Biomedical subjects

M Wareing

Publications and source records attributed to M Wareing.

At least 19 recordsLinked to original sources

PubMed2007

Relaxation of human placental arteries and veins by ATP-sensitive potassium channel openers.

BACKGROUND: Adenosine triphosphate (ATP)-sensitive potassium channels (K(ATP)) are important modulators of vascular tone. Preliminary data from our laboratory suggests that K(ATP) channels are expressed in the fetoplacental vasculature where addition of pinacidil, a specific K(ATP) opener, promotes relaxation. We aimed to assess the effects of KRN2391 and KRN4884 on the fetoplacental vasculature, which are putative K(ATP) channel openers. MATERIALS AND METHODS: Functional activity of K(ATP) channels was assessed in chorionic plate arteries and veins using wire myography. Cromakalim-, KRN2391- and KRN4884-induced relaxations were assessed in the presence and absence of agonist-induced pretone. Cromakalim, an established K(ATP) channel opener, acted as control. RESULTS: KRN2391 evoked significantly greater relaxation of chorionic plate arteries and veins than either KRN4884 or cromakalim. KRN2391-induced relaxation of precontracted arteries and veins was reduced in the presence of inhibitors of the nitric oxide pathway (L-NNA or LY83583). With KRN4884, there was no contribution of nitric oxide to the induced relaxation. CONCLUSIONS: We conclude that K(ATP) channels play an important role in controlling placental vascular tone. KRN2391 induces relaxation of human placental blood vessels by activation of K(ATP) channels and via activation of nitric oxide-dependent pathways.

Adenosine Triphosphate↗

PubMed2006

Reactivity of human placental chorionic plate vessels is modified by level of oxygenation: differences between arteries and veins.

Normal fetal development in utero is dependent upon adequate perfusion of the placental vasculature, yet how fetoplacental blood flow is matched to maternal blood flow is unknown. In the perfused placental cotyledon in vitro, reduced oxygenation promotes vasoconstriction, which may act to direct blood in fetoplacental vessels to effectively perfused regions of the intervillus space. We aimed to demonstrate that oxygen tension could directly modify placental chorionic plate vessel vasoreactivity. Small arteries and veins from the chorionic plate were dissected from biopsies from term placentae of uncomplicated pregnancies and studied using parallel wire myography. Chorionic artery and vein vasoconstriction in 20%, 7% and 2% oxygen was assessed utilizing the thromboxane-mimetic U46619. Reduced oxygenation increased arterial maximal active effective pressure production and sensitivity to U46619. This effect was cyclo-oxygenase independent. In veins, modified oxygenation did not alter vasoconstriction. Vasodilatation in response to the NO donor sodium nitroprusside was increased in lowered oxygenation in veins but not in arteries. We suggest that modified oxygenation may play a role in the control of the blood flow in the fetoplacental circulation.

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

PubMed2005

Oxygen tension and normalisation pressure modulate nifedipine-sensitive relaxation of human placental chorionic plate arteries.

Fetoplacental blood vessel constriction in response to reduced oxygenation has been demonstrated in placenta perfused in vitro. In pulmonary vessels, hypoxic vasoconstriction involves Ca2+ influx into smooth muscle through membrane ion channels including voltage-gated Ca2+ channels (VGCCs). We hypothesised that VGCCs are involved in agonist-induced constriction of fetoplacental resistance vessels and that their contribution is modulated by oxygen. Chorionic plate small arteries were studied using wire myography. Arteries were normalised at high (0.9 of L(13.3 kPa)) or low (0.9 of L(5.1 kPa)) stretch and experiments performed at 156, 38 or 15 mmHg oxygen. At low stretch, U46619 (thromboxane-mimetic) or KCl (smooth muscle depolarisation) constriction was greater at 38 than 156 or 15 mmHg oxygen. An L-type VGCC blocker nifedipine, inhibited KCl constriction by >85% but was less effective in U46619 constrictions (43-67%). At high stretch, nifedipine inhibition of KCl- and U46619-induced constriction was less at 15 than 38 or 156 mmHg oxygen. Oxygen did not affect constriction to U46619 or nifedipine-induced relaxation when vessels were normalised at high stretch. In conclusion, oxygen modulates chorionic plate arterial constriction at low stretch but regulation is lost at high stretch. U46619 constriction is underlain by VGCCs and nifedipine-insensitive processes; their relative contribution is influenced by oxygen.

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

PubMed2005

Glibenclamide inhibits agonist-induced vasoconstriction of placental chorionic plate arteries.

BACKGROUND: Preliminary data suggest that K(ATP) channels may be expressed in placental arteries and veins [Wareing M, Turner C, Greenwood SL, Baker PN, Fyfe GK. Expression of mRNA encoding K+ channels in chorionic plate arteries and veins. J Soc Gynecol Investig 2004;11:353A]. However, no data exist on glibenclamide's effects in placental chorionic plate arteries. AIM: To assess the effect of glibenclamide on placental chorionic plate arterial vasoconstriction. METHODS: Arteries were dissected from placental chorionic plate biopsies obtained at term from uncomplicated pregnancies (N=63). Arteries were mounted onto a wire myograph in HCO3- -buffered physiological salt solution (PSS) at 37 degrees C (5% O2/5% CO2 bubbling) and normalised at 0.9 of L5.1 kPa. Constriction viability was assessed with 120 mmol l(-1) potassium solution (KPSS). Dose-response curves were produced with the thromboxane-mimetics U46619 and U44069 (10(-10)-2 x 10(-6)M), arginine vasopressin (10(-10)-5 x 10(-8)M) and endothelin-1 (10(-11)-3 x 10(-7)M) in the presence or absence of 50 micromol l(-1) glibenclamide. The effect of glibenclamide on arginine vasopressin- and U46619-induced constriction was also assessed in the presence of the cyclo-oxygenase inhibitor indomethacin (10 micromol l(-1)). RESULTS: Pre-incubation with 50 micromol l(-1) glibenclamide significantly right-shifted dose-response curves to all vasoconstrictive agonists tested (repeated measures ANOVA). Indomethacin did not modify the inhibitory effect of glibenclamide. CONCLUSION: Glibenclamide's effects on agonist-induced constrictions are unlikely to be via an inhibition of ATP-sensitive K+ channels, and with U46619- and U44069-induced constrictions, glibenclamide may be acting as a competitive antagonist of thromboxane receptors.

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

PubMed2005

Umbilical artery Doppler waveform indices from normal pregnant women are related to vasodilatation of placental chorionic plate small arteries.

Blood flow control within the fetoplacental circulation is poorly understood despite the essential role of the placenta in pregnancy. Our study compared an in vitro assessment of placental chorionic plate small artery function with in vivo measures of umbilical artery blood flow. Umbilical artery Doppler waveform analysis was performed on women (N=8) with uncomplicated pregnancies within 24 hours of delivery. Small arteries (n=25) were dissected from the placental chorionic plate from biopsies at term and studied using parallel wire myography. Chorionic plate arteries developed maintained constrictions to the thromboxane-mimetic U46619. Nitric oxide (NO) donation with the endothelial-independent agent sodium nitroprusside elicited significant relaxation compared to paired control vessels. This vasodilatation correlated significantly with both pulsatility and resistance indices measured in the umbilical artery. We conclude that Doppler indices in the umbilical artery are inversely proportional to the maximal relaxation achieved by chorionic plate small arteries in response to a NO donor.

Adolescent↗

PubMed2005

Chorionic plate artery function and Doppler indices in normal pregnancy and intrauterine growth restriction.

BACKGROUND: In fetal growth restriction (FGR) abnormal umbilical artery (UA) Doppler waveform indices suggest increased vascular resistance and impaired placental blood flow. This study aimed to determine whether UA Doppler waveform indices were related to the vasoreactivity of placental chorionic plate small arteries in normal and FGR pregnancies. MATERIALS AND METHODS: UA Doppler waveform analysis was performed 24 h before delivery in 23 normal term and 15 FGR pregnancies. Post-delivery responses of chorionic plate arteries to vasoactive agents were examined using the technique of wire myography. RESULTS: Altered vascular reactivity to agonists was demonstrated in chorionic plate arteries in FGR pregnancy. Constriction to U46619 (thromboxane mimetic) and relaxation to sodium nitroprusside (nitric oxide donor) were significantly increased in the arteries of FGR pregnancies compared with normal pregnancies. No relationship existed between Doppler indices and chorionic plate responses in normal or FGR pregnancies. CONCLUSIONS: Fetoplacental vascular reactivity is altered in FGR pregnancy independently of UA Doppler waveform indices. Altered function may be additive to the pathophysiology underlying abnormal Doppler waveforms and could contribute to the inappropriate control of vascular tone in FGR.

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

PubMed2003

Vasoactive responses of veins isolated from the human placental chorionic plate.

The control of the blood flow within the fetoplacental circulation is poorly understood despite the essential role of the placenta in pregnancy. Our aim was to assess the vasoactive responses of veins from the placental chorionic plate. Biopsies were obtained from term placentae from uncomplicated pregnancies. Small veins from the chorionic plate were dissected free from surrounding tissue and studied using parallel wire myography. Human placental chorionic plate veins developed maintained constrictions to the thromboxane-mimetic U46619. Endothelium-dependent agonists did not promote venous relaxation. However, NO donation with the endothelial-independent agent, sodium nitroprusside, elicited significant relaxation. Venous constriction to U46619 and relaxation to sodium nitroprusside were modified by adjustment of media oxygen tension and normalization parameters. Human placental chorionic plate veins respond to vasoactive agents and may play a role in the control of the blood flow in the fetoplacental circulation.

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

PubMed2003

Otological trauma resulting from the Soho Nail Bomb in London, April 1999.

We report the otological effects of the April 1999 Soho Nail Bomb on 17 patients. Twenty-one (62%) tympanic membranes were perforated (pars tensa only); 78% closed spontaneously within 6 months. The mean size of the perforation in the tympanic membrane nearer to the blast was significantly larger than the opposite side [33% +/- 8.3 (mean +/- SD) and 13% +/- 4.1 respectively; P = 0.02]. All patients reported hearing losses that were mixed conductive and sensorineural but mainly high-frequency sensorineural (4, 6 and 8 kHz, pure tone average 42.3 dB +/- 20.5). The sensorineural hearing loss correlated inversely with the distance from the explosion but not with the size of perforation. There was no significant difference in the hearing loss between the ear facing the blast and the opposite ear. Fifteen patients (88%) had temporary tinnitus. No patient complained of any vestibular symptoms. The otological effects of a nail bomb in an enclosed space have not been previously reported. Furthermore, an inverse correlation between hearing loss and distance from the explosion and a significant difference in perforation size facing the blast, compared with the opposite side, are also presented for the first time. The high spontaneous closure rate of perforations and minimal ongoing disability from sensorineural losses favour conservative management in most cases.

Adult↗

PubMed2002

Characterization of small arteries isolated from the human placental chorionic plate.

Despite the essential role of the placenta in pregnancy, the control of the blood flow within the fetoplacental circulation is poorly understood. A handful of myography studies have directly assessed the role of vasoactive agonists in fetoplacental vasculature contractility but have used a range of steady-state conditions. Our aim, therefore, was to determine the optimal vessel diameter and oxygen tension to assess vascular function in small arteries isolated from the chorionic plate of normal term placentae. Biopsies were obtained from term placentae from uncomplicated pregnancies. Small arteries were dissected from the chorionic plate, mounted onto a wire myograph in HCO3(-) -buffered physiological salt solution at 37 degrees C and equilibrated for 20 min. Two methods for normalization of the optimal length/diameter for contractility of chorionic plate small arteries were assessed. Both classical normalization (CN) and length-tension curve (LTC) methods produced similar data. These data were agonist-independent. Data for CN and LTC were unaffected but maximal force generation (for U46619) was decreased in reduced oxygen tensions. Using conditions for optimal tension production in chorionic plate small arteries the thromboxane-mimetic U46619 produced the greatest and most reproducible constrictive effect. Relaxations were only achieved with endothelial-independent agonists (sodium nitroprusside and papaverine).

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

PubMed2001

Cellular localization of divalent metal transporter DMT-1 in rat kidney.

We have demonstrated that the kidney plays an important role in iron balance and that metabolically significant reabsorption of this ion occurs in the loop of Henle and the collecting ducts [Wareing M, Ferguson CJ, Green R, Riccardi D, and Smith CP. J Physiol (Lond) 524: 581-586, 2000]. To test the possibility that the divalent metal transporter DMT1 (Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, and Hediger MA. Nature 388: 482-488, 1997) could represent the apical route for iron entry in the kidney, we raised and affinity-purified an anti-DMT-1 polyclonal antibody and determined DMT-1 distribution in rat kidney by Western analysis, immunofluorescence, and confocal microscopy. The strongest DMT1-specific (i.e., peptide-protectable) immunoreactivity was found in the collecting ducts, in both principal and intercalated cells. Thick ascending limbs of Henle's loop and, more intensely, distal convoluted tubules exhibited apical immunostaining. Considerable intracellular DMT-1 immunoreactivity was seen throughout the nephron, particularly in S3 segments. The described distribution of DMT-1 protein is in agreement with our previous identification of nephron sites of iron reabsorption, suggesting that DMT-1 provides the molecular mechanism for apical iron entry in the distal nephron but not in the proximal tubule. Basolateral iron exit may be facilitated by a different system.

Animals↗

PubMed2000

In vivo characterization of renal iron transport in the anaesthetized rat.

1. In vivo microinjections of 55FeCl3 were made to assess renal iron (Fe2+/3+) transport in the anaesthetized rat. 2. Following microinjection into proximal convoluted tubules (PCTs), 18.5 +/- 2.9 % (mean +/- s.e.m., n = 11) of the 55Fe was recovered in the urine. This recovery was not dependent on the injection site indicating that iron is not reabsorbed across the surface convolutions of the proximal tubule. 3. Following microinjection into distal convoluted tubules (DCTs) 46.1 +/- 6.1 % (n = 8) of the injected 55Fe was recovered. Taken together the recovery data from the PCT and DCT microinjection studies indicate that the transport of iron occurs in the loop of Henle (LH) and collecting duct system. 4. In vivo luminal microperfusion was used to examine iron transport by the LH in more detail. In tubules perfused with 7 micromol l-1 55FeCl3, 52.7 +/- 8. 3 % (n = 8) of the perfused 55Fe was recovered in the collected fluid, indicating significant iron reabsorption in the LH. Addition of copper (Cu2+ as 7 micromol l-1 CuSO4), manganese (Mn2+ as 7 micromol l-1 MnSO4) or zinc (Zn2+ as 7 micromol l-1 ZnSO4) to the perfusate did not affect reabsorption of water, Na+ or K+, but increased recovery of 55Fe to 83.5 +/- 6.8 % (n = 8, P < 0.04), 75.8 +/- 5.9 (n = 6, not significant, n.s.) and 67.9 +/- 3.8; (n = 9, n.s. ), respectively. 5. Thus, iron transport in the LH can be reduced by the addition of copper or manganese to the luminal perfusate suggesting that these ions may compete with iron for a common transport pathway. However, this pathway may not be shared by zinc.

Anesthesia↗

PubMed2000

Working memory deficits in current and previous users of MDMA ('ecstasy').

Current and previous users of the drug MDMA ('ecstasy') were tested on measures of central executive functioning, information processing speed, and on self-report measures of arousal and anxiety. The results were compared with those for a control group who did not use MDMA. Relative to the control group, both user groups were found to be impaired in some aspects of central executive functioning. Also, there were significant group differences on the measures of anxiety (users were more anxious) and on arousal (previous users scoring higher on the arousal measure relative to current users). Users processed information as quickly as non-users but less accurately. Some possible mediators of the above group differences are discussed.

Adult↗

PubMed1999

Transgene expression in the guinea pig cochlea mediated by a lentivirus-derived gene transfer vector.

The utility of lentivirus as a gene delivery vector in the cochlea was evaluated in vitro and in vivo. Lentivirus transduction was assessed through expression analysis of a reporter gene, green fluorescent protein (GFP), integrated within the viral genome. In vitro characterization of lentivirus-GFP was assessed by infection of explants from cochleas of neonatal rat. The lentiviral vector transduced both spiral ganglion neurons (SGNs) and glial cells. In vivo characterization of lentivirus-GFP was assessed by directly infusing the vector into the guinea pig cochlea via an osmotic minipump. Sections of lentivirus-infused cochlea revealed a highly restricted fluorescence pattern limited to the periphery of the perilymphatic space. Transduction of SGNs and glial cells by lentivirus in vitro but not in vivo suggests limited dissemination of the viral vector from the perilymphatic space. The cellular and tissue architecture of the lentivirus-infused cochlea was intact and free of inflammation. Restricted transduction of cell types confined to the periphery of the perilymphatic space by the lentivirus is ideal for stable production of gene products secreted into the perilymph.

Animals↗

PubMed1999

Cationic liposome mediated transgene expression in the guinea pig cochlea.

Sensorineural hearing loss affects nearly 10% of the American population that is refractory to conventional therapy. Gene therapy represents an intervention with potential therapeutic efficacy. We studied the feasibility of cationic liposome mediated gene transfer within the guinea pig cochlea in vivo following direct microinjection into the cochlea. Transgene expression was persistent up to 14 days in the neurosensory epithelia and surrounding tissue without toxicity and inflammation in the target organ. This study represents the first successful use of cationic liposomes for cochlear gene transfer thus providing a safe and rapid alternative to the use of recombinant viral vectors in gene therapy for inner ear disorders.

Animals↗

PubMed1999

Piloting day-case surgery for prostate resection.

Some patients with benign prostatic hyperplasia need surgery. Transurethral vaporisation of the prostate (TUVP) can be managed without an inpatient stay. Specialist nurses have an important role in assessing and following up day-case patients.

Aftercare↗

PubMed1998

Potassium permeability in the absence of fluid reabsorption in proximal tubule of the anesthetized rat.

A luminal microperfusion technique was used to examine the K+ permeability of surface proximal convoluted tubules (PCT) in the kidney of anesthetized rats. Transtubular potassium concentration ([K+]) gradients were varied by altering the concentration of KCl in luminal perfusates, to which 32 mmol/l of the impermeant solute raffinose was also added to prevent net fluid reabsorption. The arithmetic mean transtubular [K+] gradient was highly predictive of net potassium flux, yielding an apparent K+ permeability of 31.9 +/- 1.7 x 10(-5) cm/s in the absence of fluid reabsorption. When compared using identical calculation techniques, we found this was not significantly different from the permeability derived in a previous study when fluid reabsorption was present [J. D. Kibble, M. Wareing, R. W. Wilson, and R.Green. Am. J. Physiol. 268 (Renal Fluid Electrolyte Physiol. 27): F778-F783, 1995]. We conclude that fluid reabsorption does not affect the apparent permeability of the proximal tubule to potassium. The apparent permeability to 86Rb, measured following its addition to luminal perfusates, was not significantly different from the value obtained for K+, suggesting that rubidium is a useful marker for net potassium movements in the PCT of the rat.

Absorption↗

PubMed1997

The role of active transport in potassium reabsorption in the proximal convoluted tubule of the anaesthetized rat.

1. We have previously assessed the contributions of diffusion and convection to net potassium reabsorption in the rat proximal convoluted tubule (PCT). The present study was conducted to evaluate the role of active transport in convective potassium reabsorption by measuring the transepithelial potassium reflection coefficient (sigmaK) in the presence and absence of cyanide in anaesthetized rats previously prepared for in vivo microperfusion. 2. Osmotic water permeability (Pf) was measured in double-perfused tubules (lumen and peritubular capillaries) by manipulating the applied transepithelial osmotic gradient between -30 and +40 mosmol (kg H2O)(-1) using raffinose added to or subtracted from luminal perfusates. Pf was unaffected by the presence of cyanide when the estimated dissipation of osmotic gradients along each tubule were taken into account. 3. The proportion of K+ (and Na+) convectively transported with water fluxes (i.e. sigmaK) was not affected by cyanide. In the absence of active transport and following correction for any diffusive component, sigmaK was 0.56 +/- 0.13, indicating substantial solvent drag which probably occurs via the paracellular pathway. 4. However, cyanide caused a reduction in net potassium flux over the entire range of fluid fluxes used in double-perfusion experiments. Subsequent single-perfusion experiments (tubule lumen only) using the specific K+-H+-ATPase inhibitor, SCH28080, failed to reveal any direct evidence for a primary active K+ transporting mechanism involved in K+ reabsorption in the PCT.

Absorption↗

PubMed1996

Laser-assisted uvulopalatoplasty: an assessment of a technique.

The Kamami technique of laser-assisted uvulopalatoplasty has recently been introduced into British practice as an office-based multistage procedure for the treatment of snoring and, in certain cases, for obstructive sleep apnoea. We have treated 50 patients with simple snoring, with a minimum follow-up of six months. Six-month telephone interview follow-up has assessed partner and patient satisfaction, as well as willingness to undergo the procedure again. We have found the procedure easy to perform with no serious intra-operative complications. Thirty-four (68 per cent) of patients' partners have been definitely satisfied with the results of treatment, with 11 (22 per cent) definitely unsatisfied. However, only 25 of these 34 satisfied patients (76 per cent) would be prepared to undergo the treatment again with post-operative pain and discomfort cited as the reason in those who would not. The failure rate doubled between one and six months post-operatively. There have been no serious complications but a 40 per cent minor side-effect rate is noted. These results are discussed in the context of previously reported results, with consideration of future strategies to improve outcome.

Adult↗