and used more aggressive conflict tactics with each other than did parents and teens in the CC group. During a neutral discussion, only the ADHD/ODD teens demonstrated more negative behavior. During the conflict discussion, however, the mothers, fathers, and teens in the ADHD/ODD group displayed more negative behavior, and the mothers and teens showed less positive behavior than did participants in the CC group. Differences in conflicts related to sex of parent were evident on only a few measures. Both mother and father self-rated hostility contributed to the level of mother-teen conflict whereas father self-rated hostility and anxiety contributed to father-teen conflict beyond the contribution made by level of teen ODD and ADHD symptoms. Results replicated past studies of mother-child interactions in ADHD/ODD children, extended these results to teens with these disorders, showed that greater conflict also occurs in father-teen interactions, and found that degree of parental hostility, but not ADHD symptoms, further contributed to levels of parent-teen conflict beyond the contribution made by severity of teen ADHD and ODD symptoms.

Adolescent↗
PubMed2001

Potentiation of halofantrine-induced QTc prolongation by mefloquine: correlation with blood concentrations of halofantrine.

1. The antimalarial drug halofantrine can prolong the QT interval and this may be enhanced by prior use of mefloquine. This possible interaction has been investigated by examining the effects of halofantrine and mefloquine alone and in combination. 2. In anaesthetized rabbits (n=6 per group), halofantrine given as bolus doses of 1, 3, 10, and 30 mg kg(-1) at 25 min intervals dose-dependently prolonged the rate-corrected QT (QTc) interval from 313+/-12 ms pre-drug to 410+/-18 ms after the highest dose. Similar doses of mefloquine did not alter QTc intervals significantly. The highest dose of mefloquine (30 mg kg(-1)) caused cardiac contractile failure. 3. Pretreatment with 3 mg kg(-1) mefloquine 25 min before the first dose of halofantrine potentiated the effects of all doses of halofantrine on QTc intervals. 4. The blood concentrations of halofantrine were two to six times higher in the group pretreated with mefloquine compared to the halofantrine alone group; e.g. 1.03+/-0.17 and 0.16+/-0.02 microM respectively after 1 mg kg(-1) halofantrine. There was a significant correlation between blood halofantrine concentrations and QTc intervals (r=0.673). Even after making allowance for overestimation of the potency of halofantrine that may result from the hypokalaemia that is prevalent in anaesthetized rabbits, these effects occurred with concentrations of halofantrine that are found in clinical use. 5. These data indicate clearly that while mefloquine does not alter QTc intervals itself, it does enhance the effects of halofantrine by increasing the circulating concentration of halofantrine.

Action Potentials↗
PubMed2001

Further investigations into the endothelium-dependent hyperpolarizing effects of bradykinin and substance P in porcine coronary artery.

In porcine coronary arteries, smooth muscle hyperpolarizations produced by the nitric oxide donor, NOR-1, and the prostacyclin analogue, iloprost, were compared with those induced by substance P and bradykinin and attributed to the endothelium-derived hyperpolarizing factor (EDHF). In the presence of 300 microM L-nitroarginine and 10 microM indomethacin, iloprost-induced hyperpolarizations were partially inhibited by 10 microM glibenclamide whereas those to NOR-1, substance P and bradykinin were unaffected. Hyperpolarizations produced by maximally-effective concentrations of NOR-1 and NS1619 were identical (to -65 mV). They were significantly less than those generated by either substance P or bradykinin (to approximately -80 mV) and were abolished by iberiotoxin 100 nM, a concentration which had essentially no effect on responses to substance P or bradykinin. Incubation of segments of intact arteries for 16 - 22 h in bicarbonate-buffered Krebs solution had little effect on EDHF responses to substance P or bradykinin. In contrast, after incubation for this period of time in HEPES-buffered Tyrode solution or Krebs containing 10 mM HEPES the EDHF response to substance P was abolished and that to bradykinin was markedly reduced. The residual bradykinin-induced hyperpolarization following incubation in Tyrode solution was inhibited by iberiotoxin and by 10 microM 17-octadecynoic acid. We conclude that substance P activates only the EDHF pathway in the presence of nitric oxide synthase and cyclo-oxygenase inhibitors. Incubation in HEPES-buffered Tyrode solution abolishes the EDHF responses to substance P and bradykinin to reveal an additional hyperpolarizing mechanism, associated with the opening of K(+) channels, activated only by bradykinin.

Animals↗
PubMed2001

Suppression of K(+)-induced hyperpolarization by phenylephrine in rat mesenteric artery: relevance to studies of endothelium-derived hyperpolarizing factor.

In intact mesenteric arteries, increasing [K(+)]o by 5 mM hyperpolarized both endothelial and smooth muscle cells. Subsequent exposure to 10 microM phenylephrine depolarized both cell types which were then repolarized by a 5 mM increase in [K(+)]o. In endothelium-denuded vessels, increasing [K(+)]o by 5 mM hyperpolarized the smooth muscle but K(+) had no effect after depolarization by 10 microM phenylephrine. On subsequent exposure to iberiotoxin plus 4-aminopyridine, the repolarizing action of 5 mM K(+) was restored. In endothelium-intact vessels exposed to phenylephrine, pretreatment with a gap junction inhibitor (gap 27) reduced K(+)-mediated smooth muscle repolarization without affecting the endothelial cell response. It is concluded that phenylephrine-induced efflux of K(+) via smooth muscle K(+) channels produces a local increase in [K(+)]o which impairs repolarization to added K(+). Thus, studies involving vessels precontracted with agonists which increase [K(+)]o maximize the role of gap junctions and minimize any contribution to the EDHF pathway from endothelium-derived K(+).

4-Aminopyridine↗