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      Conducted dilatation to ATP and K + in rat skeletal muscle arterioles

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          Abstract

          Aim

          During exercise in humans, circulating levels of ATP and K + increase at a time when blood flow increases to satisfy metabolic demand. Both molecules can activate arteriolar K + channels to stimulate vasodilatation; here, it is established whether conducted dilatation is observed in a skeletal muscle bed.

          Methods

          Isolated and cannulated rat cremaster arterioles were used to assess both local and conducted responses. Agents were either added to the bath, focally pulse‐ejected to the downstream end of arterioles, or in triple‐cannulated arterioles, luminally perfused into the downstream branches to assess both local and conducted responses.

          Results

          The endothelium‐dependent agonist ACh and the K ATP channel opener levcromakalim each stimulated both local and conducted vasodilatation. Focal, bolus delivery of ATP (10  μ m) or KCl (33 m m) to the outside of arterioles stimulated a biphasic vasomotor response: rapid vasoconstriction followed by dilatation as each washed away. At lower concentrations of KCl (19 m m), constriction was avoided, and instead, Ba 2+‐sensitive local dilatation and conducted dilatation were both observed. Luminal perfusion of ATP avoided constriction and activated P2Y 1 receptors stimulating vasodilatation secondary to opening of K C a channels. In triple‐cannulated arterioles, either ATP (10  μ m) or K + (15 m m) luminally perfused into daughter branches of a bifurcation stimulated local dilatation which conducted into the parent arteriole.

          Conclusion

          The recognized physiological autocrine and paracrine mediators ATP and K + each act to evoke both local and conducted vasodilatation in rat cremaster arterioles. Therefore, in situations when circulating levels are raised, such as during exercise, these agents can act as important regulators of blood flow.

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          Most cited references70

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          Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans.

          Animal life is controlled by neurons and in this setting cholinergic neurons play an important role. Cholinergic neurons release ACh, which via nicotinic and muscarinic receptors (n- and mAChRs) mediate chemical neurotransmission, a highly integrative process. Thus, the organism responds to external and internal stimuli to maintain and optimize survival and mood. Blockade of cholinergic neurotransmission is followed by immediate death. However, cholinergic communication has been established from the beginning of life in primitive organisms such as bacteria, algae, protozoa, sponge and primitive plants and fungi, irrespective of neurons. Tubocurarine- and atropine-sensitive effects are observed in plants indicating functional significance. All components of the cholinergic system (ChAT, ACh, n- and mAChRs, high-affinity choline uptake, esterase) have been demonstrated in mammalian non-neuronal cells, including those of humans. Embryonic stem cells (mice), epithelial, endothelial and immune cells synthesize ACh, which via differently expressed patterns of n- and mAChRs modulates cell activities to respond to internal or external stimuli. This helps to maintain and optimize cell function, such as proliferation, differentiation, formation of a physical barrier, migration, and ion and water movements. Blockade of n- and mACHRs on non-innervated cells causes cellular dysfunction and/or cell death. Thus, cholinergic signalling in non-neuronal cells is comparable to cholinergic neurotransmission. Dysfunction of the non-neuronal cholinergic system is involved in the pathogenesis of diseases. Alterations have been detected in inflammatory processes and a pathobiologic role of non-neuronal ACh in different diseases is discussed. The present article reviews recent findings about the non-neuronal cholinergic system in humans.
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            Muscle KATP channels: recent insights to energy sensing and myoprotection.

            ATP-sensitive potassium (K(ATP)) channels are present in the surface and internal membranes of cardiac, skeletal, and smooth muscle cells and provide a unique feedback between muscle cell metabolism and electrical activity. In so doing, they can play an important role in the control of contractility, particularly when cellular energetics are compromised, protecting the tissue against calcium overload and fiber damage, but the cost of this protection may be enhanced arrhythmic activity. Generated as complexes of Kir6.1 or Kir6.2 pore-forming subunits with regulatory sulfonylurea receptor subunits, SUR1 or SUR2, the differential assembly of K(ATP) channels in different tissues gives rise to tissue-specific physiological and pharmacological regulation, and hence to the tissue-specific pharmacological control of contractility. The last 10 years have provided insights into the regulation and role of muscle K(ATP) channels, in large part driven by studies of mice in which the protein determinants of channel activity have been deleted or modified. As yet, few human diseases have been correlated with altered muscle K(ATP) activity, but genetically modified animals give important insights to likely pathological roles of aberrant channel activity in different muscle types.
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              Vasodilatory mechanisms in contracting skeletal muscle.

              Skeletal muscle blood flow is closely coupled to metabolic demand, and its regulation is believed to be mainly the result of the interplay of neural vasoconstrictor activity and locally derived vasoactive substances. Muscle blood flow is increased within the first second after a single contraction and stabilizes within approximately 30 s during dynamic exercise under normal conditions. Vasodilator substances may be released from contracting skeletal muscle, vascular endothelium, or red blood cells. The importance of specific vasodilators is likely to vary over the time course of flow, from the initial rapid rise to the sustained elevation during steady-state exercise. Exercise hyperemia is therefore thought to be the result of an integrated response of more than one vasodilator mechanism. To date, the identity of vasoactive substances involved in the regulation of exercise hyperemia remains uncertain. Numerous vasodilators such as adenosine, ATP, potassium, hypoxia, hydrogen ion, nitric oxide, prostanoids, and endothelium-derived hyperpolarizing factor have been proposed to be of importance; however, there is little support for any single vasodilator being essential for exercise hyperemia. Because elevated blood flow cannot be explained by the failure of any single vasodilator, a consensus is beginning to emerge for redundancy among vasodilators, where one vasoactive compound may take over when the formation of another is compromised. Conducted vasodilation or flow-mediated vasodilation may explain dilation in vessels (i.e., feed arteries) not directly exposed to vasodilator substances in the interstitium. Future investigations should focus on identifying novel vasodilators and the interaction between vasodilators by simultaneous inhibition of multiple vasodilator pathways.
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                Author and article information

                Contributors
                kim.dora@pharm.ox.ac.uk
                Journal
                Acta Physiol (Oxf)
                Acta Physiol (Oxf)
                10.1111/(ISSN)1748-1716
                APHA
                Acta Physiologica (Oxford, England)
                John Wiley and Sons Inc. (Hoboken )
                1748-1708
                1748-1716
                22 February 2016
                January 2017
                : 219
                : 1 ( doiID: 10.1111/apha.2017.219.issue-1 )
                : 202-218
                Affiliations
                [ 1 ] Department of PharmacologyUniversity of Oxford OxfordUK
                Author notes
                [*] [* ] Correspondence: K. A. Dora, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.

                E‐mail: kim.dora@ 123456pharm.ox.ac.uk

                Article
                APHA12656
                10.1111/apha.12656
                5215486
                26804547
                d7545429-8cc5-4bd8-be19-ab193e7b78c0
                © 2016 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 October 2015
                : 25 November 2015
                : 27 December 2015
                : 19 January 2016
                Page count
                Figures: 9, Tables: 0, Pages: 17, Words: 10788
                Funding
                Funded by: British Heart Foundation (BHF)
                Award ID: FS/08/033/25111
                Award ID: FS/13/16/30199
                Award ID: IG/13/5/30431
                Funded by: Oxford BHF Centre of Research Excellence
                Categories
                Original Article
                Special Series on Endothelium‐dependent Hyperpolarizations in Health and Disease
                Custom metadata
                2.0
                apha12656
                January 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.0 mode:remove_FC converted:04.01.2017

                Anatomy & Physiology
                conducted dilatation,cremaster,electrical coupling,katp channel,kca channel,kir channel

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