Stimuli of Sensory-Motor Nerves Terminate Arterial Contractile Effects of Endothelin-1 by CGRP and Dissociation of ET-1/ETA-Receptor Complexes

Endothelin-1 (ET-1), a long-acting paracrine mediator, is implicated in cardiovascular diseases but clinical trials with ET-receptor antagonists were not successful in some areas. We tested whether the quasi-irreversible receptor-binding of ET-1 (i) limits reversing effects of the antagonists and (ii) can be selectively dissociated by an endogenous counterbalancing mechanism.-receptor complexes.-receptors by ET-1 (i) occur at an antagonist-insensitive site of the receptor and (ii) are selectively terminated by endogenously released CGRP. Hence, natural stimuli of sensory-motor nerves that stimulate release of endogenous CGRP can be considered for therapy of diseases involving ET-1

Impaired flow-induced arterial remodeling in DOCA-salt hypertensive rats

Arteries from young healthy animals respond to chronic changes in blood flow and blood pressure by structural remodeling. We tested whether the ability to respond to decreased (-90%) or increased (+100%) blood flow is impaired during the development of deoxycorticosterone acetate (DOCA)-salt hypertension in rats, a model for an upregulated endothelin-1 system. Mesenteric small arteries (MrA) were exposed to low blood flow (LF) or high blood flow (HF) for 4 or 7 weeks. The bioavailability of vasoactive peptides was modified by chronic treatment of the rats with the dual neutral endopeptidase (NEP)/endothelin-converting enzyme (ECE) inhibitor SOL1. After 3 or 6 weeks of hypertension, the MrA showed hypertrophic arterial remodeling (3 weeks: media cross-sectional area (mCSA): 10 +/- 1 x 10(3) to 17 +/- 2 x 10(3) mu m(2); 6 weeks: 13 +/- 2 x 10(3) to 24 +/- 3 x 10(3) mu m(2)). After 3, but not 6, weeks of hypertension, the arterial diameter was increased (empty set: 385 +/- 13 to 463 +/- 14 mu m). SOL1 reduced hypertrophy after 3 weeks of hypertension (mCSA: 6 x 10(3) +/- 1 x 10(3) mu m(2)). The diameter of the HF arteries of normotensive rats increased (empty set: 463 +/- 22 mu m) but no expansion occurred in the HF arteries of hypertensive rats (empty set: 471 +/- 16 mu m). MrA from SOL1-treated hypertensive rats did show a significant diameter increase (empty set: 419 +/- 13 to 475 +/- 16 mu m). Arteries exposed to LF showed inward remodeling in normotensive and hypertensive rats (mean empty set between 235 and 290 mu m), and infiltration of monocyte/ macrophages. SOL1 treatment did not affect the arterial diameter of LF arteries but reduced the infiltration of monocyte/ macrophages. We show for the first time that flow-induced remodeling is impaired during the development of DOCA-salt hypertension and that this can be prevented by chronic NEP/ECE inhibition. Hypertension Research (2012) 35, 1093-1101; doi:10.1038/hr.2012.94; published online 12 July 201

Definitions and pathophysiology of vasoplegic shock.

Vasoplegia is the syndrome of pathological low systemic vascular resistance, the dominant clinical feature of which is reduced blood pressure in the presence of a normal or raised cardiac output. The vasoplegic syndrome is encountered in many clinical scenarios, including septic shock, post-cardiac bypass and after surgery, burns and trauma, but despite this, uniform clinical definitions are lacking, which renders translational research in this area challenging. We discuss the role of vasoplegia in these contexts and the criteria that are used to describe it are discussed. Intrinsic processes which may drive vasoplegia, such as nitric oxide, prostanoids, endothelin-1, hydrogen sulphide and reactive oxygen species production, are reviewed and potential for therapeutic intervention explored. Extrinsic drivers, including those mediated by glucocorticoid, catecholamine and vasopressin responsiveness of the blood vessels, are also discussed. The optimum balance between maintaining adequate systemic vascular resistance against the potentially deleterious effects of treatment with catecholamines is as yet unclear, but development of novel vasoactive agents may facilitate greater understanding of the role of the differing pathways in the development of vasoplegia. In turn, this may provide insights into the best way to care for patients with this common, multifactorial condition

A feasibility study of ‘The StepSmart Challenge’ to promote physical activity in adolescents

Funder: Research Trainees Coordinating Centre; doi: http://dx.doi.org/10.13039/501100000659Abstract: Background: Inactive lifestyles are becoming the norm and creative approaches to encourage adolescents to be more physically active are needed. Little is known about how gamification techniques can be used in physical activity interventions for young people. Such approaches may stimulate interest and encourage physical activity behaviour. The study investigated the feasibility of implementing and evaluating a physical activity intervention for adolescents which included gamification techniques within schools. We tested recruitment and retention strategies for schools and participants, the use of proposed outcome measures, and explored intervention acceptability. Methods: This school-based feasibility study of a randomised cluster trial recruited adolescents aged 12–14 years (n = 224) from five schools (three intervention; two control) in Belfast, Northern Ireland. The 22-week intervention (The StepSmart Challenge) informed by self-determination theory and incorporating gamification strategies involved a school-based pedometer competition. Outcomes, measured at baseline, and post-intervention (at 22 weeks post-baseline and 52 weeks post-baseline) included daily minutes of moderate to vigorous physical activity (MVPA) (measured using ActiGraph accelerometer), mental wellbeing (Warwick-Edinburgh Mental Wellbeing Scale), social support for physical activity, time preference (for delayed and larger rewards or immediate and smaller rewards), pro-social behaviour (Strengths and Difficulties Questionnaire (SDQ)) and the influence of social networks. The intervention’s acceptability was explored in focus groups. Results: We invited 14 schools to participate; eight showed interest in participating. We recruited the first five who responded; all five completed the trial. Of the 236 pupils invited, 224 participated (94.9%): 84.8% (190/224) provided valid MVPA (minutes/day) at baseline and 57.2% (123/215) at 52 weeks. All other outcomes were well completed apart from the SDQ (65% at baseline). Qualitative data highlighted that participants and teachers found The StepSmart Challenge to be an acceptable intervention. Conclusions: The level of interest and high recruitment and retention rates provide support for the feasibility of this trial. The intervention, incorporating gamification strategies and the recruitment methods, using parental opt-out procedures, were acceptable to participants and teachers. Teachers also suggested that the implementation of The StepSmart Challenge could be embedded in a lifelong learning approach to health within the school curriculum. As young people’s lives become more intertwined with technology, the use of innovative gamified interventions could be one approach to engage and motivate health behavioural change in this population. Trial registration: NCT02455986 (date of registration: 28 May 2015)