Purinergic inhibitory regulation of esophageal smooth muscle is mediated by P2Y receptors and ATP-dependent potassium channels in rats.

Purines such as ATP are regulatory transmitters in motility of the gastrointestinal tract. The aims of this study were to propose functional roles of purinergic regulation of esophageal motility. An isolated segment of the rat esophagus was placed in an organ bath, and mechanical responses were recorded using a force transducer. Exogenous application of ATP (10-100 µM) evoked relaxation of the esophageal smooth muscle in a longitudinal direction under the condition of carbachol (1 µM) -induced precontraction. Pretreatment with a non-selective P2 receptor antagonist, suramin (500 µM), and a P2Y receptor antagonist, cibacron blue F3GA (200 µM), inhibited the ATP (100 µM) -induced relaxation, but a P2X receptor antagonist, pyridoxal phosphate-6-azophenyl-2,4-disulfonic acid (50 µM), did not affect it. A blocker of ATP-dependent potassium channels (KATP channels), glibenclamide (200 µM), inhibited the ATP-induced relaxation and application of an opener of KATP channels, nicorandil (50 µM), produced relaxation. The findings suggest that ATP is involved in inhibitory regulation of the longitudinal smooth muscle in the muscularis mucosae of the rat esophagus via activation of P2Y receptors and then opening of KATP channels.

Repouso eletromiográfico dos músculos mastigatórios de pacientes com disfunção temporomandibular antes e após intervenção fonoaudiológica com e sem bandagem elástica / Electromyographic rest of the masticatory muscles of patients with temporomandibular disorders before and after speech therapy with and without elastic bandage / Resto electromiográfico de los músculos masticatorios de pacientes con trastornos temporomandibulares antes y después de logopedia con y sin venda elástica

Objetivo: A pesquisa tem por objetivo verificar os limiares de repouso eletromiográfico dos músculos masseter e temporal em pacientes com disfunção temporomandibular (DTM) antes e após intervenção fonoaudiológica com e sem a utilização de bandagem elástica terapêutica. Métodos: A coleta contou com 14 participantes do sexo feminino, com idade entre 18 e 40 anos, com diagnóstico de DTM muscular ou mista. As pacientes foram divididas entre dois grupos classificados em: pacientes com bandagem associada à terapia tradicional (CB) e grupo de terapia tradicional (SB). As pacientes inicialmente foram avaliadas pelo exame de eletromiografia de superfície nas situações de contração voluntária máxima e repouso, e após quatro semanas de intervenção, foi realizada nova avaliação com os mesmos instrumentos. A análise dos dados ocorreu de forma quantitativa e qualitativa. Resultados:No grupo SB o músculo masseter direito apresentou aumento dos valores de repouso com significância, foi observado que o mesmo ocorreu para todos os músculos deste grupo, influenciando no equilíbrio da musculatura ipsilateral e contralateral, no entanto sem evidência estatística. O grupo CB não demonstrou valores estatísticos significativos, porém qualitativamente os valores de repouso muscular diminuíram e equilibraram-se de forma contralateral. Conclusão: Não foram observadas mudanças estatisticamente significantes nos limiares eletromiográficos durante repouso dos músculos masseter e temporal em ambos os grupos. Qualitativamente houve aumento dos valores eletromiográficos após terapia manual tradicional em todos os músculos do grupo SB. Com relação ao grupo CB, houve diminuição dos valores do repouso eletromiográfico após terapia, embora sem evidências estatísticas. (AU)

Purpose: Objective: The research aims to verify the electromyographic rest thresholds of the masseter and temporal muscles in patients with temporomandibular disorders (TMD) before and after speech therapy intervention with and without the use of therapeutic elastic bandage. Methods: The collection included 14 female participants, aged between 18 and 40 years, who had a diagnosis of muscular or mixed TMD. The patients were divided into two groups: with traditional therapy (CB) bandage and traditional therapy (SB) only group. The patients underwent initial evaluation, as well as surface electromyography in situations of maximum voluntary contraction and rest and at the end of the four weeks of intervention, a new evaluation was performed with the same instruments. Data analysis occurred quantitatively and qualitatively. Results: In the SB group, the right masseter muscle showed a significant increase in resting values. It was observed that the same occurred for all muscles in this group, influencing the balance of the ipsilateral and contralateral muscles, although without statistical evidence. The CB group did not show statistically significant values, but qualitatively the muscle rest values decreased and balanced in a contralateral way. Conclusion: No statistically significant changes were observed in the resting electromyographic thresholds of the masseter and temporalis muscles in both groups. Qualitatively, there was an increase in electromyographic values after traditional manual therapy in all muscles in the SB group. Regarding the CB group, there was a decrease in electromyographic resting values after therapy, although without statistical evidence. (AU)

Objetivo: La investigación tiene como objetivo verificar los umbrales electromiográficos de reposo de los músculos masetero y temporal en pacientes con trastornos temporomandibulares (TMD) antes y después de la terapia del habla con y sin el uso de venda elástica terapéutica. Métodos: La colección incluyó a 14 participantes mujeres, con edades entre 18 y 40 años, diagnosticadas con TTM muscular o mixta. Los pacientes fueron divididos en dos grupos clasificados en: pacientes con vendaje asociado a terapia tradicional (CB) y grupo de terapia tradicional (SB). Los pacientes fueron inicialmente evaluados mediante electromiografía de superficie en situaciones de máxima contracción voluntaria y reposo, luego de cuatro semanas de intervención se realizó una nueva evaluación con los mismos instrumentos. El análisis de datos se llevó a cabo cuantitativa y cualitativamente. Resultados: En el grupo SB, el músculo masetero derecho presentó un aumento significativo en los valores de reposo, se observó que lo mismo ocurrió para todos los músculos de este grupo, influyendo en el equilibrio de los músculos ipsilaterales y contralaterales, sin embargo, sin evidencia estadística. El grupo CB no mostró valores estadísticamente significativos, pero cualitativamente los valores de descanso muscular disminuyeron y se equilibraron contralateralmente. Conclusión: No se observaron cambios estadísticamente significativos en los umbrales electromiográficos en reposo de los músculos masetero y temporal en ambos grupos. Cualitativamente, hubo un aumento de los valores electromiográficos después de la terapia manual tradicional en todos los músculos del grupo SB. En cuanto al grupo CB, hubo una disminución de los valores electromiográficos de reposo después de la terapia, aunque sin evidencia estadística. (AU)

Influence of age on force and re-lengthening dynamics after tetanic stimulation withdrawal in the tibialis anterior muscle.

PURPOSE: During alternate movements across a joint, the changeover from one direction of rotation to the opposite may be influenced by the delay and rate of tension reduction and the compliance to re-lengthening of the previously active muscle group. Given the aging process may affect the above-mentioned factors, this work aimed to compare the dynamics of both the ankle torque decline and muscle re-lengthening, mirrored by mechanomyogram (MMG), in the tibialis anterior because of its important role in gait. METHODS: During the relaxation phase, after a supramaximal 35 Hz stimulation applied at the superficial motor point, in 20 young (Y) and 20 old (O) subjects, the torque (T) and MMG dynamics characteristics were measured. RESULTS: The T and MMG analysis provided: (I) the beginning of the decay after cessation of stimulation (T: 22.51 ± 5.92 ms [Y] and 51.35 ± 15.21 ms [O]; MMG: 27.38 ± 6.93 ms [Y] and 61.41 ± 18.42 ms [O]); (II) the maximum rate of reduction (T: - 110.4 ± 45.56 Nm/s [Y] and - 52.72 ± 32.12 Nm/s [O]; MMG: - 24.47 ± 10.95 mm/s [Y] and - 13.76 ± 6.54 mm/s [O]); (III) the muscle compliance, measuring the MMG reduction of every 10% reduction of torque (bin 20-10%: 15.69 ± 7.5[Y] and 10.8 ± 3.3 [O]; bin 10-0%: 22.12 ± 10.3 [Y] and 17.58 ± 5.6 [O]). CONCLUSION: Muscle relaxation results are different in Y and O and can be monitored by a non-invasive method measuring physiological variables of torque and re-lengthening dynamics at the end of the electromechanical coupling previously induced by the neuromuscular stimulation.

Detecting impaired muscle relaxation in myopathies with the use of motor cortical stimulation.

Impaired muscle relaxation is a notable feature in specific myopathies. Transcranial magnetic stimulation (TMS) of the motor cortex can induce muscle relaxation by abruptly halting corticospinal drive. Our aim was to quantify muscle relaxation using TMS in different myopathies with symptoms of muscle stiffness, contractures/cramps, and myalgia and explore the technique's diagnostic potential. In men, normalized peak relaxation rate was lower in Brody disease (n = 4) (-3.5 ± 1.3 s-1), nemaline myopathy type 6 (NEM6; n = 5) (-7.5 ± 1.0 s-1), and myotonic dystrophy type 2 (DM2; n = 5) (-10.2 ± 2.0 s-1) compared to healthy (n = 14) (-13.7 ± 2.1 s-1; all P ≤ 0.01) and symptomatic controls (n = 9) (-13.7 ± 1.6 s-1; all P ≤ 0.02). In women, NEM6 (n = 5) (-5.7 ± 2.1 s-1) and McArdle patients (n = 4) (-6.6 ± 1.4 s-1) had lower relaxation rate compared to healthy (n = 10) (-11.7 ± 1.6 s-1; both P ≤ 0.002) and symptomatic controls (n = 8) (-11.3 ± 1.8 s-1; both P ≤ 0.008). TMS-induced muscle relaxation achieved a high level of diagnostic accuracy (area under the curve = 0.94 (M) and 0.92 (F)) to differentiate symptomatic controls from myopathy patients. Muscle relaxation assessed using TMS has the potential to serve as a diagnostic tool, an in-vivo functional test to confirm the pathogenicity of unknown variants, an outcome measure in clinical trials, and monitor disease progression.

A Par3/LIM Kinase/Cofilin Pathway Mediates Human Airway Smooth Muscle Relaxation by TAS2R14.

TAS2Rs (bitter taste receptors) are GPCRs (G protein-coupled receptors) expressed on human airway smooth muscle (HASM) cells; when activated by receptor agonists they evoke marked airway relaxation. In both taste and HASM cells, TAS2Rs activate a canonical Gßγ-mediated stimulation of Ca2+ release from intracellular stores by activation of PLCß (phospholipase Cß). Alone, this [Ca2+]i signaling does not readily account for relaxation, particularly since bronchoconstrictive agonists acting at Gq-coupled receptors also increase [Ca2+]i. We established that TAS2R14 activation in HASM promotes relaxation through F-actin (filamentous actin) severing. This destabilization of actin was from agonist-promoted activation (dephosphorylation) of cofilin, which was pertussis toxin sensitive. Cofilin dephosphorylation was due to TAS2R-mediated deactivation of LIM domain kinase. The link between early receptor action and the distal cofilin dephosphorylation was found to be the polarity protein partitioning defective 3 (Par3), a known binding partner with PLCß that inhibits LIM kinase. The physiologic relevance of this pathway was assessed using knock-downs of cofilin and Par3 in HASM cells and in human precision-cut lung slices. Relaxation by TAS2R14 agonists was ablated with knock-down of either protein as assessed by magnetic twisting cytometry in isolated cells or intact airways in the slices. Blocking [Ca2+]i release by TAS2R14 inhibited agonist-promoted cofilin dephosphorylation, confirming a role for [Ca2+]i in actin-modifying pathways. These results further elucidate the mechanistic basis of TAS2R-mediated HASM relaxation and point toward nodal points that may act as asthma or chronic obstructive pulmonary disease response modifiers or additional targets for novel bronchodilators.

Sensitivity and specificity of the flexion and extension relaxation ratios to identify altered paraspinal muscles' flexion relaxation phenomenon in nonspecific chronic low back pain patients.

BACKGROUND: Among the main methods used to identify an altered flexion relaxation phenomenon (FRP) in nonspecific chronic low back pain (NSCLBP), it has been previously demonstrated that flexion relaxation ratio (FRR) and extension relaxation ratio (ERR) are more objective than the visual reference method. OBJECTIVE: To determine the sensitivity and specificity of the different methods used to calculate the ratios in terms of their ability to identify an altered FRP in NSCLBP. METHODS: Forty-four NSCLBP patients performed a standing maximal trunk flexion task. Surface electromyography (sEMG) was recorded along the erector spinae longissimus (ESL) and multifidus (MF) muscles. Altered FRP based on sEMG was visually identified by three experts (current standard). Six FRR methods and five ERR methods were used both for the ESL and MF muscles. ROC curves (with areas under the curve (AUC) and sensitivity/specificity) were generated for each ratio. RESULTS: All methods used to calculate these ratios had an AUC higher than 0.9, excellent sensitivity (>90 %), and good specificity (80-100 %) for both ESL and MF muscles. CONCLUSION: Both FRP ratios (FRR and ERR) for MF and ESL muscles, appear to be an objective, sensitive and specific method for identifying altered FRP in NSCLBP patients.

Reproducibility and robustness of motor cortical stimulation to assess muscle relaxation kinetics.

Transcranial magnetic stimulation (TMS) of the motor cortex can be used during a voluntary contraction to inhibit corticospinal drive to the muscle and consequently induce involuntary muscle relaxation. Our aim was to evaluate the reproducibility and the effect of varying experimental conditions (robustness) of TMS-induced muscle relaxation. Relaxation of deep finger flexors was assessed in 10 healthy subjects (5 M, 5 F) using handgrip dynamometry with normalized peak relaxation rate as main outcome measure, that is, peak relaxation rate divided by (voluntary plus TMS-evoked)force prior to relaxation. Both interday and interrater reliability of relaxation rate were high with intraclass correlation coefficient of 0.88 and 0.92 and coefficient of variation of 3.8 and 3.7%, respectively. Target forces of 37.5% of maximal voluntary force or higher resulted in similar relaxation rate. From 50% of maximal stimulator output and higher relaxation rate remained the same. Only the most lateral position (>2 cm from the vertex) rendered lower relaxation rate (mean ± SD: 11.1 ± 3.0 s-1 , 95% CI: 9.0-13.3 s-1 ) compared to stimulation at the vertex (12.8 ± 1.89 s-1 , 95% CI: 11.6-14.1 s-1 ). Within the range of baseline skin temperatures, an average change of 0.5 ± 0.2 s-1 in normalized peak relaxation rate was measured per 1°C change in skin temperature. In conclusion, interday and interrater reproducibility and reliability of TMS-induced muscle relaxation of the finger flexors were high. Furthermore, this technique is robust with limited effect of target force, stimulation intensity, and coil position. Muscle relaxation is strongly affected by skin temperature; however, this effect is marginal within the normal skin temperature range. We deem this technique well suited for clinical and scientific assessment of muscle relaxation.

The role of l-cysteine/Hydrogen sulfide pathway on ß3-Adrenoceptor- induced relaxation in mouse gastric fundus.

In this study, we investigated the possible role of the l-cysteine/hydrogen sulfide pathway in ß3-adrenoceptors-mediated relaxation in isolated mouse gastric fundus tissue. l-cysteine (endogenous H2S; 10-6-10-2 M), sodium hydrogen sulfide (NaHS; exogenous H2S; 10-6-10-3 M), selective ß3-adrenoceptors agonist BRL 37344 (10-9-10-4 M) and non-selective ß-adrenoceptor agonist isoprenaline (10-9-10-4 M) produced concentration-dependent relaxation in mouse gastric fundus. The non-selective ß-adrenoceptors antagonist propranolol (10-6 M) inhibited the relaxant response to isoprenaline but not to BRL 37344. On the other hand, the selective ß3-adrenoceptors antagonist SR 59230A (10-5 M) inhibited the relaxant responses to BRL 37344. In addition, cystathionine-gamma-lyase (CSE) inhibitor D,L-propargylglycine (PAG, 10-2 M), cystathionine-beta-synthase inhibitor (CBS) aminooxyacetic acid (AOAA, 10-2 M), and the combination of these inhibitors significantly reduced the relaxant responses induced by l-cysteine and BRL 37344. Pre-incubation of gastric fundal strips with propranolol (10-6 M) and SR 59230A (10-5 M) did not affect relaxations to l-cysteine and NaHS. Also, the existence of CSE, CBS, 3-mercaptopurivate sulfur transferase (3-MST) enzymes and ß3-adrenoceptors were detected in gastric fundal tissue. Furthermore, basal H2S release was detected in the measurements. H2S level increased in the presence of l-cysteine, NaHS, and BRL 37344. The increase in H2S level by l-cysteine and BRL 37344 decreased significantly with PAG and AOAA enzyme inhibitors. These results suggest that endogenous H2S is synthesized from l-cysteine at least by CBS and CSE enzymes. Also, ß3-adrenoceptors are found in the mouse stomach fundus and mediate BRL 37344-induced relaxations, and l-cysteine/hydrogen sulfide pathway plays a partial role in ß3-adrenoceptors-mediated relaxation in mouse gastric fundus tissue.

Inhibition of ABCC1 Decreases cAMP Egress and Promotes Human Airway Smooth Muscle Cell Relaxation.

In most living cells, the second-messenger roles for adenosine 3',5'-cyclic monophosphate (cAMP) are short-lived, confined to the intracellular space, and tightly controlled by the binary switch-like actions of Gαs (stimulatory G protein)-activated adenylyl cyclase (cAMP production) and cAMP-specific PDE (cAMP breakdown). Here, by using human airway smooth muscle (HASM) cells in culture as a model, we report that activation of the cell-surface ß2AR (ß2-adrenoceptor), a Gs-coupled GPCR (G protein-coupled receptor), evokes cAMP egress to the extracellular space. Increased extracellular cAMP levels ([cAMP]e) are long-lived in culture and are induced by receptor-dependent and receptor-independent mechanisms in such a way as to define a universal response class of increased intracellular cAMP levels ([cAMP]i). We find that HASM cells express multiple ATP-binding cassette (ABC) membrane transporters, with ABCC1 (ABC subfamily member C 1) being the most highly enriched transcript mapped to MRPs (multidrug resistance-associated proteins). We show that pharmacological inhibition or downregulation of ABCC1 with siRNA markedly reduces ß2AR-evoked cAMP release from HASM cells. Furthermore, inhibition of ABCC1 activity or expression decreases basal tone and increases ß-agonist-induced HASM cellular relaxation. These findings identify a previously unrecognized role for ABCC1 in the homeostatic regulation of [cAMP]i in HASM that may be conserved traits of the Gs-GPCRs (Gs-coupled family of GPCRs). Hence, the general features of this activation mechanism may uncover new disease-modifying targets in the treatment of airflow obstruction in asthma. Surprisingly, we find that serum cAMP levels are elevated in a small cohort of patients with asthma as compared with control subjects, which warrants further investigation.

Thermal and behavioral response of horses submitted to functional exercises and acupuncture / Resposta térmica e comportamental de equinos submetidos a exercícios funcionais e acupuntura

The present research evaluated muscle activation degrees and relaxation of patrolling horses submitted to dynamic mobilization exercises, associated or not with acupuncture. Twelve mixed breed gelding, aged 10 ± 2.0 years, were distributed in three treatments. Treatment with a single session of dynamic mobilization exercises (longitudinal cervical flexion of head between hooves, between carpus and to up to chest); treatment with a single acupuncture session during 20 minutes, and treatment with a single session of dynamic mobilization exercises with acupuncture. Thermographic images were analyzed before and after applying treatments to the cervical, thoracic, dorsal, abdominal and pelvic regions. Animal behavior was assessed through five minutes filming, before and ten minutes after the end of each treatment application, in an uninterrupted way. Increase in animals body temperature at the end of the single session of functional exercises (P < 0.0001) at all animal regions were reported, being cervical and thoracic areas with highest final temperature values. There was no temperature variation for other treatments (P > 0.05). All treatments stimulated higher expression frequency (P < 0.05) of relaxation behaviors. A single dynamic mobilization exercises session is enough to promote intense muscular response in entire horse body; and with acupuncture, individually or associated, promoted muscle and mental relaxation, interfering positively in animal welfare.

Objetivou-se avaliar o grau de ativação e relaxamento muscular de equinos de patrulhamento submetidos à exercícios de mobilização dinâmica associados ou não à acupuntura. Doze cavalos castrados, sem raça definida, com idade de 10 ± 2,0 anos, foram distribuídos em três tratamentos: tratamento com uma sessão única de exercícios de mobilização dinâmica (flexão cervical longitudinal da cabeça entre os cascos, entre os carpos e até o peito); tratamento com sessão única de acupuntura (20 minutos); e tratamento com sessão única composta por exercícios de mobilização dinâmica associados a acupuntura. Foram analisadas imagens termográficas antes e após a aplicação dos tratamentos das regiões cervical, torácica, dorsal, abdominal e pélvica. A avaliação comportamental foi obtida por meio de filmagens 5 minutos antes e 10 minutos após o término da aplicação dos tratamentos, de maneira ininterrupta. Houve aumento (P < 0,0001) na temperatura corporal dos animais ao final da sessão única de exercícios funcionais para todas as regiões estudadas, sendo a cervical e torácica aquelas com maior valor de temperatura final. Não houve variação da temperatura nos demais tratamentos (P > 0,05). Todos os tratamentos geraram maior frequência (P < 0,05) na expressão de comportamentos relacionados ao relaxamento. A realização de uma sessão única de exercícios de mobilização dinâmica é suficiente para promover uma intensa resposta muscular em todo o corpo do equino, e tanto os exercícios funcionais quanto a acupuntura, de maneira individual ou associada, foram capazes de promover relaxamento muscular e mental, interferindo de maneira positiva no bem-estar dos animais.

Reduced Relaxant Response to Adenine in the Superior Mesenteric Artery of Spontaneously Hypertensive Rats.

We investigated the vascular response to nucleobase adenine using freshly isolated superior mesenteric arteries of spontaneously hypertensive rats (SHR) and its control, Wistar Kyoto (WKY) rats. Endothelium-dependent and endothelium-independent relaxations were assessed in isolated segments in an organ bath. The releases of the metabolites of thromboxane A2 and prostaglandin I2 were also detected. Adenine induced vasorelaxation in both the endothelium-intact and endothelium-denuded arteries in a concentration-dependent manner. In the SHR group, the adenine-induced relaxation was slightly but significantly reduced in the endothelium-intact rings when compared with that in the WKY group. However, the relaxation in the endothelium-denuded rings were similar between the two groups. The difference in the adenine-mediated relaxation in the superior mesenteric arteries between the SHR and WKY groups was eliminated by endothelial denudation and a nitric oxide (NO) synthase inhibitor. In the absence and presence of adenine, SHR tended to have higher levels of metabolites of thromboxane A2 and prostaglandin I2 compared with WKY. However, adenine did not induce the release of these substances in the arteries in both the SHR and WKY groups. These results suggest that the reduced adenine-mediated relaxation in the superior mesenteric arteries in SHR is due to a lack of contribution from the endothelium-derived NO and not from the release of prostanoids.

Involvement of interstitial cells of Cajal in nicotinic acetylcholine receptor-induced relaxation of the porcine lower esophageal sphincter.

The interstitial cells of Cajal (ICCs) play an important role in coordinated gastrointestinal motility. The present study aimed to elucidate whether or how ICCs are involved in the lower esophageal sphincter (LES) relaxation induced by stimulation of the nicotinic acetylcholine receptor. The application of 1,1-dimethyl-4-phenyl-piperazinium (DMPP; a nicotinic acetylcholine receptor agonist) induced a transient relaxation in the circular smooth muscle of the porcine LES. DMPP-induced relaxation was abolished by not only 1 µM tetrodotoxin but also the inhibition of ICC activity by pretreatment with 100 µM carbenoxolone (a gap junction inhibitor), pretreatment with 100 µM CaCCinh-A01 (an anoctamin-1 blocker acting as a calcium-activated chloride channel inhibitor), and pretreatment with Cl--free solution. However, pretreatment with 100 µM Nω-nitro-L-arginine methyl ester had little effect on DMPP-induced relaxation. Furthermore, DMPP-induced relaxation was inhibited by pretreatment with 1 mM suramin, a purinergic P2 receptor antagonist, but not by 1 µM VIP (6-28), a vasoactive intestinal peptide (VIP) receptor antagonist. Stimulation of the purinergic P2 receptor with adenosine triphosphate (ATP) induced relaxation, which was abolished by the inhibition of ICC activity by pretreatment with CaCCinh-A01. In conclusion, membrane hyperpolarization of the ICCs via the activation of anoctamin-1 plays a central role in DMPP-induced relaxation. ATP may be a neurotransmitter for inhibitory enteric neurons, which stimulate the ICCs. The ICCs act as the interface of neurotransmission of nicotinic acetylcholine receptor in order to induce LES relaxation.

Nitric Oxide: From Gastric Motility to Gastric Dysmotility.

It is known that nitric oxide (NO) plays a key physiological role in the control of gastrointestinal (GI) motor phenomena. In this respect, NO is considered as the main non-adrenergic, non-cholinergic (NANC) inhibitory neurotransmitter responsible for smooth muscle relaxation. Moreover, many substances (including hormones) have been reported to modulate NO production leading to changes in motor responses, further underlying the importance of this molecule in the control of GI motility. An impaired NO production/release has indeed been reported to be implicated in some GI dysmotility. In this article we wanted to focus on the influence of NO on gastric motility by summarizing knowledge regarding its role in both physiological and pathological conditions. The main role of NO on regulating gastric smooth muscle motor responses, with particular reference to NO synthases expression and signaling pathways, is discussed. A deeper knowledge of nitrergic mechanisms is important for a better understanding of their involvement in gastric pathophysiological conditions of hypo- or hyper-motility states and for future therapeutic approaches. A possible role of substances which, by interfering with NO production, could prove useful in managing such motor disorders has been advanced.

Ginger metabolites and metabolite-inspired synthetic products modulate intracellular calcium and relax airway smooth muscle.

Asthma affects millions of people worldwide and its prevalence is increasing. It is characterized by chronic airway inflammation, airway remodeling, and pathologic bronchoconstriction, and it poses a continuous treatment challenge with very few new therapeutics available. Thus, many asthmatics turn to plant-based complementary products, including ginger, for better symptom control, indicating an unmet need for novel therapies. Previously, we demonstrated that 6-shogaol (6S), the primary bioactive component of ginger, relaxes human airway smooth muscle (hASM) likely by inhibition of phosphodiesterases (PDEs) in the ß-adrenergic (cyclic nucleotide PDEs), and muscarinic (phospholipase C, PLC) receptor pathways. However, oral 6S is extensively metabolized and it is unknown if the resulting metabolites remain bioactive. Here, we screened all the known human metabolites of 6S and several metabolite-based synthetic derivatives to better understand their mechanism of action and structure-function relationships. We demonstrate that several metabolites and metabolite-based synthetic derivatives are able to prevent Gq-coupled stimulation of intracellular calcium [Ca2+]i and inositol trisphosphate (IP3) synthesis by inhibiting PLC, similar to the parent compound 6S. We also show that these compounds prevent recontraction of ASM after ß-agonist relaxation likely by inhibiting PDEs. Furthermore, they potentiate isoproterenol-induced relaxation. Importantly, moving beyond cell-based assays, metabolites also retain the functional ability to relax Gq-coupled-contractions in upper (human) and lower (murine) airways. The current study indicates that, although oral ginger may be metabolized rapidly, it retains physiological activity through its metabolites. Moreover, we are able to use naturally occurring metabolites as inspiration to develop novel therapeutics for brochoconstrictive diseases.

Manual Cervical Traction and Trunk Stabilization Cause Significant Changes in Upper and Lower Esophageal Sphincter: A Randomized Trial.

OBJECTIVES: Dysfunctions in the lower esophageal sphincter (LES) and the upper esophageal sphincter (UES) levels can occur owing to poor muscle coordination, contraction, or relaxation. Such condition can possibly be addressed by functional rehabilitation. The aim of this study was to measure pressure changes in the UES and LES at rest and during routine rehabilitation techniques, that is, cervical manual traction and trunk stabilization maneuver. METHODS: This study was conducted in a University Hospital Gastrointestinal Endoscopy Center. Cervical manual traction and a trunk stabilization maneuver were performed in a convenient group of 54 adult patients with gastroesophageal reflux disease. High-resolution manometry was used to measure pressure changes in the LES and UES at rest and during manual cervical traction and trunk stabilization maneuver. RESULTS: Average initial resting UES pressure was 90.91 mmHg. A significant decrease was identified during both cervical traction (average UES pressure = 42.13 mmHg, P < .001) and trunk stabilization maneuver (average UES pressure = 62.74 mmHg, P = .002). The average initial resting LES pressure was 14.31 mmHg. A significant increase in LES pressure was identified both during cervical traction (average LES pressure = 21.39 mmHg, P < .001) and during the trunk stabilization maneuver, (average pressure = 24.09 mmHg, P < .001). CONCLUSION: Cervical traction and trunk stabilization maneuvers can be used to decrease pressure in the UES and increase LES pressure in patients with gastroesophageal reflux disease.

Changes in electromyographic activity, mechanical power, and relaxation rates following inspiratory ribcage muscle fatigue.

Muscle fatigue is a complex phenomenon enclosing various mechanisms. Despite technological advances, these mechanisms are still not fully understood in vivo. Here, simultaneous measurements of pressure, volume, and ribcage inspiratory muscle activity were performed non-invasively during fatigue (inspiratory threshold valve set at 70% of maximal inspiratory pressure) and recovery to verify if inspiratory ribcage muscle fatigue (1) leads to slowing of contraction and relaxation properties of ribcage muscles and (2) alters median frequency and high-to-low frequency ratio (H/L). During the fatigue protocol, sternocleidomastoid showed the fastest decrease in median frequency and slowest decrease in H/L. Fatigue was also characterized by a reduction in the relative power of the high-frequency and increase of the low-frequency. During recovery, changes in mechanical power were due to changes in shortening velocity with long-lasting reduction in pressure generation, and slowing of relaxation [i.e., tau (τ), half-relaxation time (½RT), and maximum relaxation rate (MRR)] was observed with no significant changes in contractile properties. Recovery of median frequency was faster than H/L, and relaxation rates correlated with shortening velocity and mechanical power of inspiratory ribcage muscles; however, with different time courses. Time constant of the inspiratory ribcage muscles during fatigue and recovery is not uniform (i.e., different inspiratory muscles may have different underlying mechanisms of fatigue), and MRR, ½RT, and τ are not only useful predictors of inspiratory ribcage muscle recovery but may also share common underlying mechanisms with shortening velocity.

Regulation of coordinated muscular relaxation in Drosophila larvae by a pattern-regulating intersegmental circuit.

Typical patterned movements in animals are achieved through combinations of contraction and delayed relaxation of groups of muscles. However, how intersegmentally coordinated patterns of muscular relaxation are regulated by the neural circuits remains poorly understood. Here, we identify Canon, a class of higher-order premotor interneurons, that regulates muscular relaxation during backward locomotion of Drosophila larvae. Canon neurons are cholinergic interneurons present in each abdominal neuromere and show wave-like activity during fictive backward locomotion. Optogenetic activation of Canon neurons induces relaxation of body wall muscles, whereas inhibition of these neurons disrupts timely muscle relaxation. Canon neurons provide excitatory outputs to inhibitory premotor interneurons. Canon neurons also connect with each other to form an intersegmental circuit and regulate their own wave-like activities. Thus, our results demonstrate how coordinated muscle relaxation can be realized by an intersegmental circuit that regulates its own patterned activity and sequentially terminates motor activities along the anterior-posterior axis.

Physiological and pathological roles of the accommodation response in lower esophageal sphincter relaxation during wet swallows.

The preparatory accommodation response of lower esophageal sphincter (LES) before swallowing is one of the mechanisms involved in LES relaxation during wet swallows, however, the physiological and/or pathological roles of LES accommodation remain to be determined in humans. To address this problem, we conducted a prospective observational study of 38 patients with normal high-resolution manometry (HRM) and 23 patients with idiopathic esophagogastric junction outflow obstruction (EGJOO) to assess dry and wet swallows. The LES accommodation measurement was proposed for practical use in evaluating the LES accommodation response. Although swallow-induced LES relaxation was observed in both dry and wet swallows, LES accommodation (6.4, 3.1-11.1 mmHg) was only observed in wet swallows. The extent of LES accommodation was impaired in idiopathic EGJOO (0.6, - 0.6-6 mmHg), and the LES accommodation measurement of patients with idiopathic EGJOO (36.8, 29.5-44.3 mmHg) was significantly higher in comparison to those with normal HRM (23.8, 18-28.6 mmHg). Successful LES relaxation in wet swallowing can be achieved by LES accommodation in combination with swallow-induced LES relaxation. Impaired LES accommodation is characteristic of idiopathic EGJOO. In addition to the IRP value, the LES accommodation measurement may be useful for evaluating the LES relaxation function in clinical practice.

Inter-joint coordination and the flexion-relaxation phenomenon among adults with low back pain during bending.

BACKGROUND: Altered inter-joint coordination and reduced flexion-relaxation at end-range trunk flexion are common in people with low back pain. Inconsistencies in these behaviors, however, make assessment and treatment challenging for this population. RESEARCH QUESTION: The study objective was to investigate patterns of regional lumbo-pelvic coordination and flexion-relaxation in adults with and without low back pain, during a bending task. METHODS: Adults with low back pain (n = 16) and a healthy group (n = 21) performed three trials of a bending task. Motion capture and surface electromyography systems measured joint kinematics (hip, lower and upper lumbar spine) and muscle activity (erector spinae longissimus, iliocostalis, and multifidus). Continuous relative phase analysis determined inter-joint coordination of the hip/lower lumbar and lower lumbar/upper lumbar joint pairs, during flexion and extension periods. Flexion-relaxation ratios using normalized surface electromyography data determined the extent of flexion-relaxation for each muscle, during each period. For inter-joint coordination, two-way repeated measure mixed ANOVAs calculated the effects of group (healthy/low back pain), period, and their interactions. Separate hierarchical linear models were constructed and tested relationships between flexion-relaxation ratios and our independent variables, group and muscle, while controlling for patient characteristics. RESULTS: The low back pain group had more out-of-phase coordination of the hip/lower lumbar joint pair compared to the healthy group (mean difference = 24.7°; 95 % confidence interval = 3.93-45.4), independent of movement period. No significant between group differences in lower lumbar/upper lumbar coordination were observed. The low back pain group demonstrated reduced flexion-relaxation of all muscles during full flexion (21.7 % reduction on average), with multifidus showing the least relaxation. SIGNIFICANCE: Regional differences in the lumbar spine and the possibility of subgroups with distinct movement pattern should be considered when analyzing coordination in people with low back pain. Multifidus showed the largest changes in flexion-relaxation and should be included when measuring this construct.

A passive increase in muscle temperature enhances rapid force production and neuromuscular function in healthy adults.

OBJECTIVE: To test the effects of hot-water immersion on the rapid force production and parameters of neuromuscular function in healthy adults. DESIGN: Cross-sectional study. METHODS: Fifteen healthy adults (24.9±5.6 years; 178±11.4cm; 72.8±16.2kg) performed neuromuscular assessments before, after and ∼15min after either 90min of 42°C (hot) or 36°C (sham-condition) water immersion (lower body). Knee extensors rate of torque development (RTD) was measured during explosive voluntary contraction in the interval of 0-50ms (RTDV50) and 0-150ms (RTDV150) and during electrically-evoked contractions by single twitches (RTDtwitch) and low- and high-frequencies doublets (RTD20Hz and 100Hz). Rate of EMG rise (RER) was calculated for voluntary contractions and half-relaxation time (HRT) and electromechanical delay (EMD) was measured during single twitches. RESULTS: After the hot-water immersion (when rectal and muscle temperature were elevated [↑1°C and ↑2.4°C, respectively]), RTDV50, RTD20Hz and RTD100Hz significantly increased and HRT decreased when compared to baseline and sham-condition (p<0.05). Approximately 15min after the hot-water immersion (when muscle temperature was still higher [↑1.4°C], but rectal temperature at baseline level), RTDV50 remained higher and RTDtwitch presented higher values than baseline and sham-condition. The RTD20Hz and RTD100Hz showed further increases compared to post hot-water immersion trials. HRT showed no changes compared to post water immersion, but the EMD presented lower values than baseline and sham-condition. No changes were observed for RTDV150 and RER at any moment. CONCLUSION: Increased muscle temperature provoked by 42°C hot-water immersion increases the early phase of the RTD (<70ms) (voluntary and evoked) and decreases HRT and EMD of the knee extensors.