Regional Measures of Sexual-Orientation Bias Predict Where Same-Gender Couples Live.

Regional explicit and implicit bias are associated with real-world discrimination and marginalization. We extended this research area by focusing on sexual minorities and where same-gender couples live. Using data on 2,939 U.S. counties from Project Implicit and other publicly available sources, we found that measures with known associations with systemic anti-lesbian, gay, and bisexual (anti-LGB) bias are similarly associated with regional implicit and explicit anti-LGB bias. Furthermore, we found that fewer same-gender couples reside in counties with more explicit and implicit anti-LGB bias, above and beyond other factors that likely influence same-gender-couple residency. These findings further suggest that explicit and implicit measures of regional bias are capturing similar, if not the same, construct of a region's culture of bias toward particular groups. Couched specifically within the ongoing systemic political antagonization of the lesbian, gay, bisexual, transgender, queer, plus (LGBTQ+) community, these findings also highlight the importance of considering contextual (in addition to individual) factors that reinforce systemic inequality.

Plantar load transfer in children: a descriptive study with two pathological case studies.

BACKGROUND: Typical gait is often considered to be highly symmetrical, with gait asymmetries typically associated with pathological gait. Whilst gait symmetry is often expressed in symmetry ratios, measures of symmetry do not provide insight into how these asymmetries affect gait variables. To fully understand changes caused by gait asymmetry, we must first develop a normative database for comparison. Therefore, the aim of this study was to describe normative reference values of regional plantar load and present comparisons with two pathological case studies. METHODS: A descriptive study of the load transfer of plantar pressures in typically developed children was conducted to develop a baseline for comparison of the effects of gait asymmetry in paediatric clinical populations. Plantar load and 3D kinematic data was collected for 17 typically developed participants with a mean age of 9.4 ± 4.0 years. Two case studies were also included; a 10-year-old male with clubfoot and an 8-year-old female with a flatfoot deformity. Data was analysed using a kinematics-pressure integration technique for anatomical masking into 5 regions of interest; medial and lateral forefoot, midfoot, and medial and lateral hindfoot. RESULTS: Clear differences between the two case studies and the typical dataset were seen for the load transfer phase of gait. For case study one, lateral bias was seen in the forefoot of the trailing foot across all variables, as well as increases in contact area, force and mean pressure in the lateral hindfoot of the leading foot. For case study two, the forefoot of the trailing foot produced results very similar to the typical dataset across all variables. In the hindfoot of the leading foot, medial bias presents most notably in the force and mean pressure graphs. CONCLUSIONS: This study highlights the clinical significance of the load transfer phase of gait, providing meaningful information for intervention planning.

LGBT workplace protections as an extension of the protected class framework.

OBJECTIVES: Many corporations in the United States have enacted nondiscrimination policies for their LGBT employees, despite that the LGBT community has not been a legally protected class concerning employment discrimination at the national level. We examined whether progressive corporate LGBT-related policies may be an extension of policies and practices designed to foster diversity and create equality for existing legally protected classes (women, ethnic minorities, veterans, and those with disabilities). We also examined whether leadership level diversity (percentage of women and ethnic minorities on company boards of directors) predicted nondiscrimination policies for LGBT employees. HYPOTHESES: We predicted companies that have been recognized and awarded for protected class diversity policies and that have a greater percentage of women and racial/ethnic minorities on their boards of directors would have more progressive LGBT-related corporate policies. METHOD: Using a sample of Fortune 500 companies, we examined protected-class diversity awards and percentage of women and racial/ethnic minorities on boards of directors as predictors of LGBT-related policies. At the company-level, we controlled for the average age of board, company size, and company revenue. At the level of company headquarter location, we controlled for political climate, Christian religiosity, and LGBT employment nondiscrimination laws. We also controlled for U.S. region and industry sector. RESULTS: Multilevel modeling results indicated that protected-class diversity awards and the percentage of women on company boards of directors significantly and independently predicted progressive LGBT policy scores, whereas the percentage of racial/ethnic minorities on boards of directors had less consistent results. CONCLUSION: Companies that address issues of diversity and equality in the workplace have been likely to include the LGBT community among their groups of concern, even in the absence of legal pressures to do so. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Enantioselective and Regiodivergent Copper-Catalyzed Electrophilic Arylation of Allylic Amides with Diaryliodonium Salts.

A catalytic enantioselective and regiodivergent arylation of alkenes is described. Chiral copper(II)bisoxazoline complexes catalyze the addition of diaryliodonium salts to allylic amides in excellent ee. Moreover, the arylation can be controlled by the electronic nature of the diaryliodonium salt enabling the preparation of nonracemic diaryloxazines or ß,ß'-diaryl enamides.

The Relationship Between Gender and Sexual Orientation in Academia.

To date, there has been no prior systematic analysis of where LGB research gets published and where LGB studies programs are housed within universities. LGB research could have a disciplinary home in any number of areas of study because of its relevance across many disciplines. Nevertheless, drawing upon the theory of sexuality-as-gendered, we predicted that LGB research and programs of study would be found predominantly within gender studies. We examine the extent to which sexual orientation research (Study 1) and U.S. university LGBTQ-related academic programming (Studies 2 and 3) has found their home in the gender studies discipline. Study 1 results showed gender studies have been the primary home of published sexual orientation research in top-ranked peer-reviewed journals over the past three decades. In Study 2, university LGBTQ academic programming was housed within gender studies departments more frequently than any other department-including standalone LGBTQ studies departments. In Study 3, Google searches for university "LGBT studies" frequently led to that university's gender studies department website as the top search result-including universities whose gender studies department offered zero LGBTQ-related courses. Combined, these results demonstrate far-reaching manifestations of the fact that gender and sexuality are inextricably intertwined constructs.

Flip-flops do not alter the neuromuscular function of the gastrocnemius muscle and tendon during walking in children.

INTRODUCTION/AIM: Flip-flops are a popular choice of footwear for children. However, their inherent design provides minimal support to the foot and ankle and has been suggested to increase the work performed by muscle and tendon structures, potentially predisposing them to injury. Therefore, the aim of this study was to compare the length change behaviour of the medial gastrocnemius (MG) muscle fascicles and muscle tendon unit (MTU) and their mechanical function at the ankle and subtalar joints in children during walking with and without flip-flop. METHODS: Eight healthy children walked barefoot and with flip-flops whilst 3D gait analysis and simultaneous B-mode ultrasound images of the MG fascicles during level walking were collected. Joint kinematics, kinetics and MTU lengths were analysed using musculoskeletal modelling and fascicle lengths using a semi-automated tracking algorithm. RESULTS: The muscles and tendons across the ankle absorbed greater amounts of power during barefoot walking compared to flip-flop walking. The muscle activations of the lateral gastrocnemius, soleus and tibialis anterior remained invariant across the conditions as did the activation, and fascicle length change behaviour of the medial gastrocnemius. In the barefoot condition, there was a trend of greater MTU lengthening, to potentially absorb greater amounts of power, although no differences in shortening was observed during late stance. CONCLUSION: Walking with flip-flops does not increase the mechanical work performed by the MG muscle at the ankle and subtalar joints, suggesting that flip-flops do not increase the stresses and strains of the Achilles tendon and hence its predisposition to strain induced injury. Instead, our results suggest that flip-flops, act as a compliant surface and absorb energy during contact and hence the strain experienced by the Achilles tendon.

Increasing level of neuromusculoskeletal model personalisation to investigate joint contact forces in cerebral palsy: A twin case study.

BACKGROUND: Cerebral palsy is a complex neuromuscular disorder that affects the sufferers in multiple different ways. Neuromusculoskeletal models are promising tools that can be used to plan patient-specific treatments for cerebral palsy. However, current neuromusculoskeletal models are typically scaled from generic adult templates that poorly represent paediatric populations. Furthermore, muscle activations are commonly computed via optimisation methods, which may not reproduce co-contraction observed in cerebral palsy. Alternatively, calibrated EMG-informed approaches within OpenSim can capture pathology-related muscle activation abnormalities, possibly enabling more feasible estimations of muscle and joint contact forces. METHODS: Two identical twin brothers, aged 13, one with unilateral cerebral palsy and the other typically developing, were enrolled in the study. Four neuromusculoskeletal models with increasing subject-specificity were built in OpenSim and CEINMS combining literature findings, experimental motion capture, EMG and MR data for both participants. The physiological and biomechanical validity of each model was assessed by quantifying its ability to track experimental joint moments and muscle excitations. FINDINGS: All developed models accurately tracked external joint moments; however EMG-informed models better tracked muscle excitations compared to neural solutions generated by static optimisation. Calibrating muscle-tendon unit parameters with EMG data allowed for more physiologically plausible joint contact forces estimates. Further scaling the maximal isometric force of muscles with MR-derived muscle volumes did not affect model predictions. INTERPRETATION: Given their ability to identify atypical joint contact forces profiles and accurately reproduce experimental data, calibrated EMG-informed models should be preferred over generic models using optimisation methods in informing the management of cerebral palsy.

Low-status compensation: A theory for understanding the role of status in cultures of honor.

The mechanisms that link herding regions to cultures of honor have never been empirically tested. The objective of the present article is to show the important role that issues of status play in linking herding regions to cultures of honor using the theory of low-status compensation (P. J. Henry, 2008b) Four studies are presented. Study 1 replicates the finding that counties in the American South conducive to herding have higher murder rates than do counties conducive to farming but shows those differences are mediated by indicators of status disparities in a county. Study 2 replicates the findings of Study 1 with an international sample of 92 countries. Study 3 tests the theoretical idea that people who are low in socioeconomic status face stigma in society and show self-defensive strategies generally. Finally, Study 4 provides experimental evidence that low-status tendencies toward aggressing in the face of insults may be due to strategies to protect their sense of social worth. The results are contextualized within the theory of low-status compensation as a theory for understanding the role status plays in predicting some forms of violence.

Immediate loading of dental implants.

The purpose of this review is to explore the concept of immediate loading as it pertains to dental implants and the indications for clinical practice. The definition of immediate loading will be considered together with a review of the relevant literature in an attempt to provide evidence-based guidelines for successful implementation into practice. A search of electronic databases including Medline, PubMed and the Cochrane Database of Systematic Reviews was undertaken using the terms "immediate loading'', "dental implants'', "immediate function'', "early loading'', "oral implants'', "immediate restoration'' and "systematic review''. This was supplemented by handsearching in peer-reviewed journals and cross-referenced with the articles accessed. Emphasis was given to systematic reviews and controlled clinical trials. A definition of immediate loading was suggested pertinent to the realities of logistics in clinical practice with respect to application and time frame. The literature was evaluated and shown to be limited with significant shortcomings. Guidelines and recommendations for clinical protocols were suggested and illustrated by examples of case types with a minimum of 1-3 years follow-up. A list of additional references for further reading was provided. Within the limitations of this review, there is evidence to suggest that immediate loading protocols have demonstrated high implant survival rates and may be cautiously recommended for certain clinical situations. However, more high level evidence studies, preferably randomized controlled trials (RCTs), over a long time frame are required to show a clear benefit over more conventional loading protocols.

Effects of hip joint centre mislocation on gait kinematics of children with cerebral palsy calculated using patient-specific direct and inverse kinematic models.

Joint kinematics can be calculated by Direct Kinematics (DK), which is used in most clinical gait laboratories, or Inverse Kinematics (IK), which is mainly used for musculoskeletal research. In both approaches, joint centre locations are required to compute joint angles. The hip joint centre (HJC) in DK models can be estimated using predictive or functional methods, while in IK models can be obtained by scaling generic models. The aim of the current study was to systematically investigate the impact of HJC location errors on lower limb joint kinematics of a clinical population using DK and IK approaches. Subject-specific kinematic models of eight children with cerebral palsy were built from magnetic resonance images and used as reference models. HJC was then perturbed in 6mm steps within a 60mm cubic grid, and kinematic waveforms were calculated for the reference and perturbed models. HJC perturbations affected only hip and knee joint kinematics in a DK framework, but all joint angles were affected when using IK. In the DK model, joint constraints increased the sensitivity of joint range-of-motion to HJC location errors. Mean joint angle offsets larger than 5° were observed for both approaches (DK and IK), which were larger than previously reported for healthy adults. In the absence of medical images to identify the HJC, predictive or functional methods with small errors in anterior-posterior and medial-lateral directions and scaling procedures minimizing HJC location errors in the anterior-posterior direction should be chosen to minimize the impact on joint kinematics.

Reliability of four models for clinical gait analysis.

Three-dimensional gait analysis (3DGA) has become a common clinical tool for treatment planning in children with cerebral palsy (CP). Many clinical gait laboratories use the conventional gait analysis model (e.g. Plug-in-Gait model), which uses Direct Kinematics (DK) for joint kinematic calculations, whereas, musculoskeletal models, mainly used for research, use Inverse Kinematics (IK). Musculoskeletal IK models have the advantage of enabling additional analyses which might improve the clinical decision-making in children with CP. Before any new model can be used in a clinical setting, its reliability has to be evaluated and compared to a commonly used clinical gait model (e.g. Plug-in-Gait model) which was the purpose of this study. Two testers performed 3DGA in eleven CP and seven typically developing participants on two occasions. Intra- and inter-tester standard deviations (SD) and standard error of measurement (SEM) were used to compare the reliability of two DK models (Plug-in-Gait and a six degrees-of-freedom model solved using Vicon software) and two IK models (two modifications of 'gait2392' solved using OpenSim). All models showed good reliability (mean SEM of 3.0° over all analysed models and joint angles). Variations in joint kinetics were less in typically developed than in CP participants. The modified 'gait2392' model which included all the joint rotations commonly reported in clinical 3DGA, showed reasonable reliable joint kinematic and kinetic estimates, and allows additional musculoskeletal analysis on surgically adjustable parameters, e.g. muscle-tendon lengths, and, therefore, is a suitable model for clinical gait analysis.

Protease-activated receptors (PARs) are partly pro-inflammatory and partly anti-inflammatory: will PAR agonists or antagonists participate in future drug therapies?

Protease-activated receptors (PARs) are characterised by a unique mechanism of activation, which enables them to act as cellular sensors for protease activity. PARs are expressed throughout the cardiovascular, gastrointestinal and pulmonary systems, where they are potential drug targets for the treatment of disease. However, there are currently very few selective PAR antagonists or potent PAR agonists available as effective research tools, and moreover, there is considerable evidence to suggest that PARs can promote both pro-inflammatory and anti-inflammatory responses in a wide range of disease models. These confounding issues have, to date, prevented us from developing a clear understanding of the role of PARs in disease. Nevertheless, this review provides an overview of the distribution and function of PARs in the cardiovascular, gastrointestinal and pulmonary systems, and attempts to evaluate whether PAR agonists or antagonists have a place in future drug therapy.

Examining the principles in principled conservatism: the role of responsibility stereotypes as cues for deservingness in racial policy decisions.

Why do educated conservatives oppose affirmative action? Those in the "principled conservatism" camp say opposition is based on principled judgments of fairness about the policies. Others, however, argue that opposition is based on racism. The present article offers an alternative perspective that may reconcile these contradictory points of view. In 2 studies, the authors show 2 major findings: (a) that conservatives oppose affirmative action more for Blacks than for other groups, in this case women, and (b) that the relationship between conservatism and affirmative action attitudes is mediated best by group-based stereotypes that offer deservingness information and not by other potential mediators like old-fashioned racism or the perceived threat that affirmative action poses to oneself. The authors conclude that educated conservatives are indeed principled in their opposition to affirmative action, but those principles are group based not policy based.

Instantaneous progression reference frame for calculating pelvis rotations: Reliable and anatomically-meaningful results independent of the direction of movement.

In motion analysis, pelvis angles are conventionally calculated as the rotations between the pelvis and laboratory reference frame. This approach assumes that the participant's motion is along the anterior-posterior laboratory reference frame axis. When this assumption is violated interpretation of pelvis angels become problematic. In this paper a new approach for calculating pelvis angles based on the rotations between the pelvis and an instantaneous progression reference frame was introduced. At every time-point, the tangent to the trajectory of the midpoint of the pelvis projected into the horizontal plane of the laboratory reference frame was used to define the anterior-posterior axis of the instantaneous progression reference frame. This new approach combined with the rotation-obliquity-tilt rotation sequence was compared to the conventional approach using the rotation-obliquity-tilt and tilt-obliquity-rotation sequences. Four different movement tasks performed by eight healthy adults were analysed. The instantaneous progression reference frame approach was the only approach that showed reliable and anatomically meaningful results for all analysed movement tasks (mean root-mean-square-differences below 5°, differences in pelvis angles at pre-defined gait events below 10°). Both rotation sequences combined with the conventional approach led to unreliable results as soon as the participant's motion was not along the anterior-posterior laboratory axis (mean root-mean-square-differences up to 30°, differences in pelvis angles at pre-defined gait events up to 45°). The instantaneous progression reference frame approach enables the gait analysis community to analysis pelvis angles for movements that do not follow the anterior-posterior axis of the laboratory reference frame.

Endothelin and the respiratory system.

Pharmacological research involving the endothelin peptides has emphasized their activities in vascular systems, from both physiological and pathophysiological perspectives. However, the endothelins are known also to be synthesized and released from respiratory epithelial cells and to have potent effects in nonvascular components of the respiratory tract. Douglas Hay, Peter Henry and Roy Goldie summarize present understanding of the pharmacology of the endothelins in the respiratory system and assess the potential pathophysiological role in asthma.

Sensitivity of the Oxford Foot Model to marker misplacement: A systematic single-case investigation.

The purpose of this paper was to systematically assess the effect of Oxford Foot Model (OFM) marker misplacement on hindfoot relative to tibia, and forefoot relative to hindfoot kinematic calculations during the stance phase of gait. Marker trajectories were recorded with an 8-camera motion analysis system (Vicon Motion Systems Ltd., UK) and ground reaction forces were recorded from three force platforms (AMTI, USA). A custom built marker cluster consisting of 4 markers in a square arrangement (diagonal distance 2 cm) was used to assess the effect of marker misplacement in the superior, inferior, anterior and posterior direction for the sustentaculum tali (STL), the proximal 1st metatarsal (P1M), distal 5th metatarsal (D5M), proximal 5th metatarsal (P5M) and lateral calcaneus (LCA) markers. In addition manual movement of the heel complex 1 cm superiorly, inferiorly, medially and laterally, and also an alignment error of 10° inversion and 10° eversion was assessed. Clinically meaningful effects of marker misplacement were determined using a threshold indicating the minimal clinically important difference. Misplacement of the heel-wand complex had the most pronounced effect on mean kinematic profiles during the stance phase across all degrees-of-freedom with respect to hindfoot-tibia and forefoot-hindfoot angles. Vertical marker misplacement of the D5M and P5M markers affected the sagittal plane, and to a lesser extent frontal plane, forefoot-hindfoot kinematics. In conclusion, the OFM is highly sensitive to misplacement of the heel-wand complex in all directions and the P5M marker in the vertical direction.

Endothelin-1 (ET-1)-induced contraction in rat isolated trachea: involvement of ETA and ETB receptors and multiple signal transduction systems.

1. Quantitative autoradiographic, biochemical and functional studies were performed to investigate the endothelin receptor subtypes and signal transduction systems that mediate endothelin-1 (ET-1)-induced contraction in rat isolated tracheal smooth muscle. 2. Specific binding of 0.5 nM [125I]-ET-1 to tracheal smooth muscle was inhibited by at least 40% in the presence of either the ETA receptor selective ligand BQ-123 (1 microM) or the ETB receptor-selective ligand sarafotoxin S6c (30 nM), indicating the presence of both ETA and ETB receptors in this tissue. 3. ET-1 and sarafotoxin S6c were both potent spasmogens of rat isolated tracheal smooth muscle preparations. Sarafotoxin S6c-induced contractions were unaffected in the presence of the ETA receptor antagonist BQ-123 (10 microM), but were markedly attenuated in tissue previously exposed to 100 nM sarafotoxin S6c to induce ETB receptor desensitization. ET-1-induced contractions were, at most, only partially attenuated either by blocking the ETA receptor-effector system (with 10 microM BQ-123) or by desensitizing the ETB receptor-effector system with sarafotoxin S6c. However, ET-1-induced contractions were markedly attenuated by blocking both receptor-effector systems simultaneously. These findings suggest that ET-1 could induce contraction by stimulating either ETA or ETB receptors. 4. ET-1 (10 microM) induced a 7 fold increase in intracellular [3H]-inositol phosphate accumulation over basal levels in rat isolated tracheal smooth muscle. In contrast, sarafotoxin S6c (2.5 microM) increased intracellular [3H]-inositol phosphate accumulation by only 2 fold. ET-1-induced accumulation of [3H]-inositol phosphates was abolished by 10 microM BQ-123. 5. In Ca2+-free Krebs bicarbonate solution, 100 nM ET-1 induced a significantly larger contraction than that induced by 100 nM sarafotoxin S6c (46.6 +/- 5.6% C,., versus 8.8 +/- 2.8% Cmax, n = 5-7). This presumed intracellular Ca2+-dependent phase of contraction induced by ET-1 was significantly inhibited by 10 microM BQ-123 (7.5 +/- 1.0% C.). Subsequent addition of 2.5 mM Ca2+ induced a second phase of contraction. The extracellular Ca2+-dependent phase of contraction induced by ET-1 was similar inmagnitude to that induced by sarafotoxin S6c (63.6 +/- 4.5% C.. versus 58.0 +/- 3.7% C.) and was not inhibited by BQ-123. Sarafotoxin S6c-induced contractions were not inhibited by the L-type Ca2+-channel antagonists, nicardipine or verapamil.6. In summary, ETA and ETB receptors coexist in rat isolated tracheal smooth muscle and stimulation of both receptor subtypes contributes to ET-l-induced contraction in this tissue. However, stimulation of these receptor subtypes appears to induce contraction by activating different second messenger pathways; ETA receptor stimulation induces phosphoinositide turnover and subsequent release of intracellular Ca2+ whereas stimulation of ETB receptors facilitates the influx of extracellular Ca2+.

Inhibitory effects of nordihydroguaiaretic acid on ETA-receptor-mediated contractions to endothelin-1 in rat trachea.

1. It has been shown previously that nordihydroguaiaretic acid (NDGA) inhibits endothelin-1 (ET-1)-induced contractions in rat isolated tracheal smooth muscle. To investigate the underlying mechanisms, this study examined the effects of NDGA on various aspects of the ETA and ETB receptor-effector systems which mediate ET-1-induced contractions in this preparation. 2. NDGA inhibited contractions induced by each of the isoforms of ET (ET-1, ET-2 and ET-3) but not those induced by the ETB receptor-selective agonist, sarafotoxin S6c, the cholinoceptor agonist, carbachol or the depolarizing spasmogen, KCl. 3. Quantitative autoradiographic studies of [125I]-ET-1 binding to rat tracheal smooth muscle indicated that NDGA was not an ET receptor antagonist. 4. NDGA inhibited the ETA receptor-mediated, intracellular Ca(2+)-dependent contractions induced by 100 nM ET-1 in Ca(2+)-free solution (by 75%, P < 0.01). Furthermore, NDGA markedly inhibited the contractions induced by ryanodine and cyclopiazonic acid; contractions purportedly due to Ca2+ release from intracellular stores. 5. Like NDGA, the sarcoplasmic reticulum Ca(2+)-ATPase inhibitors cyclopiazonic acid and thapsigargin inhibited contractions to ET-1, but not carbachol or KCl. However, cyclopiazonic acid, but not NDGA, also (a) induced transient contractions in rat trachea, (b) potentiated contractions induced by KCl, and (c) potentiated the extracellular Ca(2+)-dependent phase of ET-1-induced contractions, indicating that NDGA did not inhibit ET-1-induced contractions through Ca(2+)-ATPase inhibition and depletion of sarcoplasmic reticular Ca2+. 6. In control preparations, ET-1 induced a slowly developing, sustained contraction. However, in the presence of NDGA or the ETA receptor antagonist, BQ123, ET-1-induced contractions resembled the transient contractions induced by sarafotoxin S6c. In nominally Ca2+-free solution, ETA receptor mediated contractions induced by ET-1 developed very slowly and were inhibited by NDGA.7. Additional studies indicated that the inhibitory effects of NDGA on endothelin-1-induced contractions were not the result of any significant actions of NDGA on lipoxygenase, cytochrome P450, L- orT-type Ca2+-channels, Na+-channels or protein kinase C.8. In summary, NDGA selectively inhibited ET-1-induced contractions in rat tracheal smooth muscle via a lipoxygenase-independent mechanism involving inhibition of the ETA but not the ETB, receptor effector system. NDGA did not appear to inhibit the initial events in the ETA signal transduction pathway, such as receptor binding and protein kinase C activation. However, NDGA inhibited the intracellular Ca2+-dependent component of ET-1-induced contraction, possibly by inhibiting mobilisation of intracellular Ca2+. As an apparent direct consequence of inhibiting the ETA receptor-effector system, NDGA markedly changed the time course of ET-1-induced contractions; from a slowly developing and sustained contraction into a transient contraction resembling that induced by sarafotoxin S6c.

Potentiation by endothelin-1 of cholinergic nerve-mediated contractions in mouse trachea via activation of ETB receptors.

1. We have previously shown that endothelin-1-induced contraction of mouse isolated tracheal smooth muscle was mediated via both ETA and ETB receptors. In the current study, we have investigated endothelin-1-induced potentiation of cholinergic nerve-mediated contractions in mouse isolated trachea and have characterized pharmacologically the endothelin receptors mediating this response. 2. Electrical field stimulation (EFS; 70 V, 0.5 ms duration, 10s train, 0.1-60 Hz) of mouse isolated trachea caused frequency-dependent, monophasic contractions (magnitude of contraction of 60 Hz was 56 +/- 4% Cmax (n = 6), where Cmax is the contractile response to 10 microM carbachol). EFS-induced contractions were abolished by either 0.1 microM atropine or 3 microM tetrodotoxin, but were not affected by 1 microM hexamethonium, indicating that they were induced by stimulation of postganglionic cholinergic nerves. In contrast, contractions induced by exogenously applied acetylcholine were inhibited by atropine, but not by either tetrodotoxin or hexamethonium. 3. The ETB receptor-selective agonist, sarafotoxin S6c, caused marked concentration-dependent potentiation of EFS-induced contractions in mouse isolated tracheal segments. At 0.1 nM, sarafotoxin S6c exerted no direct contractile effect, but significantly increased a standard EFS-induced contraction of 20% Cmax by 8 +/- 2% Cmax (i.e. 1.4 fold, n = 5, P < 0.05). At higher concentrations, 10 nM sarafotoxin S6c induced a large, transient contraction (peak response of 74 +/- 2% Cmax at 10 min; 3 +/- 2% Cmax at 45 min) and enhanced the standard EFS-induced contraction by 30 +/- 4% Cmax (i.e. 2.5 fold, n = 5, P < 0.01). In contrast, 10 nM sarafotoxin S6c did not enhance contractile responses to exogenously applied acetylcholine(n = 6).4. Endothelin-1 also modulated EFS-induced contractions. At 0.1 nM, endothelin-1 exerted no direct contractile effect, but significantly increased the standard EFS-induced contraction of 20%Cmax, by 7 +/- 2%Cma, (i.e. 1.35 fold, n = 5, P<0.05). At 1 nM, endothelin-l induced a small, sustained contraction(16 +/- 3%Cmo) and increased the standard EFS-induced contraction by 19 +/- 2%Cmax (i.e. 1.95 fold,n = 5, P <0.01). Finally, 10 nM endothelin-1 induced a large, sustained contraction (98 +/- 8%Cma), but the EFS-induced contraction was significantly reduced from 20%Cmax to 6 +/- 4%Cmax (n = 6, P <0.05).In contrast, in the presence of 3 microM BQ-123 (ETA receptor-selective antagonist), 1O nM endothelin-1 induced a transient contraction mediated via ETB receptors (peak response of 59 +/- 10%Cmax at 10 min;8 +/- 2%Cmax at 45 min). Under these conditions, the standard EFS-induced contraction was increased by 26+/- l%Cmax (i.e. 2.3 fold, n = 6, P<0.01).5. The potentiation of EFS-induced contractions produced by 1 nM endothelin-1 was not mediated by ETA receptors, since 3 microM BQ-123 did not diminish this effect (n = 6). Furthermore, 1 nM endothelin-1 did not potentiate EFS-induced contractions in preparations in which the function of the ETB receptor effector system had been attenuated by desensitization (n = 6).6. In summary, endothelin-1 potentiates cholinergic nerve-mediated contractions in mouse isolated trachea, apparently by activating prejunctional ETB receptors. This neuronal pathway offers an additional mechanism through which endothelin-1 may elevate bronchomotor tone.