Pulmonary vasoconstrictor action of KCNQ potassium channel blockers

KCNQ channels have been widely studied in the nervous system, heart and inner ear, where they have important physiological functions. Recent reports indicate that KCNQ channels may also be expressed in portal vein where they are suggested to influence spontaneous contractile activity. The biophysical properties of K+ currents mediated by KCNQ channels resemble a current underlying the resting K+ conductance and resting potential of pulmonary artery smooth muscle cells. We therefore investigated a possible role of KCNQ channels in regulating the function of pulmonary arteries by determining the ability of the selective KCNQ channel blockers, linopirdine and XE991, to promote pulmonary vasoconstriction. Linopirdine and XE991 both contracted rat and mouse pulmonary arteries but had little effect on mesenteric arteries. In each case the maximum contraction was almost as large as the response to 50 mM K+. Linopirdine had an EC50 of around 1 μM and XE991 was almost 10-fold more potent. Neither removal of the endothelium nor exposure to phentolamine or α,β-methylene ATP, to block α1-adrenoceptors or P2X receptors, respectively, affected the contraction. Contraction was abolished in Ca2+-free solution and in the presence of 1 μM nifedipine or 10 μM levcromakalim

Exponential Metric Fields

The Laser Interferometer Space Antenna (LISA) mission will use advanced technologies to achieve its science goals: the direct detection of gravitational waves, the observation of signals from compact (small and dense) stars as they spiral into black holes, the study of the role of massive black holes in galaxy evolution, the search for gravitational wave emission from the early Universe. The gravitational red-shift, the advance of the perihelion of Mercury, deflection of light and the time delay of radar signals are the classical tests in the first order of General Relativity (GR). However, LISA can possibly test Einstein's theories in the second order and perhaps, it will show some particular feature of non-linearity of gravitational interaction. In the present work we are seeking a method to construct theoretical templates that limit in the first order the tensorial structure of some metric fields, thus the non-linear terms are given by exponential functions of gravitational strength. The Newtonian limit obtained here, in the first order, is equivalent to GR.Comment: Accepted for publication in Astrophysics and Space Science, 17 page

Bronchodilation induced by PGE2 is impaired in Group-III pulmonary hypertension

BACKGROUND AND PURPOSE: In patients with pulmonary hypertension (PH) associated with lung disease and/or hypoxia (Group III), a reduction of pulmonary vascular tone and tissue hypoxia are considered therapeutically beneficial. Prostaglandin (PG) E2 and PGI2 induce potent relaxation of human bronchi from non-PH (control) patients via EP4 and IP receptors, respectively. However, the effects of PGE2 /PGI2 and their mimetics on human bronchi from PH-patients are unknown. Our aim was to compare the relaxant effects of several PGI2 -mimetics approved for treating PH-Group I with several PGE2 -mimetics in bronchial preparations derived from PH-Group III and control patients. EXPERIMENTAL APPROACH: Using an organ bath system, the tone of bronchial muscle was investigated in tissue from either control or PH-Group III patients. Expression of prostanoid receptors were analyzed by Western blot and real-time PCR and endogenous PGE2 , PGI2 and cAMP levels were determined by ELISA. KEY RESULTS: Maximal relaxations induced by different EP4 agonists (PGE2 , L-902688, ONO-AE1-329) were significantly decreased in human bronchi from PH-patients versus controls. In contrast, the maximal relaxations produced by PGI2 -mimetics (iloprost, treprostinil, beraprost) were similar for both groups of patients. Both EP4 and IP receptor protein and mRNA expressions were significantly lower in human bronchi from PH-patients. cAMP levels significantly correlated with PGI2 but not with PGE2 levels. CONCLUSION AND IMPLICATIONS: This study shows that PGI2 -mimetics have preserved maximal bronchodilation in PH-Group III patients. The decreased bronchodilation induced by EP4 agonists suggests that restoration of EP4 expression in airways of PH-patients with respiratory diseases could bring additional therapeutic benefit

Characterization of Rat Meibomian Gland Ion and Fluid Transport

We establish novel primary rat meibomian gland (MG) cell culture systems and explore the ion transport activities of the rat MG

Nucleation in Systems with Elastic Forces

Systems with long-range interactions when quenced into a metastable state near the pseudo-spinodal exhibit nucleation processes that are quite different from the classical nucleation seen near the coexistence curve. In systems with long-range elastic forces the description of the nucleation process can be quite subtle due to the presence of bulk/interface elastic compatibility constraints. We analyze the nucleation process in a simple 2d model with elastic forces and show that the nucleation process generates critical droplets with a different structure than the stable phase. This has implications for nucleation in many crystal-crystal transitions and the structure of the final state

Hysteresis, Avalanches, and Disorder Induced Critical Scaling: A Renormalization Group Approach

We study the zero temperature random field Ising model as a model for noise and avalanches in hysteretic systems. Tuning the amount of disorder in the system, we find an ordinary critical point with avalanches on all length scales. Using a mapping to the pure Ising model, we Borel sum the $6-\epsilon$ expansion to $O(\epsilon^5)$ for the correlation length exponent. We sketch a new method for directly calculating avalanche exponents, which we perform to $O(\epsilon)$. Numerical exponents in 3, 4, and 5 dimensions are in good agreement with the analytical predictions.Comment: 134 pages in REVTEX, plus 21 figures. The first two figures can be obtained from the references quoted in their respective figure captions, the remaining 19 figures are supplied separately in uuencoded forma

Deleterious Effects of Cold Air Inhalation on Coronary Physiological Indices in Patients With Obstructive Coronary Artery Disease

Background Cold air inhalation during exercise increases cardiac mortality, but the pathophysiology is unclear. During cold and exercise, dual‐sensor intracoronary wires measured coronary microvascular resistance (MVR) and blood flow velocity (CBF), and cardiac magnetic resonance measured subendocardial perfusion. Methods and Results Forty‐two patients (62±9 years) undergoing cardiac catheterization, 32 with obstructive coronary stenoses and 10 without, performed either (1) 5 minutes of cold air inhalation (5°F) or (2) two 5‐minute supine‐cycling periods: 1 at room temperature and 1 during cold air inhalation (5°F) (randomized order). We compared rest and peak stress MVR, CBF, and subendocardial perfusion measurements. In patients with unobstructed coronary arteries (n=10), cold air inhalation at rest decreased MVR by 6% (P=0.41), increasing CBF by 20% (P<0.01). However, in patients with obstructive stenoses (n=10), cold air inhalation at rest increased MVR by 17% (P<0.01), reducing CBF by 3% (P=0.85). Consequently, in patients with obstructive stenoses undergoing the cardiac magnetic resonance protocol (n=10), cold air inhalation reduced subendocardial perfusion (P<0.05). Only patients with obstructive stenoses performed this protocol (n=12). Cycling at room temperature decreased MVR by 29% (P<0.001) and increased CBF by 61% (P<0.001). However, cold air inhalation during cycling blunted these adaptations in MVR (P=0.12) and CBF (P<0.05), an effect attributable to defective early diastolic CBF acceleration (P<0.05) and associated with greater ST‐segment depression (P<0.05). Conclusions In patients with obstructive coronary stenoses, cold air inhalation causes deleterious changes in MVR and CBF. These diminish or abolish the normal adaptations during exertion that ordinarily match myocardial blood supply to demand

Exercise Training in Pregnancy for obese women (ETIP): study protocol for a randomised controlled trial

<p/> <p>Background</p> <p>Both maternal pre-pregnancy obesity and excessive gestational weight gain are increasing in prevalence and associated with a number of adverse pregnancy outcomes for both mother and child. Observational studies regarding physical activity in pregnancy have found reduced weight gain in active mothers, as well as reduced risk of adverse pregnancy outcomes. There is however a lack of high quality, randomized controlled trials on the effects of regular exercise training in pregnancy, especially those with a pre-pregnancy body mass index (BMI) at or above 30 kg/m².</p> <p>Methods</p> <p>We are conducting a randomised, controlled trial in Norway with two parallel arms; one intervention group and one control group. We will enroll 150 previously sedentary, pregnant women with a pre-pregnancy BMI at or above 30 kg/m². The intervention group will meet for organized exercise training three times per week, starting in gestation week 14 (range 12-16). The control group will get standard antenatal care. The main outcome measure will be weight gain from baseline to delivery. Among the secondary outcome measures are changes in exercise capacity, endothelial function, physical activity level, body composition, serum markers of cardiovascular risk, incontinence, lumbopelvic pain and cardiac function from baseline to gestation week 37 (range 36-38). Offspring outcome measures include anthropometric variables at birth, Apgar score, as well as serum markers of inflammation and metabolism in cord blood.</p> <p>Discussion</p> <p>The results of this trial will provide knowledge about effects of regular exercise training in previously sedentary, obese pregnant women. If the program proves effective in reducing gestational weight gain and adverse pregnancy outcomes, such programs should be considered as part of routine pregnancy care for obese women.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01243554">NCT01243554</a></p

Accelerated turnover of taste bud cells in mice deficient for the cyclin-dependent kinase inhibitor p27Kip1

Background: Mammalian taste buds contain several specialized cell types that coordinately respond to tastants and communicate with sensory nerves. While it has long been appreciated that these cells undergo continual turnover, little is known concerning how adequate numbers of cells are generated and maintained. The cyclin-dependent kinase inhibitor p27Kip1 has been shown to influence cell number in several developing tissues, by coordinating cell cycle exit during cell differentiation. Here, we investigated its involvement in the control of taste cell replacement by examining adult mice with targeted ablation of the p27Kip1 gene.Results: Histological and morphometric analyses of fungiform and circumvallate taste buds reveal no structural differences between wild-type and p27Kip1-null mice. However, when examined in functional assays, mutants show substantial proliferative changes. In BrdU incorporation experiments, more S-phase-labeled precursors appear within circumvallate taste buds at 1 day post-injection, the earliest time point examined. After 1 week, twice as many labeled intragemmal cells are present, but numbers return to wild-type levels by 2 weeks. Mutant taste buds also contain more TUNEL-labeled cells and 50% more apoptotic bodies than wild-type controls. In normal mice, p27 Kip1 is evident in a subset of receptor and presynaptic taste cells beginning about 3 days post-injection, correlating with the onset of taste cell maturation. Loss of gene function, however, does not alter the proportions of distinct immunohistochemically-identified cell types.Conclusions: p27Kip1 participates in taste cell replacement by regulating the number of precursor cells available for entry into taste buds. This is consistent with a role for the protein in timing cell cycle withdrawal in progenitor cells. The equivalence of mutant and wild-type taste buds with regard to cell number, cell types and general structure contrasts with the hyperplasia and tissue disruption seen in certain developing p27Kip1-null sensory organs, and may reflect a compensatory capability inherent in the regenerative taste system