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      Endothelial Nitric Oxide Suppresses Action-Potential-Like Transient Spikes and Vasospasm in Small Resistance Arteries

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          Abstract

          Endothelial dysfunction in small arteries is a ubiquitous, early feature of cardiovascular disease, including hypertension. Dysfunction reflects reduced bioavailability of endothelium-derived nitric oxide (NO) and depressed endothelium-dependent hyperpolarization that enhances vasoreactivity. We measured smooth muscle membrane potential and tension, smooth muscle calcium, and used real-time quantitative polymerase chain reaction in small arteries and isolated tubes of endothelium to investigate how dysfunction enhances vasoreactivity. Rat nonmyogenic mesenteric resistance arteries developed vasomotion to micromolar phenylephrine (α 1-adrenoceptor agonist); symmetrical vasoconstrictor oscillations mediated by L-type voltage-gated Ca 2+ channels (VGCCs). Inhibiting NO synthesis abolished vasomotion so nanomolar phenylephrine now stimulated rapid, transient depolarizing spikes in the smooth muscle associated with chaotic vasomotion/vasospasm. Endothelium-dependent hyperpolarization block also enabled phenylephrine-vasospasm but without spikes or chaotic vasomotion. Depolarizing spikes were Ca 2+-based and abolished by either T-type or L-type VGCCs blockers with depressed vasoconstriction. Removing NO also enabled transient spikes/vasoconstriction to Bay K-8644 (L-type VGCC activator). However, these were abolished by the L-type VGCC blocker nifedipine but not T-type VGCC block. Phenylephrine also initiated T-type VGCC-transient spikes and enhanced vasoconstriction after NO loss in nonmyogenic arteries from spontaneously hypertensive rats. In contrast to mesenteric arteries, myogenic coronary arteries displayed transient spikes and further vasoconstriction spontaneously on loss of NO. T-type VGCC block abolished these spikes and additional vasoconstriction but not myogenic tone. Therefore, in myogenic and nonmyogenic small arteries, reduced NO bioavailability engages T-type VGCCs, triggering transient depolarizing spikes in normally quiescent vascular smooth muscle to cause vasospasm. T-type block may offer a means to suppress vasospasm without inhibiting myogenic tone mediated by L-type VGCCs.

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          The Concise Guide to Pharmacology 2013/14: G Protein-Coupled Receptors

          The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. G protein-coupled receptors are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates.
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            Vasomotion - what is currently thought?

            This minireview discusses vasomotion, which is the oscillation in tone of blood vessels leading to flowmotion. We will briefly discuss the prevalence of vasomotion and its potential physiological and pathophysiological relevance. We will also discuss the models that have been suggested to explain how a coordinated oscillatory activity of the smooth muscle tone can occur and emphasize the role of the endothelium, the handling of intracellular Ca(2+) and the role of smooth muscle cell ion conductances. It is concluded that vasomotion is likely to enhance tissue dialysis, although this concept still requires more experimental verification, and that an understanding at the molecular level for the pathways leading to vasomotion is beginning to emerge. © 2011 The Authors. Acta Physiologica © 2011 Scandinavian Physiological Society.
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              EDH: endothelium-dependent hyperpolarization and microvascular signalling.

              Endothelium-dependent hyperpolarizing factor (EDHF) is a powerful vasodilator influence in small resistance arteries and thus an important modulator of blood pressure and flow. As the name suggests, EDHF was thought to describe a diffusible factor stimulating smooth muscle hyperpolarization (and thus vasodilatation). However, this idea has evolved with the recognition that a factor can operate alongside the spread of hyperpolarizing current from the endothelium to the vascular smooth muscle (VSM). As such, the pathway is now termed endothelium-dependent hyperpolarization (EDH). EDH is activated by an increase in endothelial [Ca2+ ]i , which stimulates two Ca2+ -sensitive K channels, SKCa and IKCa . This was discovered because apamin and charybdotoxin applied in combination blocked EDHF responses, but iberiotoxin - a blocker of BKCa - was not able to substitute for charybdotoxin. SKCa and IKCa channels are arranged in endothelial microdomains, particularly within projections towards the adjacent smooth muscle, which are rich in IKCa channels and close to interendothelial gap junctions where SKCa channels, are prevalent. KCa activation hyperpolarizes endothelial cells, and K+ efflux through them can act as a diffusible 'EDHF' by stimulating VSM Na+ ,K+ -ATPase and inwardly rectifying K channels (KIR ). In parallel, hyperpolarizing current spreads from the endothelium to the smooth muscle through myoendothelial gap junctions located on endothelial projections. The resulting radial EDH is complemented by the spread of 'conducted' hyperpolarization along the endothelium of arteries and arterioles to affect conducted vasodilatation (CVD). Retrograde CVD effectively integrates blood flow within the microcirculation, but how the underlying hyperpolarization is sustained is unclear.
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                Author and article information

                Journal
                Hypertension
                Hypertension
                HYP
                Hypertension (Dallas, Tex. : 1979)
                Lippincott Williams & Wilkins (Hagerstown, MD )
                0194-911X
                1524-4563
                27 July 2020
                September 2020
                : 76
                : 3
                : 785-794
                Affiliations
                [1 ]From the Deptartment of Pharmacology, University of Cambridge (C.R.H.)
                [2 ]Department of Pharmacology, Universityxs of Oxford (J.F.S., H.A.L.L., L.B, K.A.D., C.J.G.).
                Author notes
                Correspondence to Professor Christopher J. Garland, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT. Email christopher.garland@ 123456pharm.ox.ac.uk
                Article
                00025
                10.1161/HYPERTENSIONAHA.120.15491
                7418934
                32713276
                a8835dbc-e924-4df5-ad5c-af434645f2f8
                © 2020 The Authors.

                Hypertension is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. 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 that the original work is properly cited.

                History
                : 8 May 2020
                : 27 May 2020
                : 1 July 2020
                Categories
                10016
                10024
                10032
                Original Articles
                Endothelium
                Custom metadata
                T
                TRUE

                cardiovascular diseases,endothelium,nitric oxide,rats,vasoconstriction,vasospasm

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