Multidisciplinary Cardiovascular Research Centre

Simon Harrison

Dr Simon Harrison

BSc, Leeds, PhD 1985, Glasgow
Senior Lecturer
Institute of Membrane and Systems Biology

Background: BSc (Leeds), PhD (Glasgow). Senior Lecturer (1999-)

Office: Garstang 7.56a
Phone: +44(0) 113 34 34262
Email: s.m.harrison@leeds.ac.uk

Centre membership: The Multidisciplinary Cardiovascular Research Centre (MCRC)

Research Interests

Heart function in health and disease

My research interests lie in understanding the mechanisms of normal excitation-contraction coupling in the heart, how these processes are regulated and how a variety of ‘disease states’ (hypertrophy, sepsis, etc) affect the strength of contraction of the heart.

High blood pressure or ‘hypertension’ affects 10 million people in the UK (http://en.wikipedia.org/wiki/ )Hypertension. In hypertensive patients the heart has to work harder to pump blood around the body and this causes the walls of the heart to thicken (hypertrophy). Eventually hypertrophy can lead to heart failure and associated with this progression are changes at the cellular level in the way heart cells contract. We have been studying the mechanisms associated with altered contraction and calcium regulation in normal and hypertrophied heart cells. In collaboration with Prof Ed White’s group we also compare ‘bad’ hypertrophy (above) with ‘good’ hypertrophy which occurs in athletes involved in endurance training. We aim to understand why bad hypertrophy leads to heart failure whereas good hypertrophy does not.

Sepsis (http://en.wikipedia.org/wiki/sepsis) is a potentially life-threatening condition associated with the release of inflammatory cytokines like tumour necrosis factor (TNF). These cytokines have direct inhibitory effects on the heart and contribute to cardiovascular complications. We have shown that combinations of TNF and interleukin-1ß dramatically increase the leakiness of the internal store of calcium so that it cannot contribute properly during the heart beat. From confocal imaging of treated cells (Figure below) it is evident that cytokine treatment leads to an increase in spark frequency, and both localised and propagated calcium waves. Sparks are even evident in the descending phase of the calcium transient (figure taken from Duncan et al., 2010, Cell Calcium 47, 378-386).

One consequence of severe sepsis is cell necrosis or death, and the contents of dying cells can be released into the vicinity of healthy cells. We are currently investigating the effects of histones (the normal function of which is to organise DNA in the nucleus) on cardiac function. Our initial experiements suggest that histones H3 and H4 induce very deleterious effects on the regulation of cytosolic calcium and therefore contractility in isolated ventricular myocytes. We aim to characterise their effects and identify a novel means of inhibiting these proteins which may prove therapeutically useful in patients suffering from severe sepsis.

Funding sources for these projects include The British Heart Foundation, Wellcome Trust, Royal Society and the Medical Research Council.

Studentship information

Postgraduate studentship areas:

Regulation of excitation-contraction coupling in the heart in normal and pathological conditions (e.g. hypertrophy and experimental sepsis).

Publications

Duncan DJ; Yang Z; Hopkins PM; Steele DS; Harrison SM TNF-alpha and IL-1 beta increase Ca2+ leak from the sarcoplasmic reticulum and susceptibility to arrhythmia in rat ventricular myocytes CELL CALCIUM 47 378-386, 2010
DOI:10.1016/j.ceca.2010.02.002

Duncan DJ; Yang Z; Hopkins PM; Steele DS; Harrison SM TNF-α and IL-1β increase Ca2+ leak from the sarcoplasmic reticulum and susceptibility to arrhythmia in rat ventricular myocytes Cell Calcium 47 378-386, 2010

Stones R; Billeter R; Zhang H; Harrison S; White E The role of transient outward K+ current in electrical remodelling induced by voluntary exercise in female rat hearts BASIC RESEARCH IN CARDIOLOGY 104 643-652, 2009
DOI:10.1007/s00395-009-0030-6

Zhang H; Tao T; Kharche S; Harrison SM Modelling changes in transmural propagation and susceptibility to arrhythmia induced by volatile anaesthetics in ventricular tissue JOURNAL OF THEORETICAL BIOLOGY 257 279-291, 2009
DOI:10.1016/j.jtbi.2008.12.004

Stones R; Natali A; Billeter R; Harrison S; White E Voluntary exercise-induced changes in beta(2)-adrenoceptor signalling in rat ventricular myocytes EXPERIMENTAL PHYSIOLOGY 93 1065-1075, 2008
DOI:10.1113/expphysiol.2008.042598

Fowler MR; Naz JR; Graham MD; Orchard CH; Harrison SM Age and hypertrophy alter the contribution of sarcoplasmic reticulum and Na+/Ca2+ exchange to Ca2+ removal in rat left ventricular myocytes JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 42 582-589, 2007
DOI:10.1016/j.yjmcc.2006.12.003

Fowler MR; Orchard CH; Harrison SM Cellular distribution of calcium current is unaltered during compensated hypertrophy in the spontaneously hypertensive rat PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY 453 463-469, 2007
DOI:10.1007/s00424-006-0147-5

Duncan DJ; Hopkins PM; Harrison SM Negative inotropic effects of tumour necrosis factor-alpha and interleukin-1 beta are ameliorated by alfentanil in rat ventricular myocytes BRITISH JOURNAL OF PHARMACOLOGY 150 720-726, 2007
DOI:10.1038/sj.bjp.0707147

Stones R; Calaghan SC; Billeter R; Harrison SM; White E Transmural variations in gene expression of stretch-modulated proteins in the rat left ventricle PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY 454 545-549, 2007
DOI:10.1007/s00424-007-0237-z

Graham MD; Hopkins PM; Harrison SM Antagonistic actions of halothane and sevolurane on spontaneous Ca2+ release in rat ventricular myocytes ANESTHESIOLOGY 105 58-64, 2006
DOI:10.1097/00000542-200607000-00013

Stones R; Billeter R; Harrison S; White E Heterogenic contractile response of rat left ventricular myocytes to beta(1)-adrenoceptor stimulation EUROPEAN JOURNAL OF PHARMACOLOGY 512 117-120, 2005
DOI:10.1016/j.ejphar.2005.02.020

Bru-Mercier G; Hopkins PM; Harrison SM Halothane and sevoflurane inhibit Na/Ca exchange current in rat ventricular myocytes BRITISH JOURNAL OF ANAESTHESIA 95 305-309, 2005
DOI:10.1093/bja/aei185

Graham MD; Bru-Mercier G; Hopkins PM; Harrison SM Transient and sustained changes in myofilament sensitivity to Ca2+ contribute to the inotropic effects of sevoflurane in rat ventricle BRITISH JOURNAL OF ANAESTHESIA 94 279-286, 2005
DOI:10.1093/bja/aei053

Fowler MR; Naz JR; Graham MD; Mercier GB; Harrison SM; Orchard CH Decreased Ca2+ extrusion via Na+/Ca2+ exchange in epicardial left ventricular myocytes during compensated hypertrophy AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 288 H2431-H2438, 2005
DOI:10.1152/ajpheart.01069.2004

Yang ZK; Harrison SM; Steele DS ATP-dependent effects of halothane on SR Ca2+ regulation in permeabilized atrial myocytes CARDIOVASCULAR RESEARCH 65 167-176, 2005
DOI:10.1016/j.cardiores.2004.09.008

Graham MD; Hopkins PM; Harrison SM The effects of alfentanil on cytosolic Ca2+ and contraction in rat ventricular myocytes ANESTHESIA AND ANALGESIA 98 1013-1016, 2004
DOI:10.1213/01.ANE.0000104481.20813.35

Fowler MR; Dobson RS; Orchard CH; Harrison SM Functional consequences of detubulation of isolated rat ventricular myocytes CARDIOVASCULAR RESEARCH 62 529-537, 2004
DOI:10.1016/j.cardiores.2004.02.008

Rithalia A; Hopkins PM; Harrison SM The effects of halothane, isoflurane, and sevoflurane on Ca2+ current and transient outward K+ current in subendocardial and subepicardial myocytes from the rat left ventricle ANESTHESIA AND ANALGESIA 99 1615-1622, 2004
DOI:10.1213/01.ANE.0000138422.40560.A9

Graham M; Qureshi A; Noueihed R; Harrison S; Howarth FC Effects of halothane, isoflurane, sevoflurane and desflurane on contraction of ventricular myocytes from streptozotocin-induced diabetic rats MOLECULAR AND CELLULAR BIOCHEMISTRY 261 209-215, 2004
DOI:10.1023/B:MCBI.0000028758.21617.44

Rithalia A; Qureshi MA; Howarth FC; Harrison SM Effects of halothane on contraction and intracellular calcium in ventricular myocytes from streptozotocin-induced diabetic rats BRITISH JOURNAL OF ANAESTHESIA 92 246-253, 2004
DOI:10.1093/bja/aeh048

Lancaster MK; Jones SA; Harrison SM; Boyett MR Intracellular Ca2+ and pacemaking within the rabbit sinoatrial node: heterogeneity of role and control JOURNAL OF PHYSIOLOGY-LONDON 556 481-494, 2004
DOI:10.1113/jphysiol.2003.057372

Rithalia A; Hopkins PM; Harrison SM Effects of halothane on action potential configuration in sub-endocardial and sub-epicardial myocytes from normotensive and hypertensive rat left ventricle BRITISH JOURNAL OF ANAESTHESIA 90 501-503, 2003
DOI:10.1093/bja/aeg093

Natali AJ; Wilson LA; Peckham M; Turner DL; Harrison SM; White E Different regional effects of voluntary exercise on the mechanical and electrical properties of rat ventricular myocytes JOURNAL OF PHYSIOLOGY-LONDON 541 863-875, 2002
DOI:10.1113/jphysiol.2001.013415

Natali AJ; Turner DL; Harrison SM; White E Regional effects of voluntary exercise on cell size and contraction-frequency responses in rat cardiac myocytes JOURNAL OF EXPERIMENTAL BIOLOGY 204 1191-1199, 2001

Lancaster MK; Jones SA; Harrison SM; Boyett MR Differences in the intracellular Ca2+ transient within the rabbit sinoatrial node JOURNAL OF PHYSIOLOGY-LONDON 533 30P-30P, 2001

Rithalia A; Gibson CN; Hopkins PM; Harrison SM Halothane inhibits contraction and action potential duration to a greater extent in subendocardial than subepicardial myocytes from the rat left ventricle ANESTHESIOLOGY 95 1213-1219, 2001
DOI:10.1097/00000542-200111000-00027

Hamilton DL; Boyett MR; Harrison SM; Davies LA; Hopkins PM The concentration-dependent effects of propofol on rat ventricular myocytes ANESTHESIA AND ANALGESIA 91 276-282, 2000
DOI:10.1097/00000539-200008000-00005

Davies LA; Gibson CN; Boyett MR; Hopkins PM; Harrison SM Effects of isoflurane, sevoflurane, and halothane on myofilament Ca2+ sensitivity and sarcoplasmic reticulum Ca2+ release in rat ventricular myocytes ANESTHESIOLOGY 93 1034-1044, 2000
DOI:10.1097/00000542-200010000-00027

Davies LA; Hopkins PM; Boyett MR; Harrison SM Effects of halothane on the transient outward K+ current in rat ventricular myocytes BRITISH JOURNAL OF PHARMACOLOGY 131 223-230, 2000
DOI:10.1038/sj.bjp.0703565

McDonald RL; Colyer J; Harrison SM Quantitative analysis of Na+-Ca2+ exchanger expression in guinea-pig heart European Journal of Biochemistry 267 5142-5148, 2000

McDonald RL; Colyer J; Harrison SM Quantitative analysis of Na+-Ca2+ exchanger expression in guinea-pig heart EUROPEAN JOURNAL OF BIOCHEMISTRY 267 5142-5148, 2000
DOI:10.1046/j.1432-1327.2000.01579.x

Davies LA; Hopkins PM; Boyett MR; Harrison SM Effects of halothane on the transient outward K + current in rat ventricular myocytes British Journal of Pharmacology 131 223-230, 2000

Harrison SM; Robinson M; Davies LA; Hopkins PM; Boyett MR Mechanisms underlying the inotropic action of halothane on intact rat ventricular myocytes British Journal of Anaesthesia 82 609-621, 1999

Davies LA; Hamilton DL; Hopkins PM; Boyett MR; Harrison SM Concentration-dependent inotropic effects of halothane, isoflurane and sevoflurane on rat ventricular myocytes BRITISH JOURNAL OF ANAESTHESIA 82 723-730, 1999

Harrison SM; Robinson M; Davies LA; Hopkins PM; Boyett MR Mechanisms underlying the inotropic action of halothane on intact rat ventricular myocytes BRITISH JOURNAL OF ANAESTHESIA 82 609-621, 1999

Fawcett JM; Harrison SM; Orchard CH A method for reversible permeabilization of isolated rat ventricular myocytes EXPERIMENTAL PHYSIOLOGY 83 293-303, 1998

McMorn SO; Harrison SM; Boyett MR The effect of temperature on the rate-dependent decrease of the rat ventricular calcium current EXPERIMENTAL PHYSIOLOGY 83 49-63, 1998

Lancaster MK; Harrison SM Changes in contraction, cytosolic Ca2+ and pH during metabolic inhibition and upon restoration of mitochondrial respiration in rat ventricular myocytes Experimental Physiology 83 349-360, 1998

Davies LA; Harrison SM; Boyett MR; Hopkins PM Dose-dependent effects of halothane on contraction of rat ventricular myocytes British Journal of Anaesthesia 79 -, 1997

Janvier NC; McMorn SO; Harrison SM; Taggart P; Boyett MR The role of Na(+)-Ca2+ exchange current in electrical restitution in ferret ventricular cells. The Journal of physiology 504 Pt 2/-Pt 2/, 1997

Janvier NC; McMorn SO; Harrison SM; Taggart P; Boyett MR The role of Na+-Ca2+ exchange current in electrical restitution in ferret ventricular cells JOURNAL OF PHYSIOLOGY-LONDON 504 301-314, 1997
DOI:10.1111/j.1469-7793.1997.301be.x

Janvier NC; Harrison SM; Boyett MR The role of inward Na+-Ca2+ exchange current in the ferret ventricular action potential JOURNAL OF PHYSIOLOGY-LONDON 498 611-625, 1997

McMorn SO; Harrison SM; Boyett MR Comparison of ultra-slow, voltage-dependent inactivation of the cardiac L-type Ca2+ channel with Ca2+ or Ba2+ as the charge carrier Experimental Physiology 81 565-575, 1996

Boyett MR; Harrison SM; Janvier NC; McMorn SO; Owen JM; Shui Z A list of vertebrate cardiac ionic currents. Nomenclature, properties, function and cloned equivalents CARDIOVASCULAR RESEARCH 32 455-481, 1996
DOI:10.1016/S0008-6363(95)00228-6

McMorn SO; Harrison SM; Zang WJ; Boyett MR Comparison of ultra-slow, voltage-dependent inactivation of the cardiac L-type Ca2+ channel with Ca2+ or Ba2+ as the charge carrier in ferret ventricular myocytes EXPERIMENTAL PHYSIOLOGY 81 565-575, 1996

McMorn SO; Harrison SM; Boyett MR The temperature dependence of inactivation of the L-type Ca2+ current in isolated rat ventricular myocytes, 1996

LUCKCUCK T; ORCHARD C; HARRISON S; WALKER J SUBCELLULAR-LOCALIZATION OF ANNEXIN-V AND ANNEXIN-VI IN ISOLATED RAT VENTRICULAR MYOCYTES AND PORCINE LEFT-VENTRICLE, 1995

Luckcuck T; Orchard CH; Harrison SM; Walker JH Subcellular localization of annexins V and VI in isolated rat ventricular myocytes and porcine left ventricle Biochemical Society Transactions 23 -, 1995

HARRISON S; BOYETT M THE ROLE OF THE NA+-CA2+ EXCHANGER IN THE RATE-DEPENDENT INCREASE IN CONTRACTION IN GUINEA-PIG VENTRICULAR MYOCYTES JOURNAL OF PHYSIOLOGY-LONDON 482 555-566, 1995

HARRISON S THE VOLTAGE-DEPENDENCE OF CONTRACTION AT DIFFERENT STIMULATION RATES IN GUINEA-PIG VENTRICULAR MYOCYTES EXPERIMENTAL PHYSIOLOGY 80 941-958, 1995

BOYETT M; HONJO H; HARRISON S; ZANG W; KIRBY M ULTRA-SLOW VOLTAGE-DEPENDENT INACTIVATION OF THE CALCIUM CURRENT IN GUINEA-PIG AND FERRET VENTRICULAR MYOCYTES PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY 428 39-50, 1994
DOI:10.1007/BF00374750

HOEY A; HARRISON S; BOYETT M; RAVENS U EFFECTS OF THE ANEMONIA-SULCATA TOXIN (ATX-II) ON INTRACELLULAR SODIUM AND CONTRACTILITY IN RAT AND GUINEA-PIG MYOCARDIUM PHARMACOLOGY&TOXICOLOGY 75 356-365, 1994

MCMORN S; HARRISON S; ZANG W; YU X; BOYETT M A DIRECT NEGATIVE INOTROPIC EFFECT OF ACETYLCHOLINE ON RAT VENTRICULAR MYOCYTES AMERICAN JOURNAL OF PHYSIOLOGY 265 H1393-H1400, 1993

HARRISON S; MILNER R; BOYETT M INFLUENCE OF CA2+ CHANNEL AGONISTS AND ANTAGONISTS ON THE POSTREST STAIRCASE EUROPEAN JOURNAL OF PHARMACOLOGY 237 83-92, 1993
DOI:10.1016/0014-2999(93)90096-Z

CANNINGS I; HARRISON S; WHITE E; BOYETT M THE EFFECT OF A RANGE OF ALCOHOLS ON THE CONTRACTION OF GUINEA-PIG VENTRICULAR MYOCYTES EUROPEAN JOURNAL OF PHARMACOLOGY-ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY SECTION 248 213-216, 1993
DOI:10.1016/0926-6917(93)90046-S

HARRISON S; FRAMPTON J; MCCALL E; BOYETT M; ORCHARD C CONTRACTION AND INTRACELLULAR CA2+, NA+, AND H+ DURING ACIDOSIS IN RAT VENTRICULAR MYOCYTES AMERICAN JOURNAL OF PHYSIOLOGY 262 C348-C357, 1992

HARRISON S; MCCALL E; BOYETT M THE RELATIONSHIP BETWEEN CONTRACTION AND INTRACELLULAR SODIUM IN RAT AND GUINEA-PIG VENTRICULAR MYOCYTES JOURNAL OF PHYSIOLOGY-LONDON 449 517-550, 1992

Frampton JE; Harrison SM; Orchard CH [Ca2+] and [Na+] in rat ventricular myocytes showing negative and positive force frequency relationships Advances in Experimental Medicine and Biology 311 335-336, 1991

BERS D; HRYSHKO L; HARRISON S; DAWSON D CITRATE DECREASES CONTRACTION AND CA CURRENT IN CARDIAC-MUSCLE INDEPENDENT OF ITS BUFFERING ACTION AMERICAN JOURNAL OF PHYSIOLOGY 260 C900-C909, 1991

FRAMPTON J; HARRISON S; BOYETT M; ORCHARD C CA-2+ AND NA+ IN RAT MYOCYTES SHOWING DIFFERENT FORCE-FREQUENCY RELATIONSHIPS AMERICAN JOURNAL OF PHYSIOLOGY 261 C739-C750, 1991

HARRISON S; BERS D TEMPERATURE-DEPENDENCE OF MYOFILAMENT CA SENSITIVITY OF RAT, GUINEA-PIG, AND FROG VENTRICULAR MUSCLE AMERICAN JOURNAL OF PHYSIOLOGY 258 C274-C281, 1990

HARRISON S; BERS D MODIFICATION OF TEMPERATURE-DEPENDENCE OF MYOFILAMENT CA SENSITIVITY BY TROPONIN-C REPLACEMENT AMERICAN JOURNAL OF PHYSIOLOGY 258 C282-C288, 1990

BERS D; HRYSHKO L; HARRISON S CITRATE INHIBITS CARDIAC CONTRACTION BY AN EFFECT ON CA CURRENT AND NOT BY SIMPLE CAO BUFFERING BIOPHYSICAL JOURNAL 57 A177-A177, 1990

BERS D; HARRISON S TROPONIN-C REPLACEMENT MODIFIES THE TEMPERATURE-DEPENDENCE OF MYOFILAMENT CA-SENSITIVITY OF SKINNED CARDIAC-MUSCLE ISOLATED FROM THE RAT JOURNAL OF PHYSIOLOGY-LONDON 418 P166-P166, 1989

Harrison SM; Bers DM Correction of proton and Ca association constants of EGTA for temperature and ionic strength American Journal of Physiology - Cell Physiology 256 -, 1989

FRY C; MILLER D; HARDING D; HARRISON S THE CONTRIBUTION OF MITOCHONDRIAL CALCIUM-ION EXCHANGE TO RELAXATION OF TENSION IN CARDIAC-MUSCLE MOLECULAR AND CELLULAR BIOCHEMISTRY 89 127-133, 1989

HARRISON S; BERS D CORRECTION OF PROTON AND CA ASSOCIATION CONSTANTS OF EGTA FOR TEMPERATURE AND IONIC-STRENGTH AMERICAN JOURNAL OF PHYSIOLOGY 256 C1250-C1250, 1989

HARRISON S; BERS D INFLUENCE OF TEMPERATURE ON THE CALCIUM SENSITIVITY OF THE MYOFILAMENTS OF SKINNED VENTRICULAR MUSCLE FROM THE RABBIT JOURNAL OF GENERAL PHYSIOLOGY 93 411-428, 1989
DOI:10.1085/jgp.93.3.411

HARRISON S; LAMONT C; MILLER D HYSTERESIS AND THE LENGTH DEPENDENCE OF CALCIUM SENSITIVITY IN CHEMICALLY SKINNED RAT CARDIAC-MUSCLE JOURNAL OF PHYSIOLOGY-LONDON 401 115-143, 1988

HARRISON S; BERS D THE INFLUENCE OF TEMPERATURE ON THE CALCIUM SENSITIVITY OF SKINNED VENTRICULAR MUSCLE FROM THE RABBIT BIOPHYSICAL JOURNAL 53 A435-A435, 1988

BERS D; HARRISON S RAPID REWARMING OF CARDIAC-MUSCLE DURING RAPID COOLING CONTRACTURES SUGGEST SPECIES-DIFFERENCES IN MYOFILAMENT CA SENSITIVITY BIOPHYSICAL JOURNAL 53 A435-A435, 1988

HARRISON S; BERS D THE MEASUREMENT OF K'CA OF EGTA, BAPTA, AND DI-BROMO-BAPTA AT A RANGE OF IONIC STRENGTHS AND TEMPERATURES BIOPHYSICAL JOURNAL 51 A102-A102, 1987

HARRISON S; BERS D THE EFFECT OF TEMPERATURE AND IONIC-STRENGTH ON THE APPARENT CA-AFFINITY OF EGTA AND THE ANALOGOUS CA-CHELATORS BAPTA AND DIBROMO-BAPTA BIOCHIMICA ET BIOPHYSICA ACTA 925 133-143, 1987
DOI:10.1016/0304-4165(87)90102-4

BERS D; HARRISON S COMPARISON OF THE NEW CALCIUM BUFFERS BAPTA AND DI-BROMO-BAPTA WITH EGTA - EVALUATION OF PURITY AND SENSITIVITY TO TEMPERATURE AND IONIC-STRENGTH JOURNAL OF PHYSIOLOGY-LONDON 386 P58-P58, 1987

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