The Journal of Physiology

Cover image for Vol. 594 Issue 3

1 February 2016

Volume 594, Issue 3

Pages 507–797

  1. Issue Information

    1. Top of page
    2. Issue Information
    3. Topical Reviews
    4. Computational physiology and modelling
    5. Molecular and Cellular
    6. Cardiovascular
    7. Muscle
    8. Integrative
    9. Corrections
    1. Issue Information (pages 507–508)

      Article first published online: 1 FEB 2016 | DOI: 10.1113/jphysiol.2015.7071

  2. Topical Reviews

    1. Top of page
    2. Issue Information
    3. Topical Reviews
    4. Computational physiology and modelling
    5. Molecular and Cellular
    6. Cardiovascular
    7. Muscle
    8. Integrative
    9. Corrections
    1. Mitochondrial dynamics, mitophagy and cardiovascular disease (pages 509–525)

      César Vásquez-Trincado, Ivonne García-Carvajal, Christian Pennanen, Valentina Parra, Joseph A. Hill, Beverly A. Rothermel and Sergio Lavandero

      Article first published online: 15 JAN 2016 | DOI: 10.1113/JP271301

      Thumbnail image of graphical abstract

      Mitochondria play an essential role in maintaining optimal performance of the heart. Mitochondrial dynamics (processes of fusion and fission, mitochondrial biogenesis and mitophagy) determine mitochondrial morphology, quality and abundance. All these processes participate in the development and progression of cardiovascular pathologies, including diabetic cardiomyopathy, atherosclerosis, damage from ischaemia-reperfusion, cardiac hypertrophy and decompensated heart failure.

    2. Sympathetic-mediated activation versus suppression of the immune system: consequences for hypertension (pages 527–536)

      Adam J. Case and Matthew C. Zimmerman

      Article first published online: 30 DEC 2015 | DOI: 10.1113/JP271516

      Thumbnail image of graphical abstract

      Increased sympathetic nerve activity is associated with hypertension. This increased sympathoexcitation and noradrenaline outflow can potentiate the effects of activated T-lymphocytes and exacerbate hypertension, but also has inhibitory effects on naive resting T-lymphocytes promoting an immunosuppressed state.

    3. Computational models of atrial cellular electrophysiology and calcium handling, and their role in atrial fibrillation (pages 537–553)

      Jordi Heijman, Pegah Erfanian Abdoust, Niels Voigt, Stanley Nattel and Dobromir Dobrev

      Article first published online: 28 DEC 2015 | DOI: 10.1113/JP271404

      Thumbnail image of graphical abstract

      Computational modelling of atrial electrophysiology: In this review, we summarize key aspects of atrial cellular Ca2+ handling in the larger context of atrial cardiomyocyte electrophysiology and summarize the methodology of computational modelling of atrial electrophysiology and Ca2+ handling. We discuss advances in both animal and human atrial cardiomyocyte models, their uses in atrial fibrillation research, the gaps in current knowledge and potential future directions.

    4. Spontaneous activity in the microvasculature of visceral organs: role of pericytes and voltage-dependent Ca2+ channels (pages 555–565)

      Hikaru Hashitani and Richard J. Lang

      Article first published online: 6 JAN 2016 | DOI: 10.1113/JP271438

      Thumbnail image of graphical abstract

      Pericytes play different roles in different microcirculatory beds In the bladder suburothelium (left), ‘non contractile’ capillary pericytes (CPCs) may generate ‘spreading’ excitation to drive venular pericytes (VPCs; upper). Excitation of VPCs upon the opening of L-type voltage-dependent Ca2+ channels (LVDCCs) spread within a VPC network to generate ‘peristaltic’ vasoconstrictions (middle). Contractions of VPCs also work against stretching during storage phase to prevent venular collapse (lower). In the myenteric layer of the stomach (right), ‘non contractile’ CPCs generate ‘spreading’ excitation upon the opening of T-type voltage-dependent Ca2+ channels (TVDCCs) to drive smooth muscle cells (SMCs; upper). Excitation of SMCs upon the opening of TVDCCs spread within a SMC network to generate ‘synchronous’ vasoconstrictions (lower). Cells in red indicate excited and contracted. Cells in light blue indicate in resting state. Cells in orange indicate excited but non-contractile.

  3. Computational physiology and modelling

    1. Top of page
    2. Issue Information
    3. Topical Reviews
    4. Computational physiology and modelling
    5. Molecular and Cellular
    6. Cardiovascular
    7. Muscle
    8. Integrative
    9. Corrections
    1. You have full text access to this OnlineOpen article
      In silico prediction of drug therapy in catecholaminergic polymorphic ventricular tachycardia (pages 567–593)

      Pei-Chi Yang, Jonathan D. Moreno, Christina Y. Miyake, Steven B. Vaughn-Behrens, Mao-Tsuen Jeng, Eleonora Grandi, Xander H. T. Wehrens, Sergei Y. Noskov and Colleen E. Clancy

      Article first published online: 30 DEC 2015 | DOI: 10.1113/JP271282

      Key points

      • The mechanism of therapeutic efficacy of flecainide for catecholaminergic polymorphic ventricular tachycardia (CPVT) is unclear.
      • Model predictions suggest that Na+ channel effects are insufficient to explain flecainide efficacy in CPVT.
      • This study represents a first step toward predicting therapeutic mechanisms of drug efficacy in the setting of CPVT and then using these mechanisms to guide modelling and simulation to predict alternative drug therapies.
  4. Molecular and Cellular

    1. Top of page
    2. Issue Information
    3. Topical Reviews
    4. Computational physiology and modelling
    5. Molecular and Cellular
    6. Cardiovascular
    7. Muscle
    8. Integrative
    9. Corrections
    1. Effects of unsaturated fatty acids on the kinetics of voltage-gated proton channels heterologously expressed in cultured cells (pages 595–610)

      Akira Kawanabe and Yasushi Okamura

      Article first published online: 5 JAN 2016 | DOI: 10.1113/JP271274

      Key points

      • Arachidonic acid (AA) greatly enhances the activity of the voltage-gated proton (Hv) channel, although its mechanism of action and physiological function remain unclear.
      • In the present study, we analysed the effects of AA on proton currents through Hv channels heterologously expressed in HEK293T cells.
      • The dramatic increase in proton current amplitude elicited by AA was accompanied by accelerated activation kinetics and a leftward shift in the voltage-dependence of activation.
      • Mutagenesis studies suggest the two aforementioned effects of AA reflect two distinct structural mechanisms.
      • Application of phospholipase A2, which liberates AA from phospholipids in the membrane, also enhances Hv channel activity, supporting the idea that AA modulates Hv channel activity within physiological contexts.
  5. Cardiovascular

    1. Top of page
    2. Issue Information
    3. Topical Reviews
    4. Computational physiology and modelling
    5. Molecular and Cellular
    6. Cardiovascular
    7. Muscle
    8. Integrative
    9. Corrections
    1. Editor's Choice

      You have full text access to this OnlineOpen article
      Biphasic decay of the Ca transient results from increased sarcoplasmic reticulum Ca leak (pages 611–623)

      Rajiv Sankaranarayanan, Yatong Li, David J. Greensmith, David A. Eisner and Luigi Venetucci

      Article first published online: 6 JAN 2016 | DOI: 10.1113/JP271473

      Key points

      • Ca leak from the sarcoplasmic reticulum through the ryanodine receptor (RyR) reduces the amplitude of the Ca transient and slows its rate of decay.
      • In the presence of β-adrenergic stimulation, RyR-mediated Ca leak produces a biphasic decay of the Ca transient with a fast early phase and a slow late phase.
      • Two forms of Ca leak have been studied, Ca-sensitising (induced by caffeine) and non-sensitising (induced by ryanodine) and both induce biphasic decay of the Ca transient.
      • Only Ca-sensitising leak can be reversed by traditional RyR inhibitors such as tetracaine.
      • Ca leak can also induce Ca waves. At low levels of leak, waves occur. As leak is increased, first biphasic decay and then slowed monophasic decay is seen. The level of leak has major effects on the shape of the Ca transient.
    2. Relationship between retinal blood flow and arterial oxygen (pages 625–640)

      Richard W. Cheng, Firdaus Yusof, Edmund Tsui, Monica Jong, James Duffin, John G. Flanagan, Joseph A. Fisher and Chris Hudson

      Article first published online: 30 DEC 2015 | DOI: 10.1113/JP271182

      Key points

      • Vascular reactivity, the response of the vessels to a vasoactive stimulus such as hypoxia and hyperoxia, can be used to assess the vascular range of adjustment in which the vessels are able to compensate for changes in inline image.
      • Previous studies in the retina have not accurately quantified retinal vascular responses and precisely targeted multiple inline image stimuli at the same time as controlling the level of carbon dioxide, thus precluding them from modelling the relationship between retinal blood flow and oxygen.
      • The present study modelled the relationship between retinal blood flow and inline image, showing them to be a combined linear and hyperbolic function.
      • This model demonstrates that the resting tonus of the vessels is at the mid-point and that they have great vascular range of adjustment, compensating for decreases in oxygen above a inline image of 32–37 mmHg but being limited below this threshold.
    3. Editor's Choice

      The mechano-gated channel inhibitor GsMTx4 reduces the exercise pressor reflex in decerebrate rats (pages 641–655)

      Steven W. Copp, Joyce S. Kim, Victor Ruiz-Velasco and Marc P. Kaufman

      Article first published online: 5 JAN 2016 | DOI: 10.1113/JP271714

      Key points

      • Mechanical and metabolic stimuli from contracting muscles evoke reflex increases in blood pressure, heart rate and sympathetic nerve activity. Little is known, however, about the nature of the mechano-gated channels on the thin fibre muscle afferents that contribute to evoke this reflex, termed the exercise pressor reflex.
      • We determined the effect of GsMTx4, an inhibitor of mechano-gated Piezo channels, on the exercise pressor reflex evoked by intermittent contraction of the triceps surae muscles in decerebrated, unanaesthetized rats.
      • GsMTx4 reduced the pressor, cardioaccelerator and renal sympathetic nerve responses to intermittent contraction but did not reduce the pressor responses to femoral arterial injection of compounds that stimulate the metabolically-sensitive thin fibre muscle afferents.
      • Expression levels of Piezo2 channels were greater than Piezo1 channels in rat dorsal root ganglia.
      • Our findings suggest that mechanically-sensitive Piezo proteins contribute to the generation of the mechanical component of the exercise pressor reflex in rats.
    4. You have free access to this content
      Exercise training reduces the acute physiological severity of post-menopausal hot flushes (pages 657–667)

      Tom G. Bailey, N. Timothy Cable, Nabil Aziz, Greg Atkinson, Daniel J. Cuthbertson, David A. Low and Helen Jones

      Article first published online: 30 DEC 2015 | DOI: 10.1113/JP271456

      Key points

      • A post-menopausal hot flush consists of profuse physiological elevations in cutaneous vasodilatation and sweating that are accompanied by reduced brain blood flow. These responses can be used to objectively quantify hot flush severity.
      • The impact of an exercise training intervention on the physiological responses occurring during a hot flush is currently unknown.
      • In a preference-controlled trial involving 21 post-menopausal women, 16 weeks of supervised moderate intensity exercise training was found to improve cardiorespiratory fitness and attenuate cutaneous vasodilatation, sweating and the reductions in cerebral blood flow during a hot flush.
      • It is concluded that the improvements in fitness that are mediated by 16 weeks of exercise training reduce the severity of physiological symptoms that occur during a post-menopausal hot flush.
    5. The contributions of cardiac myosin binding protein C and troponin I phosphorylation to β-adrenergic enhancement of in vivo cardiac function (pages 669–686)

      Kenneth S. Gresham and Julian E. Stelzer

      Article first published online: 1 FEB 2016 | DOI: 10.1113/JP270959

      Key points

      • β-adrenergic stimulation increases cardiac myosin binding protein C (MyBP-C) and troponin I phosphorylation to accelerate pressure development and relaxation in vivo, although their relative contributions remain unknown.
      • Using a novel mouse model lacking protein kinase A-phosphorylatable troponin I (TnI) and MyBP-C, we examined in vivo haemodynamic function before and after infusion of the β-agonist dobutamine.
      • Mice expressing phospho-ablated MyBP-C displayed cardiac hypertrophy and prevented full acceleration of pressure development and relaxation in response to dobutamine, whereas expression of phosphor-ablated TnI alone had little effect on the acceleration of contractile function in response to dobutamine.
      • Our data demonstrate that MyBP-C phosphorylation is the principal mediator of the contractile response to increased β-agonist stimulation in vivo.
      • These results help us understand why MyBP-C dephosphorylation in the failing heart contributes to contractile dysfunction and decreased adrenergic reserve in response to acute stress.
    6. Extracellular matrix fibronectin initiates endothelium-dependent arteriolar dilatation via the heparin-binding, matricryptic RWRPK sequence of the first type III repeat of fibrillar fibronectin (pages 687–697)

      Ingrid H. Sarelius, Patricia A. Titus, Nir Maimon, William Okech, Susan J. Wilke-Mounts, James R. Brennan and Denise C. Hocking

      Article first published online: 15 JAN 2016 | DOI: 10.1113/JP271478

      Key points

      • The local arteriolar dilatation produced by contraction of skeletal muscle is dependent upon multiple signalling mechanisms.
      • In addition to the many metabolic signals that mediate this vasodilatation, we show here that the extracellular matrix protein fibronectin also contributes to the response.
      • This vasodilatory signal requires the heparin-binding matricryptic RWRPK sequence in the first type III repeat of fibrillar fibronectin.
      • The fibronectin-dependent component of the integrated muscle contraction-dependent arteriolar vasodilatation is coupled through an endothelial cell-dependent signalling pathway.
    7. Calcium-activated chloride current determines action potential morphology during calcium alternans in atrial myocytes (pages 699–714)

      Giedrius Kanaporis and Lothar A. Blatter

      Article first published online: 15 JAN 2016 | DOI: 10.1113/JP271887

      Key points

      • Cardiac alternans – periodic beat-to-beat alternations in contraction, action potential (AP) morphology or cytosolic calcium transient (CaT) amplitude – is a high risk indicator for cardiac arrhythmias and sudden cardiac death. However, it remains an unresolved issue whether beat-to-beat alternations in intracellular Ca2+ ([Ca2+]i) or AP morphology are the primary cause of pro-arrhythmic alternans.
      • Here we show that in atria AP alternans occurs secondary to CaT alternans.
      • CaT alternans leads to complex beat-to-beat changes in Ca2+-regulated ion currents that determine alternans of AP morphology.
      • We report the novel finding that alternans of AP morphology is largely sustained by the activity of Ca2+-activated Cl channels (CaCCs). Suppression of the CaCCs significantly reduces AP alternans, while CaT alternans remains unaffected.
      • The demonstration of a major role of CaCCs in the development of AP alternans opens new possibilities for atrial alternans and arrhythmia prevention.
    8. Intrathecal fentanyl abolishes the exaggerated blood pressure response to cycling in hypertensive men (pages 715–725)

      Thales C. Barbosa, Lauro C. Vianna, Igor A. Fernandes, Eliza Prodel, Helena N. M. Rocha, Vinicius P. Garcia, Natalia G. Rocha, Niels H. Secher and Antonio C. L. Nobrega

      Article first published online: 15 JAN 2016 | DOI: 10.1113/JP271335

      Key points

      • The increase in blood pressure observed during physical activities is exaggerated in patients with hypertension, exposing them to a higher cardiovascular risk.
      • Neural signals from the skeletal muscles appear to be overactive, resulting in this abnormal response in hypertensive patients.
      • In the present study, we tested whether the attenuation of these neural signals in hypertensive patients could normalize their abnormal increase in blood pressure during physical activity.
      • Attenuation of the neural signals from the leg muscles with intrathecal fentanyl injection reduced the blood pressure of hypertensive men during cycling exercise to a level comparable to that of normotensive men.
      • Skeletal muscle afferent overactivity causes the abnormal cardiovascular response to exercise and was reverted in this experimental model, appearing as potential target for treatment.
  6. Muscle

    1. Top of page
    2. Issue Information
    3. Topical Reviews
    4. Computational physiology and modelling
    5. Molecular and Cellular
    6. Cardiovascular
    7. Muscle
    8. Integrative
    9. Corrections
    1. Satellite cell response to erythropoietin treatment and endurance training in healthy young men (pages 727–743)

      Andrea Hoedt, Britt Christensen, Birgitte Nellemann, Ulla Ramer Mikkelsen, Mette Hansen, Peter Schjerling and Jean Farup

      Article first published online: 30 DEC 2015 | DOI: 10.1113/JP271333

      Key points

      • Erythropoietin (Epo) treatment may induce myogenic differentiation factor (MyoD) expression and prevent apoptosis in satellite cells (SCs) in murine and in vitro models.
      • Endurance training stimulates SC proliferation in vivo in murine and human skeletal muscle.
      • In the present study, we show, in human skeletal muscle, that treatment with an Epo-stimulating agent (darbepoetin-α) in vivo increases the content of MyoD+ SCs in healthy young men. Moreover, we report that Epo receptor mRNA is expressed in adult human SCs, suggesting that Epo may directly target SCs through ligand-receptor interaction.
      • Moreover, endurance training, but not Epo treatment, increases the SC content in type II myofibres, as well as the content of MyoD+ SCs.
      • Collectively, our results suggest that Epo treatment can regulate human SCs in vivo, supported by Epo receptor mRNA expression in human SCs. In effect, long-term Epo treatment during disease conditions involving anaemia may impact SCs and warrants further investigation.
    2. Regulation of autophagy in human skeletal muscle: effects of exercise, exercise training and insulin stimulation (pages 745–761)

      Andreas M. Fritzen, Agnete B. Madsen, Maximilian Kleinert, Jonas T. Treebak, Anne-Marie Lundsgaard, Thomas E. Jensen, Erik A. Richter, Jørgen Wojtaszewski, Bente Kiens and Christian Frøsig

      Article first published online: 15 JAN 2016 | DOI: 10.1113/JP271405

      Key points

      • Regulation of autophagy in human muscle in many aspects differs from the majority of previous reports based on studies in cell systems and rodent muscle.
      • An acute bout of exercise and insulin stimulation reduce human muscle autophagosome content.
      • An acute bout of exercise regulates autophagy by a local contraction-induced mechanism.
      • Exercise training increases the capacity for formation of autophagosomes in human muscle.
      • AMPK activation during exercise seems insufficient to regulate autophagosome content in muscle, while mTORC1 signalling via ULK1 probably mediates the autophagy-inhibiting effect of insulin.
  7. Integrative

    1. Top of page
    2. Issue Information
    3. Topical Reviews
    4. Computational physiology and modelling
    5. Molecular and Cellular
    6. Cardiovascular
    7. Muscle
    8. Integrative
    9. Corrections
    1. Effects of acute and chronic systemic methamphetamine on respiratory, cardiovascular and metabolic function, and cardiorespiratory reflexes (pages 763–780)

      Sarah F. Hassan, Travis A. Wearne, Jennifer L. Cornish and Ann K. Goodchild

      Article first published online: 6 JAN 2016 | DOI: 10.1113/JP271257

      Key points

      • Methamphetamine (METH) abuse is escalating worldwide, with the most common cause of death resulting from cardiovascular failure and hyperthermia; however, the underlying physiological mechanisms are poorly understood.
      • Systemic administration of METH in anaesthetised rats reduced the effectiveness of some protective cardiorespiratory reflexes, increased central respiratory activity independently of metabolic function, and increased heart rate, metabolism and respiration in a pattern indicating that non-shivering thermogenesis contributes to the well-described hyperthermia.
      • In animals that showed METH-induced behavioural sensitisation following chronic METH treatment, no changes were evident in baseline cardiovascular, respiratory and metabolic measures and the METH-evoked effects in these parameters were similar to those seen in saline-treated or drug naïve animals.
      • Physiological effects evoked by METH were retained but were neither facilitated nor depressed following chronic treatment with METH.
      • These data highlight and identify potential mechanisms for targeted intervention in patients vulnerable to METH overdose.
    2. You have full text access to this OnlineOpen article
      Sway-dependent changes in standing ankle stiffness caused by muscle thixotropy (pages 781–793)

      Tania E. Sakanaka, Martin Lakie and Raymond F. Reynolds

      Article first published online: 30 DEC 2015 | DOI: 10.1113/JP271137

      Key points

      • The passive stiffness of the calf muscles contributes to standing balance, although the properties of muscle tissue are highly labile.
      • We investigated the effect of sway history upon intrinsic ankle stiffness and demonstrated reductions in stiffness of up to 43% during conditions of increased baseline sway.
      • This sway dependence was most apparent when using low amplitude stiffness-measuring perturbations, and the short-range stiffness component was smaller during periods of high sway.
      • These characteristics are consistent with the thixotropic properties of the calf muscles causing the observed changes in ankle stiffness.
      • Periods of increased sway impair the passive stabilization of standing, demanding more active neural control of balance.
  8. Corrections

    1. Top of page
    2. Issue Information
    3. Topical Reviews
    4. Computational physiology and modelling
    5. Molecular and Cellular
    6. Cardiovascular
    7. Muscle
    8. Integrative
    9. Corrections
    1. You have free access to this content
      Corrigendum (page 795)

      Article first published online: 19 JAN 2016 | DOI: 10.1113/JP271912

      This article corrects:

      KATP channels in the nodose ganglia mediate the orexigenic actions of ghrelin

      Vol. 593, Issue 17, 3973–3989, Article first published online: 1 SEP 2015

    2. You have free access to this content
      Erratum (page 797)

      Article first published online: 30 DEC 2015 | DOI: 10.1113/JP271680

      This article corrects:

      Low haemoglobin concentration in Tibetan males is associated with greater high-altitude exercise capacity

      Vol. 593, Issue 14, 3207–3218, Article first published online: 25 JUN 2015

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