Biomedical subjects

Linda Shaw

Publications and source records attributed to Linda Shaw.

9 recordsLinked to original sources

PubMed2006

Caveolae and sarcoplasmic reticular coupling in smooth muscle cells of pressurised arteries: the relevance for Ca2+ oscillations and tone.

OBJECTIVE: A close association of caveolae and sarcoplasmic reticulum (SR) has been suggested to be important for contractile activation of smooth muscle. Here, we investigate the presence of such arrangements in pressurised resistance arteries and examine the influence of two agents purported to disrupt caveolae and/or SR conformations by different mechanisms of action. METHODS: Rat mesenteric small arteries (RMSA) were mounted on a pressure myograph and the functional (lumen diameter and Ca(2+) oscillations) and ultrastructural effects of the phosphatase inhibitor calyculin-A (cal-A), or the cholesterol binding agent methyl-beta-cyclodextrin (mbetacd), examined by light and electron microscopy. RESULTS: Smooth muscle cells of RMSA exhibited a prominent peripheral SR that often encircled individual caveolae. The peripheral SR on occasion was observed to make contact with centrally located SR allowing for a structural association of caveoale-SR-myofilaments. Cal-A maximally constricted RMSA and disrupted the regular SR-caveolae appearance such that concentrated swirls of SR not enveloping caveolae were evident. Mbetacd treatment, in contrast, inhibited agonist contractility and reduced the appearance of caveolae whilst peripheral SR apposition to the plasmalemma could still be observed. Treatment with either agent inhibited agonist-mediated smooth muscle Ca(2+) oscillations. CONCLUSION: We present data that supports a structural arrangement of caveolae and underlying peripheral SR in smooth muscle cells of pressurised resistance arteries that serves to regulate Ca(2+) oscillations and contractile activation.

Animals↗

PubMed2006

Middle cerebral artery structure and distensibility during developing and established phases of hypertension in the spontaneously hypertensive rat.

OBJECTIVE: The aims of the current study were to examine the structural properties of middle cerebral arteries (MCA) from young (5-7 weeks) and adult (20-24 weeks) spontaneously hypertensive rats (SHR), compared with age-matched Wistar-Kyoto (WKY) control rats. DESIGN: MCA segments (8-10 per group) were secured onto glass pipettes in a small vessel chamber and studied using a pressure arteriograph system. Vessels were perfused in Ca2+-free physiological salt solution to ensure the absence of tone. The wall thickness and lumen diameter were recorded at intraluminal pressures ranging from 3 to 180 mmHg using a video dimension analyser. RESULTS: There was a borderline increase in systolic pressure of the young SHR, compared with WKY controls, but the systolic pressure of the older SHR was significantly raised. The MCA lumen diameter from young SHR was reduced across the entire pressure range and arterial distensibility was not reduced, compared with WKY vessels. The MCA lumen diameter from adult SHR was reduced at high pressure, but converged with the lumen diameter of the WKY vessels at 3 mmHg, and the stress-strain relation was shifted to the left, compared with the WKY vessels; nevertheless, the slope of the tangential elastic modulus-stress relation was not significantly increased. The pressure-wall cross-sectional area relationship did not differ between strains at either time point. CONCLUSIONS: These data demonstrate eutrophic inward remodelling of the MCA from young SHR, compared with WKY controls. In the adult SHR the structural changes are probably a consequence of a reduced arterial distensibility.

Aging↗

PubMed2005

alphaV integrins are necessary for eutrophic inward remodeling of small arteries in hypertension.

Human essential hypertension is characterized by eutrophic remodeling of small arteries, with little evidence of hypertrophy. Likewise, vessels of young hypertensive TGR(mRen2)27 animals have undergone similar structural alterations. The role of integrins in resistance arteries of TGR(mRen2)27 during the eutrophic-remodeling process was examined as blood pressure rose. Initially, 8 alpha and 3 beta integrins were identified and levels of expression investigated using RT-PCR. As pressure increased and remodeling advanced, integrin expression profiles revealed that only alphaV was significantly raised. In conjunction, we confirmed elevated integrin alphaV protein levels in TGR(mRen2)27 rat arteries and localization to the media using immunofluorescence. beta1 and beta3, but not beta5 integrin subunits were coprecipitated with integrin alphaV and are implicated in the eutrophic remodeling process. Administration of a peptide antagonist of alphaVbeta3 abolished remodeling but enhanced growth, indicating that hypertrophy supervened as a response to hypertension-induced increases in wall stress. We have established that the only upregulated integrin, the alphaV subunit of integrin alphaVbeta3, has a crucial role in the hypertensive remodeling process of TGR(mRen2)27 rat resistance arteries. During hypertensive remodeling, functions of specific alphaVbeta3-extracellular matrix interactions are likely to allow vascular smooth muscle cell-length autoregulation, which includes a migratory process, to maintain a narrowed lumen after a prolonged constricted state.

Animals↗

PubMed2005

Erosive effect of a new sports drink on dental enamel during exercise.

PURPOSE: To compare the potential erosive effect of a prototype carbohydrate-electrolyte drink (PCE) with a neutral control (water) and a commercially available carbohydrate-electrolyte drink (CCE) during exercise. METHODS: : Nineteen healthy adults (male, N = 16; female, N = 3) took part in this single blind, three-way crossover study. Subjects were given each of the three drinks according to a randomization schedule, approximately balanced for first-order carryover effects. At the beginning of each of the three study periods, the volunteers were fitted with an intraoral appliance containing two human enamel blocks. During each study period, volunteers exercised for 75 min.d(-1) (5 repetitions of 15 min of exercise, with 5-min rests between exercise repetitions), 5 d.wk(-1) for 3 wk. Each day, drink aliquots of 200 mL were consumed during a 5-min period before exercise and after every 15-min bout of exercise, followed by a final 400-mL aliquot ingested over a 10-min period: a total of 1400 mL per study day. Dental erosion was measured as tissue loss from the enamel blocks by profilometry at the end of each study period. RESULTS: Water, PCE, and CCE produced 0.138 microm (SD 0.090 microm), 0.138 microm (SD 0.038 microm), and 4.238 microm (SD 3.872 microm) of enamel loss, respectively. A Wilcoxon t statistic showed a significant statistical difference between the PCE and CCE drinks (P < 0.001), whereas no significant difference could be detected between the PCE drink and water (P = 0.740). CONCLUSION: The PCE solution showed minimal erosion compared with the commercially available drink, and was statistically indistinguishable from water under the conditions of this study. Use of CE solutions formulated to minimize erosion during exercise may provide significant dental benefits.

Adult↗

PubMed2004

Comparison of the pharmacokinetics of fosfluconazole and fluconazole after single intravenous administration of fosfluconazole in healthy Japanese and Caucasian volunteers.

OBJECTIVES: To investigate the bioavailability of fluconazole (FLCZ) from fosfluconazole (phosphate pro-drug of FLCZ) and to compare the pharmacokinetics of fosfluconazole and FLCZ in Japanese and Caucasian subjects. METHODS: In a randomised, double-blind, double-dummy, single-dose, two-period, crossover study, 12 Japanese and 12 Caucasian healthy subjects received a bolus intravenous injection of 1000 mg fosfluconazole or an intravenous infusion of 800 mg FLCZ in random order. Concentrations of fosfluconazole and FLCZ were determined in plasma and urine samples taken up to 144 h and 48 h post-dose, respectively. RESULTS: The bioavailability of FLCZ after administration of fosfluconazole was 95.2% (95% confidence interval: 89.0, 102.0) in Japanese subjects and 100.6% (94.0, 107.7) in Caucasian subjects. The ratio of bioavailabilities (Japanese/Caucasian) was 94.7% (86.0, 104.3). There were no statistically significant differences in the pharmacokinetic parameters of fosfluconazole (except for AUC(inf)) and FLCZ between Japanese and Caucasian subjects. Although mean AUC(inf) of fosfluconazole was 25.6% (5.6, 49.2) greater in Japanese subjects, the lack of a statistically significant difference in weight-adjusted CL of fosfluconazole demonstrates that the difference in AUC(inf) was due to a difference in body weight. The adverse-event profile was similar in Japanese and Caucasian subjects after both fosfluconazole and FLCZ dosing, and both treatments were well tolerated in each group. CONCLUSIONS: The pharmacokinetics of fosfluconazole and FLCZ were similar in Japanese and Caucasian subjects. Fosfluconazole is almost completely converted to FLCZ and similar systemic exposure to FLCZ is achieved after single doses of fosfluconazole in both Japanese and Caucasian subjects.

Adult↗

PubMed2004

Comparison of U46619-, endothelin-1- or phenylephrine-induced changes in cellular Ca2+ profiles and Ca2+ sensitisation of constriction of pressurised rat resistance arteries.

1. In pressurised rat mesenteric small arteries (50 mmHg), we examined the effects of stimulation with U46619, endothelin-1 (ET-1) or phenylephrine (PE) on changes in vessel diameter, global [Ca(2+)](i), individual smooth muscle cell [Ca(2+)](i) and Ca(2+)-sensitisation of contraction. 2. U46619 or ET-1 gave tonic diameter reductions, whereas PE-stimulated vessels gave tonic contractions or initial vasoconstrictions followed by diameter oscillations. Global [Ca(2+)](i) changes were transient for each agonist, with tonic constrictions being accompanied by maintained submaximal global [Ca(2+)](i) levels. 3. U46619, ET-1 or PE tonic constrictions were accompanied by apparently asynchronous [Ca(2+)](i) waves in individual smooth muscle cells of the vessel wall, as examined by confocal fluorescent microscopy. In vessels exhibiting vasomotion to PE, some apparent synchrony of activation of individual cells was evident; however, this was incomplete with many cells responding out of phase with their neighbours. 4. In alpha-toxin-permeabilised preparations, agonist-induced Ca(2+)-sensitisation of constriction at submaximal Ca(2+) (pCa6.7) in the presence of GTP was greater with U46619 or ET than PE. 5. We conclude that, in pressurised mesenteric arteries, (i) a general feature of receptor-coupled constriction is the generation of periodic smooth muscle [Ca(2+)](i) waves; (ii) complete synchrony of Ca(2+) oscillations between smooth muscle cells is not a prerequisite for receptor-coupled vasomotion; (iii) varied Ca(2+)-sensitising actions of agonists may partly determine tonic or phasic vessel responses to different stimuli.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2004

OBE honour.

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Awards and Prizes↗

PubMed2003

Acute effects of oestrogen receptor subtype-specific agonists on vascular contractility.

This study shows for the first time that both the putatively selective oestrogen receptor alpha and oestrogen receptor beta agonists PPT (4,4',4"-(4-propyl-[(1)H]-pyrazole-1,3,5-triyl) tris-phenol) and DPN (2,3-bis(4-hydroxyphenyl)-propionitrile) can acutely relax precontracted isolated rat mesenteric arteries at pharmacological (i.e. micro M) concentrations. When compared to responses observed to similar concentrations of 17beta-oestrogen obtained on the same tissues, PPT had a significantly greater vasodilatory effect, while DPN had a significantly smaller effect. All responses were rapid being complete within 5 min exposure time. Thus, both PPT and DPN can acutely relax isolated mesenteric arteries with the relative potency of PPT>17beta-oestrogen>DPN.

Animals↗

PubMedDate not supplied

Inhibitors of actin filament polymerisation attenuate force but not global intracellular calcium in isolated pressurised resistance arteries.

Receptor-coupled contractile activation of arterial smooth muscle involves increases in intracellular calcium ([Ca(2+)](i)) and subsequent alteration of myosin light chain phosphorylation. An additional mechanism whereby agonists could regulate vascular contractility may be alteration of actin filament dynamics. Therefore, in this study, we have investigated the influence of two inhibitors of actin filament polymerisation, cytochalasin D and latrunculin B, on the [Ca(2+)](i) and force responsiveness of pressurised rat mesenteric arteries to alpha-adrenergic stimulation. Following cytochalasin D or latrunculin B treatment, phenylephrine-induced constrictions were significantly reduced to 11 +/- 3.2% (n = 6) and 10 +/- 4.4% (n = 6) of control, respectively, whereas [Ca(2+)](i) remained at 98 +/- 21% and 104 +/- 7.0% of control, respectively. Such effects of cytochalasin D were not restricted to mesenteric small arteries. Cytochalasin D also significantly reduced the force, but not [Ca(2+)](i) responses to agonist stimulation in other vascular (portal vein) and non-vascular (uterine) tissues. These data indicate that inhibitors of net actin polymerisation attenuate maximum agonist-induced force responsiveness without similar reductions in [Ca(2+)](i) in pressurised resistance vessels and other smooth muscle tissues. This suggests that modulation of the dynamic equilibrium between filamentous F-actin and monomeric globular actin (G-actin) may be an important mechanism, acting independently of global [Ca(2+)](i) homeostasis, to regulate the smooth muscle contractile state.

Actin Cytoskeleton↗