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Papers by Philip Langton

We describe an inquiry activity that aims to develop students' ability to interpret findings ... more We describe an inquiry activity that aims to develop students' ability to interpret findings that span whole body systems and so encourage the integration of knowledge. The scenario we choose was the physiological challenge posed by diarrhea and the physiological mechanisms that underpin oral rehydration therapy. Before the staff-facilitated inquiry activity, students engage with an online information resource and complete a formative, but mandatory, prelaboratory quiz. These tasks encourage students to develop some mastery of the relevant physiology before the timetabled inquiry activity. The 3-h inquiry activity is driven by a paper workbook containing data from published studies, mainly from veterinary physiology, of the various consequences of diarrhea. Figures from published data are arranged so that, initially, the impact of dehydration on a single system (the cardiovascular system) could be appreciated. Integration with other systems (respiratory and renal systems) is the...

Anatomical Sciences Education, 2013

This paper describes the introduction of a virtual microscope (VM) that has allowed preclinical h... more This paper describes the introduction of a virtual microscope (VM) that has allowed preclinical histology teaching to be fashioned to better suit the needs of approximately 900 undergraduate students per year studying medicine, dentistry or veterinary science at the University of Bristol, UK. Features of the VM implementation include: 1) the facility for students and teachers to make annotations on the digital slides; 2) in-house development of VM-based quizzes that are used for both formative and summative assessments; 3) archiving of teaching materials generated each year, enabling students to access their personalized learning resources throughout their programs; 4) retention of light microscopy capability alongside the VM. Student feedback on the VM is particularly positive about its ease of use, the value of the annotation tool, the quizzes and the accessibility of all components off-campus. Analysis of login data indicates considerable, although variable, use of the VM by students outside timetabled teaching. The median number of annual logins per student account for every course exceeded the number of timetabled histology classes for that course (1.6-3.5 times). The total number of annual student logins across all cohorts increased from approximately 9,000 in 2007-08 to 22,000 in 2010-11. The implementation of the VM has improved teaching and learning in practical classes within the histology laboratory and facilitated consolidation and revision of material outside the laboratory. Discussion is provided of some novel strategies that capitalize on the benefits of introducing a VM, as well as strategies adopted to overcome some potential challenges.

The Journal of Physiology, 1998

So-called resistance arteries (50-300 ìm diameter) often develop a [Ca¥]ï-dependent constriction ... more So-called resistance arteries (50-300 ìm diameter) often develop a [Ca¥]ï-dependent constriction when pressurized in vitro, which is independent of endothelial, neural or hormonal influences (McCarron, Osol & Halpern, 1989; Bevan & Laher, 1991; Liu, Harder & Lombard, 1994). The putative pressure-sensing mechanism is not yet understood but mechanical deformation of vascular myocytes is thought to initiate the response (Meininger & Davis, 1992; Harder, Narayanan, Gebrebedhin & Roman, 1995). Pronounced depolarization (•30 mV) of smooth muscle membrane is associated with myogenic activation of renal and cerebral vessels and entry of extracellular Ca¥ appears to be essential for maintenance of the response (Harder, 1984; Harder, Gilbert & Lombard, 1987; Knot, Standen & Nelson, 1997). The conductance change responsible for myogenic depolarization has not been elucidated. Stretch-activated, non-selective cation channels, which have been demonstrated to be present in vascular myocytes, could play a role in the myogenic response (Davis, Donovitz & Hood, 1992). Since the reversal potential for Cl¦ is around −20 mV in vascular smooth muscle, stretch activation of a Cl¦ conductance would also provide depolarizing current (Aickin, 1990; Nelson, Conway, Knot & Brayden, 1997). The ability to inhibit stretch-activated channels selectively in intact preparations would permit the contribution made by non-selective cation current to the myogenic response to be assessed. Aminoglycoside antibiotics, such as streptomycin sulphate, have been reported to concentration-dependently inhibit stretch-induced changes in the electrophysiology of several cell types, including cardiac cells (Gannier, White, Lacampagne, Garnier & Le Guennec, 1994) and sensory hair cells (Ohmori, 1985; Kroese, Das & Hudspeth, 1989) and have been shown to inhibit mechanosensitive channels (Winegar, Haws & Lansman, 1996). However, like other aminoglycosides, streptomycin is also known to block Ca¥ channels (Haws, Winegar & Lansman, 1996), but the ICÛÑ is sufficiently high that a window of specificity for selective block of stretch-activated cation channels appears to exist. Streptomycin has not been evaluated previously as a tool for the study of stretch-activated conductances in vascular muscle. The present study investigates the effects of streptomycin on myogenic (pressure-induced) tone and compares them with the effects on K¤ depolarizationinduced force in arterial segments, as well as on voltagegated Ca¥ channels from single isolated vascular smooth muscle cells. An abstract of this study has been published previously (Miller & Langton, 1996).

British Journal of Pharmacology, 1996

We have investigated the actions of NS1619, a putative activator of large conductance calciumacti... more We have investigated the actions of NS1619, a putative activator of large conductance calciumactivated potassium channels (BKCa) by use of the patch-clamp technique on smooth muscle cells enzymatically isolated from the rat basilar artery. 2 Using whole cell current-clamp to measure membrane potential, addition of 30 gM NS1619 produced cellular hyperpolarization, moving the membrane potential towards the calculated equilibrium potential for potassium. This hyperpolarization was rapidly reversed by IbTX (100 nM), a selective inhibitor of BKCa. 3 In whole cell recordings made from cells voltage-clamped at 0 mV using the perforated-patch technique, addition of NS1619 (10-30 gM) activated an outward current, which reversed following washout of NS1619. 4 This outward current was unaffected by application of either glibenclamide (5 gM), an inhibitor of ATP-sensitive potassium channels, or apamin (100 nM), an inhibitor of small-conductance calciumactivated potassium channels. However, this current was almost completely abolished by iberiotoxin (IbTX; 50-lOOnM). 5 Depolarizing voltage steps activated small outward currents from cells held at-15 mV. Application of NS1619 (10-30 gM) increased the size of these currents, producing a shift to the left of the currentvoltage (I-V) relationship. These currents were largely inhibited by IbTX (100 nM). 6 Measurements of the unitary amplitude of the single channels activated by NS1619 which could be resolved in whole cell recordings yielded a value of 5.6+0.14 pA at 0 mV. 7 NS1619 (10-30 gM) directly activated single channels contained in excised inside-out and outside-out membrane patches. In both configurations NS1619 (10-30 gM) rapidly increased the open probability of a large conductance calcium-dependent channel. The activation produced by NS1619 was calciumdependent and inhibited by external IbTX (100 nM). The unitary current amplitude was unaffected by NS1619. 8 By use of conventional whole cell recording methods and conditions that suppressed BKCa openings, outward potassium currents were activated by depolarizing potentials positive to-35 mV from a holding potential of-65 mV. NS1619 (10-30 gM) inhibited this current in a concentration-dependent manner. This inhibition was reversed following washout of NS1619, recovering to 60-90% of control values within 2 min. 9 Ba2+ currents, measured by conventional whole cell recording, were activated by depolarizing voltage steps from negative holding potentials. NS1619 (1-30 gM) inhibited the evoked current in a concentration-dependent manner, yielding an IC50 value of 7 gM with a Hill coefficient approaching unity. This inhibition was reversible, with the currents recovering to 65-100% of control values after washout of NS1619 for 2 min. 10 NS1619 (0.3-100 pM) induced concentration-dependent relaxation of basilar artery segments contracted with histamine/5-HT (IC50 = 12.5 + 2.0 gM; n = 4). This relaxation curve was shifted to the right, but not abolished, when the tissue was treated with a blocker of BKCa channels (IbTX; lOOnM). Additionally, NS1619 produced concentration-dependent relaxation of basilar artery contracted with a depolarizing, isotonic salt solution containing 80 mM K+. 11 Thus NS1619 produces hyperpolarization of basilar artery myocytes through direct activation of BKCa and also directly inhibits Ca2+ currents and voltage-activated K+ channels. We discuss the implications of these results for its vasorelaxant actions. Keywords: NS1619; large-conductance, calcium-activated K+ channel; iberiotoxin; delayed rectifier K+ channel; L-type calcium channel; vasorelaxation; basilar artery ' Author for correspondence at: Department of Cell Physiology and the large unitary conductance of BKca channels, BKCa openers Pharmacology. are potentially potent vasorelaxing agents.

British Journal of Pharmacology, 2000

1 K + has been proposed to be EDHF in small arteries. We compared ACh-stimulated, EDHFmediated di... more 1 K + has been proposed to be EDHF in small arteries. We compared ACh-stimulated, EDHFmediated dilatation/relaxation with raised [K + ] o in rat mesenteric arteries. 2 In pressurized arteries, ACh (10 mM) dilated all arteries. Raising [K + ] o from 5.88 to 10.58 mM only dilated 30% of arteries. Ba 2+ (30 mM) did not aect dilatation to ACh, but abolished 40% of dilatations to raised [K + ] o. 3 If [K + ] o was lowered to 1.18 mM, restoring [K + ] o to 5.88 mM produced dilatation which was depressed by Ba 2+ or ouabain (1 mM). Combined application of Ba 2+ and ouabain abolished dilatation. In 1.18 mM K + , dilatation to ACh was depressed by ouabain, but not by Ba 2+. Combined application of Ba 2+ and ouabain depressed dilatation further. Gap junction inhibitors (Gap-27; 300 mM and 18-a-glycyrrhetinic acid; 100 mM) also depressed dilatation to ACh. 4 In arteries mounted isometrically, ACh (1 mM) relaxed endothelium intact (+E), but not endothelium denuded (7E) arteries. Raising [K + ] o from 5.9 ± 10.9 mM failed to relax all arteries. When [K + ] o was lowered to 1 mM, raising [K + ] o to 6 mM produced relaxation. In 7E arteries, relaxation was unaected by Ba 2+ but abolished by ouabain. In +E arteries, Ba 2+ depressed and ouabain abolished relaxation. In +E arteries, with 1 mM K + , ACh relaxation was depressed by ouabain but not Ba 2+. The combined application of Ba 2+ and ouabain further depressed relaxation. 5 In summary, both EDHF and raised [K + ] o dilate/relax rat mesenteric arteries, though sensitivities to barium and ouabain dier. K + may be a relaxing factor in this tissue, but its characteristics dier from EDHF. Gap junction inhibitors depress EDHF, implying an important role for myo-endothelial gap junctions.

British Journal of Pharmacology, 2003

It is widely established that in rat mesenteric arteries, endothelium-derived hyperpolarizing fac... more It is widely established that in rat mesenteric arteries, endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation evoked by acetylcholine is abolished by a combination of charybdotoxin plus apamin. 4-Aminopyridine, an inhibitor of voltage-gated (Kv) K +-channels, in combination with apamin had moderate effects on the EDHF-mediated relaxation. Maurotoxin (MTX), an inhibitor of Kv and intermediate-conductance Ca 2+-activated K +-channels (IK), had no effect on EDHF-mediated relaxation. However, MTX in combination with apamin completely abolished EDHF-mediated relaxation and endothelial cell hyperpolarization. The selective IK inhibitor 2-(2chlorophenyl)-2,2-diphenyl acetonitrile (TRAM-39) had no significant effect on EDHF-mediated relaxation. EDHF-mediated vasorelaxation and hyperpolarization was abolished by a combination of TRAM-39 and apamin. These data demonstrate two new combinations of K +-channel inhibitors for the investigation of EDHF. Furthermore, by using TRAM-39, a potent selective inhibitor of IK channels, we provide the first direct evidence that abolition of EDHF requires the simultaneous presence of intermediate-and small-conductance Ca 2+-activated K +-channel inhibitors.

American Journal of Physiology-Heart and Circulatory Physiology, 1999

In rat mesenteric artery, endothelium-derived hyperpolarizing factor (EDHF) is blocked by a combi... more In rat mesenteric artery, endothelium-derived hyperpolarizing factor (EDHF) is blocked by a combination of apamin and charybdotoxin (ChTX). The site of action of these toxins has not been established. We compared the effects of ChTX and apamin applied selectively to the endothelium and to the smooth muscle. In isometrically mounted arteries, ACh (0.01–10 μm), in the presence of indomethacin (2.8 μM) and N ω-nitro-l-arginine methyl ester (l-NAME) (100 μM), concentration dependently relaxed phenylephrine (PE)-stimulated tone (EC50 50 nM; n = 10). Apamin (50 nM) and ChTX (50 nM) abolished this relaxation ( n = 5). In pressurized arteries, ACh (10 μM), applied intraluminally in the presence of indomethacin (2.8 μM) andl-NAME (100 μM), dilated both PE-stimulated (0.3–0.5 μM; n = 5) and myogenic tone ( n = 3). Apamin (50 nM ) and ChTX (50 nM) applied intraluminally abolished ACh-induced dilatations. Bath superperfusion of apamin and ChTX did not affect ACh-induced dilatations of either PE...

British Journal of Pharmacology, 2001

Advances in Physiology Education

This laboratory practical requires first-year students to anticipate the effects of drugs active ... more This laboratory practical requires first-year students to anticipate the effects of drugs active at cholinergic and adrenergic receptors on gut motility in order to design experiments during an authentic inquiry exercise. Rather than specifying a strict sequence of drug additions that aim to provide ideal demonstrations of pharmacological and physiological antagonism, I have instead designed switches into the drugs provided and set students, working in small teams, the task of identifying the switched drugs, an inquiry activity. To extend the teamwork aspect, laboratory reports were submitted by the student teams rather than individual students. Staff observed that discussions within the teams were stimulated by the inquiry-led nature of the practical. The quality of the laboratory reports submitted by teams were substantially improved over the individual reports submitted in previous years. (Students previously worked in teams, but simply followed a list of prescribed experiments a...

Comparative Biochemistry and Physiology Part C: Comparative Pharmacology

Auxotonic contractions of the radular protractor muscle (RPM) of Busycon contrarium have often be... more Auxotonic contractions of the radular protractor muscle (RPM) of Busycon contrarium have often been used for bioassay of FMRFamide (Fa). Until now, however, sucrose gap recording of electrical responses of the RPM of Busycon cunaliculurum has invariably been accompanied by isometric recording of contractions. 2. We find that isometric responses of the RPM of B. cunuliculutum seem to be less sensitive detectors of Fa than the auxotonic responses of the RPM of B. confrurium, which are used for bioassay. Therefore, we have now combined sucrose gap recording of electrical responses with auxotonic recording of contractions. 3. The most interesting outcome of this study was the discovery that the responses of RPMs to FMRFamide are accompanied by very little depolarization, compared to their responses to potassium (K) or acetylcholine (ACh). 4. We have also found that low concentrations of Fa induce very weak, slow contractions for which auxotonic recording provided more reliable detection of threshold responses than did isometric recording. However, strength of contraction (but not depolarization) increased remarkably with concentration.

Journal of Physiology, 1990