Importance of the subscapularis muscle after total shoulder arthroplasty.

BACKGROUND: The rotator cuff muscles are the main stabilizer of the glenohumeral joint. After total shoulder arthroplasty using anterior approaches, a dysfunction of the subscapularis muscle has been reported. In the present paper we tested the hypothesis that a deficient subscapularis following total shoulder arthroplasty can induce joint instability. METHODS: To test this hypothesis we have developed an EMG-driven musculoskeletal model of the glenohumeral joint. The model was based on an algorithm that minimizes the difference between measured and predicted muscular activities, while satisfying the mechanical equilibrium of the glenohumeral joint. A movement of abduction in the scapular plane was simulated. We compared a normal and deficient subscapularis. Muscle forces, joint force, contact pattern and humeral head translation were evaluated. FINDINGS: To satisfy the mechanical equilibrium, a deficient subscapularis induced a decrease of the force of the infraspinatus muscle. This force decrease was balanced by an increase of the supraspinatus and middle deltoid. As a consequence, the deficient subscapularis induced an upward migration of the humeral head, an eccentric contact pattern and higher stress within the cement. INTERPRETATION: These results confirm the importance of the suscapularis for the long-term stability of total shoulder arthroplasty.

Conceptual framework for strengthening exercises to prevent hamstring strains

High-speed running accounts for the majority of hamstring strains in many sports. The terminal swing phase is believed to be the most hazardous as the hamstrings are undergoing an active lengthening contraction in a long muscle length position. Prevention-based strength training mainly focuses on eccentric exercises. However, it appears crucial to integrate other parameters than the contraction type. Therefore, the aim of this study is to present a conceptual framework based on six key parameters (contraction type, load, range of motion, angular velocity, uni-/bilateral exercises, kinetic chain) for the hamstring's strength exercise for strain prevention. Based on the biomechanical parameters of sprinting, it is proposed to use high-load eccentric contractions. The movement should be performed at a slow to moderate angular velocity and focused at the knee joint, while the hip is kept in a large flexion position in order to reach a greater elongation stress of the hamstrings than in the terminal swing phase. In this way, we believe that, during sprinting, athletes would be better trained to brake the knee extension effectively in the whole range of motion without overstretch of the hamstrings. Finally, based on its functional application, unilateral open kinetic chain should be preferred.

Intercellular calcium waves in primary cultured rat mesenteric smooth muscle cells are mediated by connexin43.

Intercellular Ca(2+) wave propagation between vascular smooth muscle cells (SMCs) is associated with the propagation of contraction along the vessel. Here, we characterize the involvement of gap junctions (GJs) in Ca(2+) wave propagation between SMCs at the cellular level. Gap junctional communication was assessed by the propagation of intercellular Ca(2+) waves and the transfer of Lucifer Yellow in A7r5 cells, primary rat mesenteric SMCs (pSMCs), and 6B5N cells, a clone of A7r5 cells expressing higher connexin43 (Cx43) to Cx40 ratio. Mechanical stimulation induced an intracellular Ca(2+) wave in pSMC and 6B5N cells that propagated to neighboring cells, whereas Ca(2+) waves in A7r5 cells failed to progress to neighboring cells. We demonstrate that Cx43 forms the functional GJs that are involved in mediating intercellular Ca(2+) waves and that co-expression of Cx40 with Cx43, depending on their expression ratio, may interfere with Cx43 GJ formation, thus altering junctional communication.

Artificial muscle: the human chimera is the future.

Severe heart failure and cerebral stroke are broadly associated with the impairment of muscular function that conventional treatments struggle to restore. New technologies enable the construction of "smart" materials that could be of great help in treating diseases where the main problem is muscle weakness. These materials "behave" similarly to biological systems, because the material directly converts energy, for example electrical energy into movement. The extension and contraction occur silently like in natural muscles. The real challenge is to transfer this amazing technology into devices that restore or replace the mechanical function of failing muscle. Cardiac assist devices based on artificial muscle technology could envelope a weak heart and temporarily improve its systolic function, or, if placed on top of the atrium, restore the atrial kick in chronic atrial fibrillation. Artificial sphincters could be used to treat urinary incontinence after prostatectomy or faecal incontinence associated with stomas. Artificial muscles can restore the ability of patients with facial paralysis due to stroke or nerve injury to blink. Smart materials could be used to construct an artificial oesophagus including peristaltic movement and lower oesophageal sphincter function to replace the diseased oesophagus thereby avoiding the need for laparotomy to mobilise stomach or intestine. In conclusion, in the near future, smart devices will integrate with the human body to fill functional gaps due to organ failure, and so create a human chimera.

Artificial muscle for end-stage heart failure.

We describe a device made of artificial muscle for the treatment of end-stage heart failure as an alternative to current heart assist devices. The key component is a matrix of nitinol wires and aramidic fibers called Biometal muscle (BM). When heated electrically, it produces a motorless, smooth, and lifelike motion. The BM is connected to a carbon fiber scaffold, tightening the heart and providing simultaneous assistance to the left and right ventricles. A pacemaker-like microprocessor drives the contraction of the BM. We tested the device in a dedicated bench model of diseased heart. It generated a systolic pressure of 75 mm Hg and ejected a maximum of 330 ml/min, with an ejection fraction of 12%. The device required a power supply of 6 V, 250 mA. This could be the beginning of an era in which BMs integrate or replace the mechanical function of natural muscles.

Assessment of quadriceps muscle inactivation with a new electrical stimulation paradigm.

INTRODUCTION: In this study we evaluated the validity of garment-based quadriceps stimulation (GQS) for assessment of muscle inactivation in comparison with femoral nerve stimulation (FNS). METHODS: Inactivation estimates (superimposed doublet torque), self-reported discomfort, and twitch and doublet contractile properties were compared between GQS and FNS in 15 healthy subjects. RESULTS: Superimposed doublet torque was significantly lower for GQS than for FNS at 20% and 40% maximum voluntary contraction (MVC) (P < 0.01), but not at 60%, 80%, and 100% MVC. Discomfort scores were systematically lower for GQS than for FNS (P < 0.05). Resting twitch and doublet peak torque were lower for GQS, and time to peak torque was shorter for GQS than for FNS (P < 0.01). CONCLUSIONS: GQS can be used with confidence for straightforward evaluation of quadriceps muscle inactivation, whereas its validity for assessment of contractile properties remains to be determined. Muscle Nerve 51: 117-124, 2015.

CARDIAC AND MUSCLE CHANNELOPATHIES: ROLES AND REGULATION OF VOLTAGE-GATED SODIUM CHANNELS

Abstract :The contraction of the heart or skeletal muscles is mainly due to the propagation, through excitable cells, of an electrical influx called action potential (AP). The AP results from the sequential opening of ion channels that generate inward or outward currents through the cell membrane. Among all the channels involved, the voltage-gated sodium channel is responsible for the rising phase of the action potential. Ten genes encode the different isoforms of these channels (from Nav1.1 to Nav1.9 and an atypical channel named NavX). Nav1.4 and Nav1.5 are the main skeletal muscle and cardiac sodium channels respectively. Their importance for muscle and heart function has been highlighted by the description of mutations in their encoding genes SCN4A and SCNSA. They lead respectively to neuromuscular disorders such as myotonia or paralysis (for Nav1.4), and to cardiac arrhythmias that can deteriorate into sudden cardiac death (for Nav1.5).The general aim of my PhD work has been to study diseases linked with channels dysfunction, also called channelopathies. In that purpose, I investigated the function and the regulation of the muscle and cardiac voltage-gated sodium channels. During the two first studies, I characterized the effects of two mutations affecting Nav1.4 and Nav1.5 function. I used the HEK293 model cells to express wild-type or mutant channels and then studied their biophysical properties with the patch-clamp technique, in whole cell configuration. We found that the SCN4A mutation produced complex alterations of the muscle sodium channel function, that could explain the myotonic phenotype described in patients carrying the mutation. In the second study, the index case was an heterozygous carrier of a SCNSA mutation that leads to a "loss of function" of the channel. The decreased sodium current measured with mutated Nay 1.5 channels, at physiological temperature, was a one of the factors that could explain the observed Brugada syndrome. The last project aimed at identifying a new potential protein interacting with the cardiac sodium channel. We found that the protein SAP97 binds the three last amino-acids of the C-terminus of Na,, 1.5. Our results also indicated that silencing the expression of SAP97 in HEK293 cells decreased the sodium current. Sodium channels lacking their three last residues also produced a reduced INa. These preliminary results suggest that SAP97 is implicated in the regulation of sodium channel. Whether this effect is direct or imply the action of an adaptor protein remains to be investigated. Moreover, our group has previously shown that Nav1.5 channels are localized to lateral membranes of cardiomyocytes by the dystrophin multiprotein complex (DMC). This suggests that sodium channels are distributed in, at least, two different pools: one targeted at lateral membranes by DMC and the other at intercalated discs by another protein such as SAP97.These studies reveal that cardiac and muscle diseases may result from ion channel mutations but also from regulatory proteins affecting their regulation.Résumé :La contraction des muscles et du coeur est principalement due à la propagation, à travers les cellules excitables, d'un stimulus électrique appelé potentiel d'action (PA). C'est l'ouverture séquentielle de plusieurs canaux ioniques transmembranaires, permettant l'entrée ou la sortie d'ions dans la cellule, qui est à l'origine de ce PA. Parmi tous les canaux ioniques impliqués dans ce processus, les canaux sodiques dépendant du voltage sont responsables de la première phase du potentiel d'action. Les différentes isoformes de ces canaux (de Nav1.1 à Nav1.9 et NavX) sont codées par dix gènes distincts. Nav1.4 et Nav1.5 sont les principaux variants exprimés respectivement dans le muscle et le coeur. Plusieurs mutations ont été décrites dans les gènes qui codent pour ces deux canaux: SCN4A (pour Nav1.4) et SCNSA (pour Nav1.5). Elles sont impliquées dans des pathologies neuromusculaires telles que des paralysies ou myotonies (SCN4A) ou des arythmies cardiaques pouvant conduire à la mort subite cardiaque (SCNSA).Mon travail de thèse a consisté à étudier les maladies liées aux dysfonctionnements de ces canaux, aussi appelées canalopathies. J'ai ainsi analysé la fonction et la régulation des canaux sodiques dépendant du voltage dans le muscle squelettique et le coeur. A travers les deux premières études, j'ai ainsi pu examiner les conséquences de deux mutations affectant respectivement les canaux Nav1.4 et Nav1.5. Les canaux sauvages ou mutants ont été exprimés dans des cellules HEK293 afin de caractériser leurs propriétés biophysiques par la technique du patch clamp en configuration cellule entière. Nous avons pu déterminer que la mutation trouvée dans le gène SCN4A engendrait des modifications importantes de la fonction du canal musculaire. Ces altérations fournissent des indications nous permettant d'expliquer certains aspects de la myotonie observée chez les membres de la famille étudiée. Le patient présenté dans la deuxième étude était hétérozygote pour la mutation identifiée dans le gène SCNSA. La perte de fonction des canaux Nav1.5 ainsi engendrée, a été observée lors d'analyses à températures physiologiques. Elle représente l'un des éléments pouvant potentiellement expliquer le syndrome de Brugada du patient. La dernière étude a consisté à identifier une nouvelle protéine impliquée dans la régulation du canal sodique cardiaque. Nos expériences ont démontré que les trois derniers acides aminés de la partie C-terminale de Nav1.5 pouvaient interagir avec la protéine SAP97. Lorsque que l'expression de la SAP97 est réduite dans les cellules HEK293, cela induit une baisse importante du courant sodique. De même, les canaux tronqués de leurs trois derniers acides aminés génèrent un flux ionique réduit. Ces résultats préliminaires suggèrent que SAP97 est peut-être impliquée dans la régulation du canal Na,,1.5. Des expériences complémentaires permettront de déterminer si ces deux protéines interagissent directement ou si une protéine adaptatrice est nécessaire. De plus, nous avons préalablement montré que les canaux Nav1.5 étaient localisés au niveau de la membrane latérale des cardiomyocytes par le complexe multiprotéique de la dystrophine (DMC). Ceci suggère que les canaux sodiques peuvent être distribués dans un minimum de deux pools, l'un ciblé aux membranes latérales pax le DMC et l'autre dirigé vers les disques intercalaires par des protéines telles que SAP97.L'ensemble de ces études met en évidence que certaines maladies musculaires et cardiaques peuvent être la conséquence directe de mutations de canaux ioniques, mais que l'action de protéines auxiliaires peut aussi affecter leur fonction.

Electromyographic, cerebral, and muscle hemodynamic responses during intermittent, isometric contractions of the biceps brachii at three submaximal intensities.

This study examined the electromyographic, cerebral and muscle hemodynamic responses during intermittent isometric contractions of biceps brachii at 20, 40, and 60% of maximal voluntary contraction (MVC). Eleven volunteers completed 2 min of intermittent isometric contractions (12/min) at an elbow angle of 90° interspersed with 3 min rest between intensities in systematic order. Surface electromyography (EMG) was recorded from the right biceps brachii and near infrared spectroscopy (NIRS) was used to simultaneously measure left prefrontal and right biceps brachii oxyhemoglobin (HbO2), deoxyhemoglobin (HHb), and total hemoglobin (Hbtot). Transcranial Doppler ultrasound was used to measure middle cerebral artery velocity (MCAv) bilaterally. Finger photoplethysmography was used to record beat-to-beat blood pressure and heart rate. EMG increased with force output from 20 to 60% MVC (P < 0.05). Cerebral HbO2 and Hbtot increased while HHb decreased during contractions with differences observed between 60% vs. 40% and 20% MVC (P < 0.05). Muscle HbO2 decreased while HHb increased during contractions with differences being observed among intensities (P < 0.05). Muscle Hbtot increased from rest at 20% MVC (P < 0.05), while no further change was observed at 40 and 60% MVC (P > 0.05). MCAv increased from rest to exercise but was not different among intensities (P > 0.05). Force output correlated with the root mean square EMG and changes in muscle HbO2 (P < 0.05), but not changes in cerebral HbO2 (P > 0.05) at all three intensities. Force output declined by 8% from the 1st to the 24th contraction only at 60% MVC and was accompanied by systematic increases in RMS, cerebral HbO2 and Hbtot with a leveling off in muscle HbO2 and Hbtot. These changes were independent of alterations in mean arterial pressure. Since cerebral blood flow and oxygenation were elevated at 60% MVC, we attribute the development of fatigue to reduced muscle oxygen availability rather than impaired central neuronal activation.

Muscle artificiel : analyse in-vitro de deux systèmes d'assistance ventriculaire externes

Contexte : L'insuffisance cardiaque touche environ 150 personnes sur 100'000 habitants en Suisse, avec une¦prévalence évaluée à 1.45 %, et cause 42.3 décès par 100'000 habitants. Globalement, la prévalence de¦l'insuffisance cardiaque augmente, d'une part à cause du vieillissement de la population, d'autre part par¦l'amélioration de la prise en charge de pathologies cardiaques. La transplantation reste actuellement le gold¦standard pour l'insuffisance cardiaque réfractaire au traitement pharmacologique, mais les organes sont¦rares. Une alternative a donc été développée, celle des systèmes d'assistance ventriculaire (ventricular assist¦device, VAD). Les appareils existants actuellement sur le marché fonctionnent en déviant le sang du¦ventricule vers un système de projection à flux pulsatile ou continu placé dans la cage thoracique, avant de le¦renvoyer vers l'artère. Ils comportent certains défauts, en particulier la nécessité de léser le coeur pour les¦implanter et les risques hémorragique et thrombo-embolique importants. Pour remédier à ces défauts, des¦VAD externes sont en cours de développement. Fixés autour du coeur, ils permettent de l'assister dans la¦contraction, sans contact direct avec le sang ni lésion du coeur. Dans cette étude, nous avons créé deux¦prototypes de VAD externes basés sur la technique du muscle artificiel. Ils sont faits de fils de Nitinol, un¦alliage à mémoire de forme qui raccourcit lorsqu'il est chauffé. Placés autour du coeur, ils lui impriment un¦mouvement de contraction, tel un muscle artificiel.¦Méthode : deux VAD externes ont été créés en utilisant du Nitinol. Les fibres de Nitinol du VAD N°1¦passent à travers des charnières qui augmentent son pouvoir de contraction. Celles du VAD N°2 sont¦orientées dans un maillage de fibres de Kevlar de manière à reproduire la direction des fibres musculaires du¦ventricule humain. Ils ont été testés sur un banc d'essai avec un coeur en silicone. Nous avons mesuré la¦fraction d'éjection, le débit et la pression générée, à différentes valeurs de précharge et post-charge. Les¦VAD étaient alimentés par une génératrice ou par une unité de contrôle, qui permettait de fournir l'énergie¦précisément dans chaque fil de Nitinol et d'imposer une certaine fréquence cardiaque.¦Résultats : Tant avec la génératrice que l'unité de contrôle, le ventricule gauche du VAD N°1 fournit une¦fraction d'éjection maximale de 16.09 %. Le débit maximal est de 191.42 ml/min. La génératrice permet au¦VAD N°2 de fournir une fraction d'éjection de 6.18 %, contre 2.48 % avec l'unité de contrôle. Le débit¦maximal est de 27.37 ml/min. La pression générée atteint 75 mmHg pour le VAD N°1 et 6 mmHg pour le¦VAD N°2.¦Discussion/conclusion : Le VAD N°1 est le plus performant, il permet une augmentation significative de la¦fraction d'éjection et pourrait avoir un impact sur la qualité de vie des patients. L'unité de contrôle apporte¦un avantage sur la génératrice pour le VAD N°1, en dirigeant plus précisément l'énergie dans les fils de¦Nitinol et en limitant les pertes. Le VAD N°2, lui, est peu performant et l'unité de contrôle n'améliore pas¦ses performances. Cela est probablement dû à sa configuration initiale, la taille du VAD n'étant pas adaptée¦au coeur en silicone. Cette étude prouve qu'il est possible d'assister un coeur depuis l'extérieur, sans l'altérer,¦et que la position des fibres de Nitinol a plus d'importance que leur nombre.

Effect of hip flexion angle on hamstring optimum length after a single set of concentric contractions.

The eccentric contraction mode was proposed to be the primary stimulus for optimum angle (angle at which peak torque occurs) shift. However, the training range of motion (or muscle excursion range) could be a stimulus as important. The aim of this study was to assess the influence of the training range of motion stimulus on the hamstring optimum length. It was hypothesised that performing a single set of concentric contractions beyond optimal length (seated at 80° of hip flexion) would lead to an immediate shift of the optimum angle to longer muscle length while performing it below (supine at 0° of hip flexion) would not provide any shift. Eleven male participants were assessed on an isokinetic dynamometer. In both positions, the test consisted of 30 consecutive knee flexions at 4.19 rad · s⁻¹. The optimum angle was significantly shifted by ∼15° in the direction of longer muscle length after the contractions at 80° of hip flexion, while a non-significant shift of 3° was found at 0°. The hamstring fatigability was not influenced by the hip position. It was concluded that the training range of motion seems to be a relevant stimulus for shifting the optimum angle to longer muscle length. Moreover, fatigue appears as a mechanism partly responsible for the observed shift.

Evaluation et prise en charge des risques de blessure des ischio-jambiers chez le sprinteur

La déchirure des ischio-jambiers est la blessure non-traumatique la plus fréquemment rencontrée dans les sports demandant une course à haute vitesse. Les ischio-jambiers sont particulièrement vulnérables lors de la fin de phase d'oscillation du sprint étant donné qu'ils se contractent excentriquement alors qu'ils sont en position d'allongement. Le renforcement excentrique a été montré comme étant une méthode efficace pour diminuer le risque de blessure. Cependant, les exercices classiquement utilisés comme le Nordic hamstring ne soumettent pas les ischio-jambiers à un niveau d'allongement spécifique au sprint. Dès lors, l'objectif de cette thèse était d'évaluer le fonctionnement des ischio-jambiers à différents niveaux d'allongement musculo- tendineux puis de transposer dans la pratique les résultats obtenus afin de concevoir des exercices plus spécifiques aux besoins des athlètes. Avant cela, une première partie avait pour but de proposer de nouvelles méthodes d'évaluation de terrain des ischio-jambiers. Les différents travaux réalisés pour cette thèse ont permis : 1) de proposer deux nouveaux outils de terrain pour l'évaluation de la flexibilité et de la force des ischio-jambiers ; 2) de montrer que le niveau d'allongement influence directement la force produite par les ischio-jambiers et de suggérer que ce niveau d'allongement semble être un stimulus au moins aussi déterminant que le mode de contraction musculaire pour générer des adaptations de l'architecture musculaire propices à la diminution du risque de blessure ; 3) de proposer des modalités spécifiques de renforcement des ischio-jambiers destinées aux sprinteurs dans une perspective de prévention des blessures et de montrer l'efficacité de ces recommandations sur l'amélioration d'un certain nombre de facteurs de risque de blessure. Finalement, ce travail a ouvert de nouvelles perspectives allant de la proposition d'exercices de renforcement de terrain au développement d'un système motorisé spécifique au sprint permettant le renforcement et l'évaluation de la force des ischio-jambiers en passant par différents projets de recherche. -- High-speed running sports accounts for the majority of hamstring strains. The terminal swing phase of the running cycle is believed to be the most hazardous as the hamstrings are undergoing an active lengthening contraction in a long muscle length position. Prevention-based strength training relies mainly on eccentric exercises. However, most hamstrings exercises like the Nordic hamstring are performed at an inadequately low hip-flexion angle. Thus, the objective of this thesis was to assess the hamstring function at different muscle lengths and depending on the obtained results to design strength exercises more specific to the athlete's need. Before that, a first part of this thesis aimed to develop new assessment methods of the hamstring on site. The different studies included in the present thesis allowed: 1) to propose two new methods to test the hamstring flexibility and strength on the field; 2) to show that the hamstring muscle length directly influences its level of strength, and to suggest that the training range of motion could be a dominant stimulus (as important than contraction type) for modifying the muscle architecture, which leads to a decrease in hamstring injury risk; 3) to define sprint specific parameters for prevention-based strength training, and to show the efficiency of these recommendations on the improvement of several injury risk factors for the hamstring. Finally, this thesis proposed new perspectives: 1) new strength exercises on site; 2) the development of a motorised device specific for the sprint which could be used to strength and to assess the hamstring; 3) several future research projects.

ß2-adrenergic agonists actions on the human skeletal muscle

Les ß2-agonistes sont des bronchodilatateurs qui sont prescrits pour traiter l'asthme et l'asthme induite par l'exercice (AIE). Il est relevant de comprendre s'il y a une utilisation adéquate de ces médicaments pour traiter l'AIE chez les athlètes de haut niveau, ou s'ils sont utilisés pour leur potentiel effet ergogénique sur la performance physique. Ce travail examine les actions centrales et périphériques sur la fonction contractile du muscle squelettique humain in vivo induits par l'ingestion d'une dose thérapeutique de ß2- agonistes. Le premier but était d'évaluer si les ß2-agonistes exerçaient une potentialisation de la contractilité du muscle humain et/ou un effet "anti¬fatigue" comme observé dans le modèle animal. Les résultats n'ont fournit aucune évidence d'une potentialisation sur le muscle squelettique humain in vivo non-fatigué et fatigué induit par l'administration orale de ß2-agonistes. Tout effet excitateur exercé par ce traitement sur le système nerveux central a été aussi exclu. Le deuxième but était de déterminer si les ß2-agonistes affaiblissaient la contractilité du muscle squelettique humain à contraction lente, et d'évaluer si ce changement pouvait interférer avec le contrôle moteur au muscle. Les résultats ont montré que les ß2-agonistes affaiblissent la contractilité des fibres lentes, comme conséquence de l'effet lusitrope positif se produisant dans ces fibres. La capacité de développer une force maximale n'est pas réduite par le traitement, même si une augmentation de la commande centrale au muscle est requise pour produire la même force lors de contractions sous-maximales. Le but final était d'examiner si une adaptation du contrôle moteur était re¬quis pour compenser l'affaiblissement des fibres lentes exercée par les ß2- agonistes pendant un exercice volontaire, et de déterminer si cette adaptation centrale pouvait accroître la fatigue musculaire. Malgré le fait que les résultats confirment l'effet affaiblissant induit par les ß2-agonistes, ce changement contractile n'influence pas le contrôle moteur au muscle pendant les contractions sous-maximales de l'exercice fatiguant, et n'accroît pas le degré de fatigue. Ce travail éclaircit les actions spécifiques des ß2-agonistes sur la fonction contractile du muscle squelettique humain in vivo et leurs influence sur le contrôle moteur. Les mécanismes sous-jacents de l'action ergogénique sur la performance physique produit par les ß2-agonistes sont aussi élucidés. -- ß2-Agonists are bronchodilators that are widely prescribed for the treatment of asthma and exercise-induced asthma (EIA). The extensive use of ß2-agonists by competitive athletes has raised the question as to whether there is a valid need for this class of drugs because of EIA or a misuse because of their potential ergogenic effect on exercise performance. This work investigated the central and peripheral actions that were elicited by the ingestion of a therapeutic dose of ß2-agonists on the contractility of human skeletal muscle in vivo. The first objective was to investigate whether ß2-agonists would potentiate muscle contractility and/or exert the "anti-fatigue" effect observed in animal models. The findings did not provide any evidence for the ß2-agonist-induced potentiation of in vivo human non-fatigued and fatigued skeletal muscle. Moreover, the findings exclude any excitatory action of this treatment on the central nervous system. The second objective was to explore whether the weakening action on the contractile function would occur after ß2-agonist intake in human slow-twitch skeletal muscle and to ascertain whether this contractile change may interfere with muscle motor control. The results showed that ß2-agonists weaken the contractility of slow-twitch muscle fibres as a result of the lusitropic effect occurring in these fibres. The maximal force-generating capacity of the skeletal muscle is not reduced by ß2-agonists, even though an augmented neural drive to muscle is required to develop the same force during submaximal contractions. The final objective was to examine whether a motor control adjustment is needed to compensate for the ß2-agonist-induced weakening effect on slow- twitch fibres during a voluntary exercise and to also assess whether this central adaptation could exaggerate muscle fatigue. Despite the findings confirming the occurrence of the weakening action that is exerted by ß2- agonists, this contractile change did not interfere with muscle motor control during the submaximal contractions of the fatiguing exercise and did not augment the degree of the muscle fatigue. This work contributes to a better understanding of the specific actions of ß2-agonists on the contractile function of in vivo human skeletal muscles and their influence on motor control. In addition, the findings elucidate mechanisms that could underlie the ergogenic effect that is exerted by ß2- agonists on physical performance.

Effects of piperitenone oxide on the intestinal smooth muscle of the guinea pig

We investigated the effects of piperitenone oxide (PO), a major constituent of the essential oil of Mentha x villosa, on the guinea pig ileum. PO (30 to 740 µg/ml) relaxed basal tonus without significantly altering the resting membrane potential. In addition, PO relaxed preparations precontracted with either 60 mM K+ or 5 mM tetraethylammonium in a concentration-dependent manner. At concentrations from 0.1 to 10 µg/ml PO potentiated acetylcholine-induced contractions, while higher concentrations (>30 µg/ml) blocked this response. These higher PO concentrations also inhibited contractions induced by 60 mM K+. PO also blocked the components of acetylcholine contraction which are not sensitive to nifedipine or to solutions with nominal zero Ca2+ and EGTA. These results show that PO is a relaxant of intestinal smooth muscle and suggest that this activity may be mediated at least in part by an intracellular effect

Characterization of nerve-induced relaxation of gastrointestinal sphincteric smooth muscle in a South American opossum (Didelphis albiventris)

The presence of inhibitory nonadrenergic noncholinergic (NANC) intrinsic innervation of the circular muscle of the gastrointestinal sphincters of the South American (SA) opossum was investigated in vitro. Isolated circular muscle strips from the esophagogastric and ileocolonic junctions but not from the gastroduodenal (pylorus) region developed spontaneous tension. Tetrodotoxin (TTX, 1 µM) augmented the spontaneous tension only in the ileocolonic junction strips. Electrical field stimulation of esophagogastric and ileocolonic junction strips caused frequency-dependent responses consisting of a relaxation at lower frequencies (<1 Hz) and a biphasic response or contraction at higher frequencies. In the strips from the pyloric region electrical field stimulation abolished the spontaneous activity at lower frequencies and induced contractions at higher frequencies. The responses elicited by electrical field stimulation in the three sphincters were abolished by TTX (1 µM). Electrical field-induced contractions were reduced while relaxations were enhanced by atropine (1 µM). In the presence of atropine (1 µM) and guanethidine (3 µM), electrical field stimulation, nicotine and ATP induced frequency- or concentration-dependent relaxations of the three sphincters that were abolished by TTX (1 µM). Isoproterenol and sodium nitroprusside caused concentration-dependent relaxations which were TTX-resistant. These findings indicate that the sphincteric circular muscle of the SA opossum gastrointestinal tract is relaxed by the activation of intrinsic NANC nerves and therefore can be used as a model for the study of the mechanisms involved in these responses

The effect of L-arginine on guinea-pig and rabbit airway smooth muscle function in vitro

We have investigated the effects of L-arginine, D-arginine and L-lysine on airway smooth muscle responsiveness to spasmogens in vitro. Both L-arginine and D-arginine (100 mM) significantly reduced the contractile potency and maximal contractile response to histamine but not to methacholine or potassium chloride in guinea-pig epithelium-denuded isolated trachea. Similarly, the contractile response to histamine was significantly reduced by L-arginine (100 mM) in rabbit epithelium-denuded isolated bronchus. The amino acid L-lysine (100 mM) failed to significantly alter the contractile potency of histamine in guinea-pig isolated trachea (P>0.05). In guinea-pig isolated trachea precontracted with histamine, both L-arginine and D-arginine produced a concentration-dependent relaxation which was not significantly altered by epithelium removal or by the presence of the nitric oxide synthase inhibitor, NG-nitro L-arginine methyl ester (L-NAME; 50 µM). Thus, at very high concentrations, arginine exhibit a non-competitive antagonism of histamine-induced contraction of isolated airway preparations that was independent of the generation of nitric oxide and was not dependent on charge. These observations confirm previous studies of cutaneous permeability responses and of contractile responses of guinea-pig isolated ileal smooth muscle. Taken together, the data suggest that high concentrations of arginine can exert an anti-histamine effect.