Block of SK channels by the sigma agonist 1,3-di-o-tolyl-guanidine: evidence for a novel site of action for SK blockers

Poster (2010, October 16)

Among ion channels involved in the control of neuronal activity, small conductance calcium-activated potassium channels (SK) represent an interesting therapeutic target. Indeed, they underlie medium ... [more ▼]

Among ion channels involved in the control of neuronal activity, small conductance calcium-activated potassium channels (SK) represent an interesting therapeutic target. Indeed, they underlie medium duration afterhyperpolarizations (mAHPs) in many types of neurons, thus inhibiting cell excitability. Three subtypes of SK subunits, SK1, SK2 and SK3, have been cloned and are expressed differentially within the central nervous system (CNS). Blocking SK channels might be beneficial in the treatment of several CNS disorders such as depression (SK3), Parkinson’s disease (SK3) and cognitive disorders (SK2). So far, the prototypical blocker of SK channels is apamin, an octadecapeptide from bee venom. We have recently shown that apamin blocks SK channels by binding to a site distinct from that used by classical pore blockers such as tetraethylammonium (TEA) (Lamy et al. J. Biol. Chem. 2010, 285, 27067-77). We have also demonstrated that the nonpeptide blocker N-methyl-laudanosine (NML) (Scuvée-Moreau et al. J. Pharmacol. Exp. Ther. 2002, 302, 1176-83) competes for the binding site of the toxin. Further, our research team has recently shown that the sigma agonist 1,3-di-o-tolyl-guanidine (DTG) directly blocks SK currents in a voltage-independent manner (Lamy et al. Eur. J. Pharmacol. 2010, 641, 23-8). We have combined patch clamp experiments on cell lines with molecular modelling and mutagenesis, to try to identify the site where DTG blocks. DTG was found to be equipotent on wild-type (WT) and apamin-insensitive (e.g. SK2H337N) channels. Moreover, mutated channels with increased sensitivity to TEA (SK3V520F: mean IC50 of TEA: 0.34 mM versus 11 mM for WT channels) were blocked by DTG with the same potency as WT channels. Thus, DTG does not seem to share the site of either apamin or TEA. Modelling data were in agreement with this possibility because of the identification of various potential binding sites. Although preliminary, these results suggest the existence of yet another binding site in the outer pore region of SK channels. [less ▲]

Blockade of ethanol-induced potentiation of glycine receptors by a peptide that interferes with Gbetagamma binding.

in Journal of Pharmacology and Experimental Therapeutics (2009)

Blogs littéraires : par-delà le moi

Article for general public (2006)

Blood collection while using a continuous glucose analyzer without insertion of an additional venous catheter.

in Diabetologia (1983), 25(2), 120-2

A new method for continuous blood collection using the Biostator is described. Blood is withdrawn through the double lumen catheter by a tube installed in the optional channel of the infusion pump. The ... [more ▼]

A new method for continuous blood collection using the Biostator is described. Blood is withdrawn through the double lumen catheter by a tube installed in the optional channel of the infusion pump. The amount of blood withdrawn from the patient is slightly greater than that necessary for continuous glucose analysis; the excess blood can be collected into assay tubes. Blood collection is continuous and produces a sample of diluted heparinized blood. The volume of blood collected depends on the size of the tube used, i.e. for a tube with a lumen diameter of 0.020 inches, the mean (+/- SD) volume collected was 1.21 +/- 0.07 ml/10 min (n = 13). The mean time interval between sampling and arrival at the glucose sensor by the double lumen catheter was 119 versus 108 s with the conventional method. The proposed modification does not affect blood glucose measurements (correlation coefficient compared with the reference method r = 0.9572; n = 13). To compensate for blood dilution, a dilution-factor depending on tubing diameter has to be calculated in each experiment. [less ▲]

Blood culturing in the 90's: Why and When?

Conference (1997, February)

Blood Flow under External Strains; Phenomenological Approach, Theoretical Developments & Numerical Analysis

in International Journal of Design & Nature and Ecodynamics (2010), 78

In the medical field, the measurement of blood flow characteristics is often necessary. More specifically, blood pressure is an essential measure when it comes to assessing health. All over the world ... [more ▼]

In the medical field, the measurement of blood flow characteristics is often necessary. More specifically, blood pressure is an essential measure when it comes to assessing health. All over the world, many people suffer from hyper- or hypotension, and as it is known that these diseases can lead to serious complications, it is of great interest to determine the blood pressure with high accuracy. Nowadays, such information requires the use of specifi c materials; the present method for the measurement of the arterial pressure, by applying pressure using an armband (with a control device called sphygmomanometer), is known to introduce significant errors due to the inadequacy of the band dimensions (both the length and the circumference). The objective of the present research is to study and simulate the discharge of the blood in an artery subjected to external strains using theoretical developments and a numerical approach. Based on these modelling results, the response of the fluid to the external pressure of the band can be studied, and fi nally appropriate corrective factors for the true pressure and the measured pressure could be assessed. This research has been carried out with the aim of sharing medical and engineering views on the subject. The artery can be modelled as a deformable pipe, where the blood fl owing in it is a fl uid with specifi c properties. Thus, two complementary and interconnected domains are covered, solid mechanics (to obtain analytic relations between the strains and the deformations, using either linear or non-linear theories) and fluid mechanics (to study the discharge of blood in a deformable pipe, using finite volume methods), therefore considering the problem as a loose fl uid–structure interaction (FSI). These two domains, which are well studied for common materials in civil engineering applications, are applied here not only to specifi c materials but especially to uncommon structures that, besides the somehow common FSI developments, lead to the investigation and research of very specifi c boundary conditions, giving them a physically based behaviour. At present, the research has reached the penultimate step, with the two main mentioned axes being fully developed and tested on their own. In particular, the boundary conditions developed for the models have been investigated and modelled in depth. [less ▲]

Blood glucose concentration profile after 10 mg dexamethasone in non-diabetic and type 2 diabetic patients undergoing abdominal surgery

in British Journal of Anaesthesia (2006), 97(2), 164-170

BACKGROUND: Dexamethasone prevents postoperative nausea and vomiting but may increase blood glucose. We compared blood glucose concentrations after dexamethasone in non-diabetic and type 2 diabetic ... [more ▼]

BACKGROUND: Dexamethasone prevents postoperative nausea and vomiting but may increase blood glucose. We compared blood glucose concentrations after dexamethasone in non-diabetic and type 2 diabetic patients undergoing surgery and looked for any association with preoperative glycosylated haemoglobin [HbA (1c)] and BMI. METHODS: Sixty three patients were enrolled: 32 were non-diabetic (Group ND) and 31 type 2 diabetic (Group D) without insulin treatment. Anaesthesia was induced using i.v. anaesthetic agents and maintained with sevoflurane. All patients received 10 mg dexamethasone at induction. Blood glucose concentrations were measured at induction and then every 60 min for 240 min. Data were analysed using anova. Effects of HbA (1c) and BMI were investigated using linear correlation and logistic regression. RESULTS: Blood glucose concentrations increased significantly over time and peaked at 120 min after 10 mg dexamethasone in both groups. The magnitude of increase was comparable between the groups [mean (SD) 29 (19) and 35 (19)% of baseline in Group D and Group ND, respectively]. Maximum concentrations were higher in Group D [8.97 (1.51) mmol litre(-1), range 6.67-12.94 mmol litre(-1)] than in Group ND [7.86 (1.00) mmol litre(-1), range 5.78-10.00 mmol litre(-1)]. There was a significant correlation between the maximum concentrations and BMI (R(2)=0.21) or HbA (1c) (R(2)=0.26). Logistic regression analysis revealed that the higher the BMI, the lower the HbA (1c) threshold associated with an increased probability (>0.5) of observing blood glucose levels higher than 8.33 mmol litre(-1) during 240 min after dexamethasone administration. Similarly, the higher the HbA (1c), the lower the BMI threshold associated with the same probability. CONCLUSIONS: After 10 mg dexamethasone, blood glucose levels increase in non-diabetic and type 2 diabetic patients undergoing abdominal surgery. Poorly controlled diabetes and severe obesity can influence the development of hyperglycaemia. [less ▲]

Blood Mononuclear Cells Mobilization and Cytokines Secretion During Prolonged Exercises

in International Journal of Sports Medicine (1996), 17(2), 156-60

This study was designed to compare the effects of three prolonged exercises varying in their intensity and duration, on blood mononuclear cell mobilization and cytokine secretion (IL1(1)-IL(2)). Seven ... [more ▼]

This study was designed to compare the effects of three prolonged exercises varying in their intensity and duration, on blood mononuclear cell mobilization and cytokine secretion (IL1(1)-IL(2)). Seven healthy subjects underwent three effort trials (45 % VO(2)max during 4 h - 60% VO(2)max during 3 h - 75 % VO(2)max during 2 h) at one-month intervals. Blood samples were drawn before, different times during exercise and also after exercise. Prolonged exercises induced a transient increase in blood mononuclear cells which occurred across all intensity levels. We also observed a significant increase in plasma IL(1) level during exercise which correlates with the exercise intensity. The mean IL(1) level increased up to 2.5 times after the three proposed exercises (p <0.05). Plasma IL(2) level decreased at the end of prolonged exercises irrespective of the exercise intensity. No correlation was observed between blood mononuclear count and cytokine determination. Our data suggest that blood mononuclear cells mobilization is associated but not correlated with alterations of cytokine levels. [less ▲]

Blood oxygen binding in hypoxaemic calves

in Veterinary Research (2002), 33(3), 283-290

Blood oxygen transport and tissue oxygenation were studied in 28 calves from the Belgian White and Blue breed (20 healthy and 8 hypoxaemic ones). Hypoxaemic calves were selected according to their high ... [more ▼]

Blood oxygen transport and tissue oxygenation were studied in 28 calves from the Belgian White and Blue breed (20 healthy and 8 hypoxaemic ones). Hypoxaemic calves were selected according to their high respiratory frequency and to their low partial oxygen pressure (PaO2) in the arterial blood. Venous and arterial blood samples were collected, and 2,3-diphosphoglycerate, adenosine triphosphate, chloride, inorganic phosphate and hemoglobin concentrations, and pH, PCO, and PO2 were determined. An oxygen equilibrium curve (OEC) was measured in standard conditions, for each animal. The arterial and venous OEC were calculated, taking body temperature, pH and PCO2 values in arterial and venous blood into account. The oxygen exchange fraction (OEF%), corresponding to the degree of blood desaturation between the arterial and the venous compartments, and the amount of oxygen released at the tissue level by 100 mL of blood (OEF Vol%) were calculated from the arterial and venous OEC combined with the PO2 and hemoglobin concentration. In hypoxaemic calves investigated in this study, the hemoglobin oxygen affinity, measured under standard conditions, was not modified. On the contrary, in vivo acidosis and hypercapnia induced a decrease in the hemoglobin oxygen affinity in arterial blood, which combined to the decrease in PaO2 led to a reduced hemoglobin saturation degree in the arterial compartment. However, this did not impair the oxygen exchange fraction (OEF%), since the hemoglobin saturation degree in venous blood was also diminished. [less ▲]

Blood pressure control in treated hypertensive patients: clinical experience

Poster (2003, May 13)

Too many treated hypertensive patients remain uncontrolled all over the world. Patients' compliance but also the management of adequate treatment by the physician are essential to improve blood pressure ... [more ▼]

Too many treated hypertensive patients remain uncontrolled all over the world. Patients' compliance but also the management of adequate treatment by the physician are essential to improve blood pressure control. Aim: The present study assesses the prevalence of control of SBP and DBP among patients referred to an hypertension clinic by general practitioners and specialists to measure treatment efficacy. Characteristics of uncontrolled patients' treatment are analysed. Were recorded: Office Blood Pressure (OBP), 24hours ABPM, history of cardiovascular risk factors and detailed current antihypertensive treatment. [less ▲]