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Biomedical subjects

C D Foster

Publications and source records attributed to C D Foster.

18 recordsLinked to original sources
PubMed1998

Defective potassium currents in ataxia telangiectasia fibroblasts.

Similarities exist between the progressive cerebellar ataxia in ataxia telangiectasia (AT) patients and a number of neurodegenerative diseases in both mouse and man involving specific mutations in ion channels and/or ion channel activity. These relationships led us to investigate the possibility of defective ion channel activity in AT cells. We examined changes in the membrane potential of AT fibroblasts in response to extracellular cation addition and found that the ability of AT fibroblasts to depolarize in response to increasing concentrations of extracellular K+ is significantly reduced when compared with control fibroblasts. Electrophysiological measurements performed with a number of AT cell lines, as well as two matched sets of primary AT fibroblast cultures, reveal that outward rectifier K+ currents are largely absent in AT fibroblasts in comparison with control cells. These K+ current defects can be corrected in AT fibroblasts transfected with the full-length ATM cDNA. These data implicate, for the first time, a role for ATM in the regulation of K+ channel activity and membrane potential.

Ataxia Telangiectasia↗
PubMed1996

Cloning, expression, and distribution of a Ca(2+)-activated K+ channel beta-subunit from human brain.

We have cloned and expressed a Ca(2+)-activated K+ channel beta-subunit from human brain. The open reading frame encodes a 191-amino acid protein possessing significant homology to a previously described subunit cloned from bovine muscle. The gene for this subunit is located on chromosome 5 at band q34 (hslo-beta). There is no evidence for alternative RNA splicing of this gene product. hslo-beta mRNA is abundantly expressed in smooth muscle, but expression levels are low in most other tissues, including brain. Brain subregions in which beta-subunit mRNA expression is relatively high are the hippocampus and corpus callosum. The coexpression of hslo-beta mRNA together with hslo-alpha subunits in either Xenopus oocytes or stably transfected HEK 293 cells give rise to Ca(2+)-activated potassium currents with a much increased calcium and/or voltage sensitivity. These data indicate that the beta-subunit shows a tissue distribution different to that of the alpha-subunit, and in many tissues there may be no association of alpha-subunits with beta-subunits. These beta-subunits can play a functional role in the regulation of neuronal excitability by tuning the Ca2+ and/or the voltage dependence of alpha-subunits.

Amino Acid Sequence↗
PubMed1996

Xenopus laevis oocytes contain endogenous large conductance Ca2(+)-activated K+ channels.

Xenopus laevis oocytes have become a pre-eminent tool for studying cloned ion channels, primarily because they intrinsically express low levels of most types of ion channels. However, when these cells are used for single channel studies, it is essential to determine whether or not oocytes contain even low levels of endogenous ion channels with properties similar to the channel being investigated. We show here that X. laevis oocytes express endogenous large-conductance Ca2(+)-activated K+ channels with properties similar to mammalian isoforms of this channel. The endogenous channels exhibit a voltage-dependence of 12-14 mV per e-fold change in open probability (po), can be activated by micromolar Ca2+ concentrations, and have a single channel conductance of approximately 200 pS in symmetrical 110 mM K+ solutions. Patch clamp experiments indicate that this endogenous channel is present at low densities (approximately 1 channel/3000 microns2). If endogenous channel subunits can form functional tetramers with other exogenous potassium channel subunits, then they will give rise to the expression of a heterogeneous channel population. Therefore, studies involving the heterologous expression of large-conductance Ca2(+)-activated K+ channels in Xenopus laevis oocytes require careful analysis and interpretation.

Animals↗
PubMed1995

Planning nursing education for the 21st century.

In looking towards the 21st century, the faculty at the Presbyterian Hospital School of Nursing, along with the Presbyterian Health Services Corporation and Queen's College, adopted a 1-2-1 programme. The process of developing a new nursing curriculum is presented as the task force proceeded from the philosophy and goals to conceptual framework and curriculum objectives. After discussions with nurse administrators and educators, extensive literature reviews and brainstorming sessions, concepts and subconcepts were chosen to form a philosophy. The metaparadigm of nursing and other related concepts were then organized into a conceptual framework. Ongoing communication and feedback from the faculty ensured group ownership of all documents. The eclectic organizational scheme was a good fit for a large faculty with differing beliefs and values about a nursing curriculum. The process of developing a future orientated nursing curriculum has been exciting, challenging and rewarding. The faculty is committed to the new philosophy, goals and conceptual framework and believe that the 1-2-1 programme will educate future practitioners who are prepared to meet the challenges and changes in health care for the 21st century.

Curriculum↗
PubMed1994

Cloned Ca(2+)-dependent K+ channel modulated by a functionally associated protein kinase.

Calcium-dependent potassium (KCa) channels carry ionic currents that regulate important cellular functions. Like some other ion channels, KCa channels are modulated by protein phosphorylation. The recent cloning of complementary DNAs encoding Slo KCa channels has enabled KCa channel modulation to be investigated. We report here that protein phosphorylation modulates the activity of Drosophila Slo KCa channels expressed in Xenopus oocytes. Application of ATP-gamma S to detached membrane patches increases Slo channel activity by shifting channel voltage sensitivity. This modulation is blocked by a specific inhibitor of cyclic AMP-dependent protein kinase (PKA). Mutation of a single serine residue in the channel protein also blocks modulation by ATP-gamma S, demonstrating that phosphorylation of the Slo channel protein itself modulates channel activity. The results also indicate that KCa channels in oocyte membrane patches can be modulated by an endogenous PKA-like protein kinase which remains functionally associated with the channels in the detached patch.

Adenosine Triphosphate↗
PubMed1994

Cloning, expression, and distribution of functionally distinct Ca(2+)-activated K+ channel isoforms from human brain.

We have cloned and expressed nine Ca(2+)-activated K+ channel isoforms from human brain. The open reading frames encode proteins ranging from 1154 to 1195 amino acids, and all possess significant identity with the slowpoke gene products in Drosophila and mouse. All isoforms are generated by alternative RNA splicing of a single gene on chromosome 10 at band q22.3 (hslo). RNA splicing occurs at four sites located in the carboxy-terminal portion of the protein and gives rise to at least nine ion channel constructs (hbr1-hbr9). hslo mRNA is expressed abundantly in human brain, and individual isoforms show unique expression patterns. Expression of hslo mRNA in Xenopus oocytes produces robust voltage and Ca(2+)-activated K+ currents. Splice variants differ significantly in their Ca2+ sensitivity, suggesting a broad functional role for these channels in the regulation of neuronal excitability.

Alternative Splicing↗
PubMed1993

Regulation of Na+/H+ exchange in mesenteric arteries from spontaneously hypertensive rats.

The kinetic properties of Na+/H+ exchange are significantly different in segments of mesenteric arteries from spontaneously hypertensive rats (SHR) as compared to normotensive Wistar-Kyoto (WKY) rats. Both the maximal rate of Na+/H+ exchange and the sensitivity of Na+/H+ exchange to intracellular [H+] are greater in vessels from hypertensive animals. Prehypertensive SHR do not exhibit these features, thus the present studies examined the role of blood pressure in mediating the response. Both SHR and WKY rats were treated with captopril for 4 weeks, after which the characteristics of the Na+/H+ exchanger were examined. The Na+/H+ exchange was monitored in tissue segments by measuring Nao-dependent, dimethyl amiloride-sensitive recovery of intracellular pH after acid loading (pHi determined using the pH-sensitive fluorescent dye 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein). In SHR, captopril reduced mean arterial pressure from 153 to 118 mm Hg and altered Na+/H+ exchange. Maximal transport rate decreased from 0.164 to 0.056 mmol/L H+/sec and the sensitivity of the Na+/H+ exchange to internal H+ decreased (ie, the Hill coefficient decreased from 6.6 to 2.2). In WKY rats captopril reduced blood pressure from 108 to 71 mm Hg, but had no effect on the Na+/H+ exchange. Since reduced pressure affected Na+/H+ exchange in SHR, but not in WKY, it is likely that the Na+/H+ exchanger, or the cellular processes regulating its properties, differ in the two rat strains. Supporting this notion was the finding that ouabain treatment reduced the Hill coefficient of SHR vessels but had no effect in WKY vessels.

Animals↗
PubMed1992

A peptide derived from the Shaker B K+ channel produces short and long blocks of reconstituted Ca(2+)-dependent K+ channels.

A 20 amino acid synthetic peptide, corresponding to the amino-terminal region of the Shaker B (ShB) K+ channel and responsible for its fast inactivation, can block large conductance Ca(2+)-dependent K+ channels from rat brain and muscle. The ShB inactivation peptide produces two kinetically distinct blocking events in these channels. At lower concentrations, it produces short blocks, and at higher concentrations long-lived blocks also appear. The L7E mutant peptide produces only infrequent short blocks (no long-lived blocks) at a much higher concentration. Internal tetraethylammonium competes with the peptide for the short block, which is also relieved by K+ influx. These results suggest that the peptide induces the short block by binding within the pore of Ca(2+)-dependent K+ channels. The long block is not affected by increased K+ influx, indicating that the binding site mediating this block may be different from that involved in the short block. The short block of Ca(2+)-dependent K+ channels and the inactivation of Shaker exhibit similar characteristics with respect to blocking affinity and open pore blockade. This suggests a conserved binding region for the peptide in the pore regions of these very different classes of K+ channel.

Animals↗
PubMed1992

Characterization of Na(+)-H+ exchange in segments of rat mesenteric artery.

To develop a technique for measuring Na(+)-H+ exchange activity and intracellular pH (pH(i)) "on line" in resistance vessels, we utilized strips of rat mesenteric arteries loaded with the pH-sensitive dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. Strips were held at a fixed length within a 3-ml cuvette, and fluorescence emission was monitored at 530 nm. The spectrofluorimeter was monitored in the ratio mode, and the excitation wavelength was alternated between 440 and 505 nm. Tissues were maintained by perfusing with N-2-hydroxyethylpiperazine-N'-2-ethane-sulfonic acid containing buffers. The introduction of ammonium chloride produced a rapid alkalinization. Washout of ammonium caused rapid acidification. Restoration of pH(i) was Na+ dependent and inhibited by dimethyl amiloride (concentration that produces half-maximal inhibition, K0.5 = 30 microM), features characteristic of Na(+)-H+ exchange. Further studies assessed the transport rate of the exchanger, which averaged 0.19 +/- 0.02 pH U/min (means +/- SE, n = 8). An estimate of the dependence of Na(+)-H+ exchange on external Na+ gave an apparent Michaelis constant for external Na+ of 10 mM and an apparent maximal velocity of 0.1 mM H+/s. Intracellular H+ was found to have a cooperative effect (Hill coefficient = 4) on Na(+)-H+ exchange.

Ammonium Chloride↗
PubMed1992

Alterations in Na(+)-H+ exchange in mesenteric arteries from spontaneously hypertensive rats.

Na(+)-H+ exchange was examined in segments of the superior mesenteric artery from spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats using the pH-sensitive dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF). Basal pH values were identical in the two strains (SHR = 7.18 +/- 0.02, WKY = 7.15 +/- 0.01) and exposure to 20-50 mM NH4Cl produced comparable changes in pH in both strains (tissues acidified to pH 6.8). The recovery of intracellular pH (pH(i)) from acid loading in bicarbonate-free buffer was dependent on extracellular Na+, inhibited by dimethyl amiloride, and thus was presumably mediated by Na(+)-H+ exchange. Exchange activity was markedly increased in SHR (0.308 vs. 0.182 pH U/min), and the increased activity could not be explained by differences in intracellular buffer capacity or in the Na+ affinity of the transporter. The rate of Na(+)-H+ exchange was more steeply dependent on pH(i) in SHR vessels Hill coefficient = 6.6 in SHR vs. 4.1 in WKY), suggesting an alteration in the transport protein. Young SHR (4-6 wk) exhibited kinetic characteristics resembling those of 12- to 14-wk-old WKY rats. Exposure to the Ca2+ ionophore bromo-A23187 significantly increased the Hill coefficient of WKY arteries but had no effect on vessels from SHR. Exposure of vessels from either strain to the phorbol ester phorbol 12-myristate 13 acetate (PMA) had no effect on Na(+)-H+ exchange.

Amiloride↗
PubMed1990

Potassium channel blockers and the effects of cromakalim on the smooth muscle of the guinea-pig bladder.

1. The K+ channel blocking drugs tetraethylammonium Cl (TEA), procaine, 4-aminopyridine (4AP) and quinidine all produced concentration-dependent contractions of strips of smooth muscle from the guinea-pig urinary bladder. Apamin and glibenclamide caused little increase in the mechanical activity, and tolbutamide inhibited it. 2. TEA, procaine, 4AP, quinidine and apamin all increased the frequencies of spontaneous action potentials recorded with microelectrodes. TEA, quinidine and procaine all caused prolongation of the falling phase of the spike, and procaine and apamin completely abolished the after-hyperpolarization. 3. TEA and procaine increased K+ efflux from the tissue, an effect blocked by nifedipine. TEA and apamin increased, whereas quinidine, procaine and 4AP decreased K+ uptake. 4. Cromakalim caused a concentration-dependent hyperpolarization of the membrane, abolished spike activity, increased K+ fluxes and relaxed the smooth muscle. The relaxant effect of cromakalim was unaffected by apamin, and in its presence the effects of cromakalim on membrane potential and K+ fluxes were unchanged. Procaine abolished all the effects of cromakalim, and TEA at high concentrations reduced but did not abolish these effects. Quinidine reduced the effects of cromakalim on tension and membrane potential, but its actions were surmounted by higher concentrations of cromakalim. The effects of 4AP on tension and membrane properties were transitory, but it had some effects on the actions of cromakalim. Glibenclamide and tolbutamide reversed the relaxant effects of submaximal cromakalim concentrations, tolbutamide only transiently. 5. It is concluded that the channels opened by cromakalim are not those involved in generating the spike after-hyperpolarization. They have properties similar to the delayed rectifier K+ channels responsible for spike repolarization, and also are similar to the ATP-dependent K channels in vascular smooth muscle.

4-Aminopyridine↗
PubMed1989

The effects of cromakalim on the detrusor muscle of human and pig urinary bladder.

The effects of cromakalim, a potassium channel activating drug, have been studied on isolated detrusor muscle strips from normal Landrace boar, normal and unstable mini-pig and unstable human bladder. Cromakalim abolished spontaneous activity in all strips but did not abolish the ability of the detrusor muscle from any of the specimens studied to respond to carbachol, increased extracellular K+ or transmural nerve stimulation. Intravenous infusion of cromakalim in the urethral obstructed mini-pig caused the characteristic unstable contractions associated with bladder outflow obstruction to be abolished, leaving the animal able to void. Experiments with potassium isotopes and the sucrose gap technique demonstrated that cromakalim increased the potassium permeability and hyperpolarised the cell membrane, consistent with its reported actions on other smooth muscles. These results suggest that drugs such as cromakalim, which act by reducing membrane excitability without inhibiting responses to existing innervation, may have a clinical application in the treatment of instability which is secondary to bladder outflow obstruction.

Animals↗
PubMed1989

The effect of cromakalim on the smooth muscle of the guinea-pig urinary bladder.

1. The actions of cromakalim were studied on the detrusor muscle from guinea-pig urinary bladder. Cromakalim reduced the frequency and amplitude of spontaneous contractile activity of the smooth muscle of the guinea-pig urinary bladder at 5 x 10(-8)M and abolished the activity at concentrations above 5 x 10(-7)M. 2. Electrophysiological experiments demonstrated that cromakalim increased membrane conductance, caused a dose-dependent hyperpolarization of the cell membrane and loss of spike activity. These events are consistent with the opening of K+ channels. 3. The effects of 10(-6)M and 10(-5)M cromakalim on the contractile responses to carbachol, potassium and transmural nerve stimulation were studied. Cromakalim did not prevent the detrusor from responding to these agents, although it significantly reduced the contractile response to K+ at concentrations below 70 mM. 4. Uptake and efflux experiments using 86Rb+ were unable to demonstrate any significant effect on transmembrane movement produced by cromakalim (10(-5)M). 5. 43K+ efflux showed a dose-dependent increase in the rate constant on addition of cromakalim. The difference in the selectivity for K+ over Rb+ was confirmed in dual label uptake experiments. 6. Substitution experiments in which the K+ ions in the tissue were gradually replaced by Rb+ demonstrated that cromakalim had a progressively decreasing effect on spontaneous activity as internal K+ was lowered. When all the K+ was replaced by Rb+, cromakalim no longer inhibited spontaneous activity, confirming that the channel opened by cromakalim appears relatively impermeant to Rb+.

Animals↗
PubMed1986

Effect of renacidin on suture material.

Renacidin solution is used sometimes to irrigate renal units with retained calculi after definitive stone surgery. The effects of this solution on the integrity of suture material utilized to close kidneys have not been determined previously. In an attempt to define the best suture material to use when postoperative renacidin irrigation is contemplated, we studied the effects of this solution on a variety of sutures commonly used in genitourinary surgery.

Benzenesulfonates↗