scholarly journals Adaptive study design to assess effect of TRPV4 inhibition in patients with chronic cough

2021 ◽  
pp. 00269-2021
Author(s):  
Valerie J. Ludbrook ◽  
Kate E. Hanrott ◽  
James L. Kreindler ◽  
Joanna E. Marks-Konczalik ◽  
Nick P. Bird ◽  
...  
Keyword(s):  
Study Design ◽  
Chronic Cough ◽  
Transient Receptor Potential ◽  
Sensory Nerves ◽  
Transient Receptor Potential Vanilloid ◽  
Investigational Drug ◽  
Study Results ◽  
Size Adjustment ◽  
Sample Size Adjustment ◽  
Trpv4 Channel

ObjectiveAirway sensory nerves involved in the cough reflex are activated by adenosine triphosphate (ATP) agonism of P2X purinoceptor 3 (P2X3) receptors. Transient receptor potential vanilloid 4 (TRPV4) channel activation causes ATP release from airway cells and it is hypothesised that a TRPV4-ATP-P2X3 axis contributes to chronic cough. An adaptive study was run to determine if TRPV4 inhibition, using the selective TRPV4 channel blocker GSK2798745, was effective in reducing cough.MethodsA two-period randomised, double blinded, placebo-controlled crossover study was designed with interim analyses for futility and sample size adjustment. Refractory chronic cough patients received either GSK2798745 or placebo once daily for 7 days with a wash-out between treatments. PK samples were collected for analysis of GSK2798745 at end of study. The primary endpoint was total cough counts assessed objectively during day-time hours (10 h) following 7 days of dosing.ResultsInterim analysis was performed after 12 participants completed both treatment periods. This showed a 32% increase in cough counts on Day 7 for GSK2798745 compared to placebo; the pre-defined negative criteria for the study were met and the study was stopped. At this point 17 participants had been enrolled (Mean 61yrs; 88% female), and 15 had completed the study. Final study results for posterior median cough counts showed a 34% (90% CrI: −3%, +85%) numerical increase for GSK2798745 compared to placebo.ConclusionThere was no evidence of an anti-tussive effect of GSK2798745. The study design allowed the decision on lack of efficacy to be made with minimal participant exposure to the investigational drug.

scholarly journals Exploring maternal nutrition counseling provided by health professionals during antenatal care follow-up: a qualitative study in Addis Ababa, Ethiopia-2019

BMC Nutrition ◽  
2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Matyas Atnafu Alehegn ◽  
Tsegaye Kebede Fanta ◽  
Agumas Fentahun Ayalew
Keyword(s):  
Pregnant Women ◽  
Study Design ◽  
Health Professionals ◽  
Maternal Nutrition ◽  
Addis Ababa ◽  
Nutrition Counseling ◽  
Institutional Barriers ◽  
Size Adjustment ◽  
Sample Size Adjustment ◽  
Pregnant Mothers

Abstract Background Nutritional awareness and practice of women during pregnancy could be determining their nutritional status, which significantly affects the outcome of pregnancy. Therefore this study aims to explore the maternal nutrition counseling provided by health professionals for pregnant women, Barriers to maternal nutrition, and major interventions. Methods A descriptive study design with a qualitative method by using ground theory tradition, based on constructivist research approach and Charmaz’s (2000) study design has been conducted from September-01/2019 _November-16/2019 among pregnant women who got ANC service in Addis Ababa, Ethiopia. A purposive sampling technique was used. Practical observations and in-depth interviews were conducted. The sample size adjustment has been carried out according to the information saturation obtained, and finally, 81 practical observations, In-depth interview with two center managers, nine health professionals and eleven term pregnant women has been conducted. An observational checklist and Semi-structured, open-ended questionnaires were used. Data, the environment, and methodological triangulation were carried out. A conceptual framework has been established based on the data collected about the whole process of maternal nutrition counseling during pregnancy. ATLAS TI software was utilized for information analysis. The results Most participants responded that maternal nutrition counseling provided to pregnant mothers is not adequate and neglected by most stakeholders. From 81 practical observations, health professionals counseled to mothers were 10 what to feed, 4 what to limit to consume, and 5 were counseled about what to eat during pregnancy. Close to all the respondents agreed on the importance of providing nutrition counseled by the nutritionists. Most of the study participants emphasized a shortage of time as primary barriers. Institutional Barriers, Professional Barriers, Maternal Barriers, and Community Barriers were major barriers to nutrition counseling. Conclusions Generally, maternal nutrition counseling provided to pregnant mothers was not adequate and neglected by most stakeholders. Shortage of time due to client flow, Institutional Barriers, Professional Barriers, Maternal Barriers, and Community Barriers were major categories of maternal nutritional counseling barriers. Information update and timely preparation were recommended to health professionals.

scholarly journals NGF Enhances CGRP Release Evoked by Capsaicin from Rat Trigeminal Neurons: Differential Inhibition by SNAP-25-Cleaving Proteases

2022 ◽  
Vol 23 (2) ◽  
pp. 892
Author(s):  
Mariia Belinskaia ◽  
Tomas Zurawski ◽  
Seshu Kumar Kaza ◽  
Caren Antoniazzi ◽  
J. Oliver Dolly ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Sensory Nerves ◽  
Neonatal Rat ◽  
Transient Receptor Potential Vanilloid ◽  
C Terminus ◽  
Low Concentrations ◽  
Transient Receptor ◽  
Neuronal Functions ◽  
Differential Ability

Nerve growth factor (NGF) is known to intensify pain in various ways, so perturbing pertinent effects without negating its essential influences on neuronal functions could help the search for much-needed analgesics. Towards this goal, cultured neurons from neonatal rat trigeminal ganglia—a locus for craniofacial sensory nerves—were used to examine how NGF affects the Ca2+-dependent release of a pain mediator, calcitonin gene-related peptide (CGRP), that is triggered by activating a key signal transducer, transient receptor potential vanilloid 1 (TRPV1) with capsaicin (CAP). Measurements utilised neurons fed with or deprived of NGF for 2 days. Acute re-introduction of NGF induced Ca2+-dependent CGRP exocytosis that was inhibited by botulinum neurotoxin type A (BoNT/A) or a chimera of/E and/A (/EA), which truncated SNAP-25 (synaptosomal-associated protein with Mr = 25 k) at distinct sites. NGF additionally caused a Ca2+-independent enhancement of the neuropeptide release evoked by low concentrations (<100 nM) of CAP, but only marginally increased the peak response to ≥100 nM. Notably, BoNT/A inhibited CGRP exocytosis evoked by low but not high CAP concentrations, whereas/EA effectively reduced responses up to 1 µM CAP and inhibited to a greater extent its enhancement by NGF. In addition to establishing that sensitisation of sensory neurons to CAP by NGF is dependent on SNARE-mediated membrane fusion, insights were gleaned into the differential ability of two regions in the C-terminus of SNAP-25 (181–197 and 198–206) to support CAP-evoked Ca2+-dependent exocytosis at different intensities of stimulation.

Responses of thoracic spinal neurons to activation and desensitization of cardiac TRPV1-containing afferents in rats

2006 ◽  
Vol 291 (6) ◽  
pp. R1700-R1707 ◽  
Author(s):  
Chao Qin ◽  
Jay P. Farber ◽  
Kenneth E. Miller ◽  
Robert D. Foreman
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Male Rats ◽  
Transient Receptor Potential Vanilloid ◽  
Spinal Neurons ◽  
Thoracic Spinal ◽  
Afferent Fibers ◽  
Study Results ◽  
Transient Receptor ◽  
Excitatory Responses

The purpose of this study was to examine how upper thoracic spinal neurons responded to activation and desensitization of cardiac transient receptor potential vanilloid-1 (TRPV1)-containing afferent fibers. Extracellular potentials of single T3 spinal neurons were recorded in pentobarbital-anesthetized, paralyzed, and ventilated male rats. To activate cardiac nociceptive receptors, a catheter was placed in the pericardial sac to administer various chemicals: bradykinin (BK; 10 μg/ml, 0.2 ml), capsaicin (CAP, 10 μg/ml, 0.2 ml), or a mixture of algesic chemicals (AC; 0.2 ml) containing adenosine 10−3 M, BK, serotonin, histamine, and PGE2, 10−5 M for each. Spinal neurons that responded to intrapericardial BK and/or CAP were used in this study. Results showed that 81% (35/43) of the neurons had excitatory responses to both intrapericardial BK and CAP, and the remainder responded to either BK or CAP. Intrapericardial resiniferatoxin (RTX) (0.2 μg/ml, 0.2 ml, 1 min), which desensitizes TRPV1-containing nerve endings, abolished excitatory responses to both BK ( n = 8) and CAP ( n = 7), and to AC ( n = 5) but not to somatic stimuli. Intrapericardial capsazepine (1 mg/ml, 0.2 ml, 3 min), a specific antagonist of TRPV1, sharply attenuated excitatory responses to CAP in 5/5 neurons, but responses to BK in 5/5 neurons was maintained. Additionally, intrapericardial capsazepine had no significant effect on excitatory responses to AC in 3/3 neurons. These data indicated that intrapericardial BK-initiated spinal neuronal responses were linked to cardiac TRPV1-containing afferent fibers, but were not dependent on TRPV1. Intraspinal signaling for cardiac nociception was mediated through CAP-sensitive afferent fibers innervating the heart.

scholarly journals Capsaicin-Sensitive Sensory Nerves and the TRPV1 Ion Channel in Cardiac Physiology and Pathologies

2020 ◽  
Vol 21 (12) ◽  
pp. 4472
Author(s):  
Tamara Szabados ◽  
Kamilla Gömöri ◽  
Laura Pálvölgyi ◽  
Anikó Görbe ◽  
István Baczkó ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ion Channel ◽  
Transient Receptor Potential ◽  
Heart Diseases ◽  
Receptor Potential ◽  
Cell Types ◽  
Sensory Nerves ◽  
Transient Receptor Potential Vanilloid ◽  
Cardiac Diseases ◽  
Trpv1 Channels

Cardiovascular diseases, including coronary artery disease, ischemic heart diseases such as acute myocardial infarction and postischemic heart failure, heart failure of other etiologies, and cardiac arrhythmias, belong to the leading causes of death. Activation of capsaicin-sensitive sensory nerves by the transient receptor potential vanilloid 1 (TRPV1) capsaicin receptor and other receptors, as well as neuropeptide mediators released from them upon stimulation, play important physiological regulatory roles. Capsaicin-sensitive sensory nerves also contribute to the development and progression of some cardiac diseases, as well as to mechanisms of endogenous stress adaptation leading to cardioprotection. In this review, we summarize the role of capsaicin-sensitive afferents and the TRPV1 ion channel in physiological and pathophysiological functions of the heart based mainly on experimental results and show their diagnostic or therapeutic potentials. Although the actions of several other channels or receptors expressed on cardiac sensory afferents and the effects of TRPV1 channel activation on different non-neural cell types in the heart are not precisely known, most data suggest that stimulation of the TRPV1-expressing sensory nerves or stimulation/overexpression of TRPV1 channels have beneficial effects in cardiac diseases.

PLA2 and TRPV4 channels regulate endothelial calcium in cerebral arteries

2007 ◽  
Vol 292 (3) ◽  
pp. H1390-H1397 ◽  
Author(s):  
Sean P. Marrelli ◽  
Roger G. O'Neil ◽  
Rachel C. Brown ◽  
Robert M. Bryan
Keyword(s):  
Transient Receptor Potential ◽  
Cerebral Arteries ◽  
Receptor Potential ◽  
Ruthenium Red ◽  
Transient Receptor Potential Vanilloid ◽  
Middle Cerebral Arteries ◽  
Trpv Channels ◽  
Intracellular Ca ◽  
Transient Receptor ◽  
Trpv4 Channel

We previously demonstrated that endothelium-derived hyperpolarizing factor (EDHF)-mediated dilations in cerebral arteries are significantly reduced by inhibitors of PLA2. In this study we examined possible mechanisms by which PLA2 regulates endothelium-dependent dilation, specifically whether PLA2 is involved in endothelial Ca2+ regulation through stimulation of TRPV4 channels. Studies were carried out with middle cerebral arteries (MCA) or freshly isolated MCA endothelial cells (EC) of male Long-Evans rats. Nitro-l-arginine methyl ester (l-NAME) and indomethacin were present throughout. In pressurized MCA, luminally delivered UTP produced increased EC intracellular Ca2+ concentration ([Ca2+]i) and MCA dilation. Incubation with PACOCF3, a PLA2 inhibitor, significantly reduced both EC [Ca2+]i and dilation responses to UTP. EC [Ca2+]i was also partially reduced by a transient receptor potential vanilloid (TRPV) channel blocker, ruthenium red. Manganese quenching experiments demonstrated Ca2+ influx across the luminal and abluminal face of the endothelium in response to UTP. Interestingly, PLA2-sensitive Ca2+ influx occurred primarily across the abluminal face. Luminal application of arachidonic acid, the primary product of PLA2 and a demonstrated activator of certain TRPV channels, increased both EC [Ca2+]i and MCA diameter. TRPV4 mRNA and protein was demonstrated in the endothelium by RT-PCR and immunofluorescence, respectively. Finally, application of 4α-phorbol 12,13-didecanoate (4αPDD), a TRPV4 channel activator, produced an increase in EC [Ca2+]i that was significantly reduced in the presence of ruthenium red. We conclude that PLA2 is involved in EC Ca2+ regulation through its regulation of TRPV4 channels. Furthermore, the PLA2-sensitive component of Ca2+ influx may be polarized to the abluminal face of the endothelium.

scholarly journals Local control of TRPV4 channels by AKAP150-targeted PKC in arterial smooth muscle

2014 ◽  
Vol 143 (5) ◽  
pp. 559-575 ◽  
Author(s):  
Jose Mercado ◽  
Rachael Baylie ◽  
Manuel F. Navedo ◽  
Can Yuan ◽  
John D. Scott ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Transient Receptor Potential ◽  
Critical Role ◽  
Super Resolution ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Anchoring Protein ◽  
Channel Interactions ◽  
Transient Receptor ◽  
Trpv4 Channel

Transient receptor potential vanilloid 4 (TRPV4) channels are Ca2+-permeable, nonselective cation channels expressed in multiple tissues, including smooth muscle. Although TRPV4 channels play a key role in regulating vascular tone, the mechanisms controlling Ca2+ influx through these channels in arterial myocytes are poorly understood. Here, we tested the hypothesis that in arterial myocytes the anchoring protein AKAP150 and protein kinase C (PKC) play a critical role in the regulation of TRPV4 channels during angiotensin II (AngII) signaling. Super-resolution imaging revealed that TRPV4 channels are gathered into puncta of variable sizes along the sarcolemma of arterial myocytes. Recordings of Ca2+ entry via single TRPV4 channels (“TRPV4 sparklets”) suggested that basal TRPV4 sparklet activity was low. However, Ca2+ entry during elementary TRPV4 sparklets was ∼100-fold greater than that during L-type CaV1.2 channel sparklets. Application of the TRPV4 channel agonist GSK1016790A or the vasoconstrictor AngII increased the activity of TRPV4 sparklets in specific regions of the cells. PKC and AKAP150 were required for AngII-induced increases in TRPV4 sparklet activity. AKAP150 and TRPV4 channel interactions were dynamic; activation of AngII signaling increased the proximity of AKAP150 and TRPV4 puncta in arterial myocytes. Furthermore, local stimulation of diacylglycerol and PKC signaling by laser activation of a light-sensitive Gq-coupled receptor (opto-α1AR) resulted in TRPV4-mediated Ca2+ influx. We propose that AKAP150, PKC, and TRPV4 channels form dynamic subcellular signaling domains that control Ca2+ influx into arterial myocytes.

Sign in / Sign up

Export Citation Format

Share Document