University roles and responsibilities
- Senior Lecturer in Cardiac Electrophysiology
Affiliations and memberships
- Honorary Director of Translational Research, Ashford and St Peters NHS Trust
- Honorary Assistant Professor, University of Pittsburgh
- Representative of the Physiological Society, University of Surrey
- Honorary Teaching Fellow, Department of Physiology, Royal Free and University College Medical School (2008-2010)
- Professional Development Spine Tutor/Facilitator, Academic Centre for Medical Education, Medical Education, University College London (2002-2008)
My research concerns the characterisation of intracellular and intercellular signalling pathways, primarily in cardiac and smooth muscle, in relation to normal and pathological excitation-contraction coupling. In particular, I am interested in evaluating these signalling pathways to explain the fundamental processes regulating: excitation and conduction of electrical signals; generation of contractile force; regulation of cell growth. I have translated these fundamental studies to characterise the basic intracellular and intercellular changes that underlie pathological situations associated with the heart (e.g. arrhythmias, heart failure, hypertrophic muscle growth) and smooth muscle organs (e.g. pulmonary hypertension, atherosclerosis, overactive bladder). My work involves investigative laboratory experimentation with well-characterised animal models of normal function and human pathological conditions, as well as collaboration with clinicians to extend this work to the use of tissues obtained from patients with clinically characterised pathological conditions.
My particular expertise, for which I have international recognition, is concerned with the role of intracellular phosphatises and kinases to regulate the activity of several key stages concerned with electrical signal transmission, contractile regulation and tissue growth and development. I have pioneered studies that have characterised the role of the intracellular Ca2+-dependent phosphatase, calcineurin, in these fundamental physiological pathways/
These explore the role of serine-threonine protein phosphatase 3, calcineurin, its intracellular targets and the contribution it has to the normal and pathological function of cardiac and visceral smooth muscle organs. In particular I am investigating:
- The regulation of gap junction and ion channel function in myocardium, including tissue from patients with atrial fibrillation and animal models of left ventricular hypertrophy. This is motivated to understand the cell and tissue basis of cardiac arrhythmias.
- Regulation by intracellular phosphatases of myocardial and visceral organ hypertrophy and characterisation of consequent changes to the key intracellular regulatory pathways associated with pathologies such as cardiac arrhythmias, myocardial failure, benign lower urinary tract disorders and initiation of visceral pain.
- Protocols to devise and validating more accurate methods to measure the electrical properties of cells (e.g. with impedance and dielectrophoresis methodologies) to generate more reliable experimental models to evaluate the action of the above phosphatises and kinases.
- Investigation of the role of the above intracellular signalling pathways to control chronobiological rhythms and their association with atrial fibrillation.
- Prof CH Fry on regulation of the biophysical properties of cardiac and smooth muscle, including novel methods to measure gap junction properties in multicellular tissues, as well as control of epithelial transmitter release and downstream modulation of smooth muscle function.
- Dr Michaele Mahmoudi.on biomarkers in cardiac pathologies.
- Prof M Hughes and Dr F Labeed, FEPS, Biochemical engineering division; Faculty of Engineering and Physical Sciences, University of Surrey on the development of techniques to measure the biophysical properties of muscle cells.
- Cardiologists/cardiac surgeons at St George's Hospital, Ashford & St Peters and The Royal Surrey County Hospital NHS trusts to characterise abnormal functional properties of myocardium with well-characterised cardiac pathologies.1. I am the lead on the investigative component on the HASTE foundation funded grant in collaboration with Royal Surrey.2. Honorary director of translational research, Ashford and St Peters NHS Trust.
- Prof R La Ragione, School of Veterinary Medicine, University of Surrey. Prof La Ragione is a collaborator in my currently funded BHF grant.
- Dr Richard Heads at King's College London concerning the role of calcineurin in fibroblast dysfunction during cardiac inflammation.
- I have recently expanded the atrial fibrillation project (HASTE) and initiated collaborations with Prof David Paterson, Oxford University and Dr Andrew James, University of Bristol.
- Dr Van Der Veen (University of Surrey) Dr Sam Boatang (University of Reading) on role of clock genes in cardiac arrhythmias.
- Dr A Aiello, Centre for Cardiovascular Sciences, University of La Plata, Buenos Aires, Argentina. Dr Aiello's expertise is in Na loading transporters in the heart. This was facilitated by:
- Santander Staff Award (£2K) to visit and conduct research at University of La Plata, Argentina (2012 and 2014)
- Santander PhD students award (£5K) for a PhD student from La Plata University (2012)
- Awarded a Santander scholarship certificate for an outstanding performance and dedication in the field of study - FHMS - (March 2013).
- Dr Perrino, Department of Physiology and Cell Biology, University of Nevada Reno, USA. Dr Perrino is an experienced biochemist in manufacturing constitutively active calcineurin isoforms.
- Prof P Lampe, Fred Hutchinson, Cancer Research Centre, Seattle, USA. Prof Lampe is an expert in gap junctions biochemistry and phosphorylation.
- Patch-clamp technique
- Intracellular microelectrode or extracellular monophasic action potential recording simultaneously with isometric muscle contractions
- Tissue impedance measurement
- Multi-electrode array system
- Recording isometric muscle contractions in cardiac and smooth muscle preparations
- Measurement of isolated cardiomyocyte mechanics
- Immunofluorescence with laser scanning confocal microscopy
- Real-time intracellular Ca2+ imaging by epifluorescence microscopy, cell shortening by video-scanning methods
- Protein phosphatase activity assays
- Subcellular tissue fractionation
- SDS-PAGE and western blotting
- Mouse genotyping
- Baculovirus protein expression system.
- Single cardiac and vascular smooth muscle cells isolation techniques
- Primary and cell-line tissue culture
- Proliferation assay
- 2013-2015 (£128,000; PI: R Jabr, Co-I: CH Fry). Title: Investigation of the role of calcineurin in persistent electrophysiological myocardial changes following regression from left ventricular hypertrophy. Funded by British Heart Foundation
- 2013-2014 (£8,000; Co-PI: R Jabr). Title: MicroRNAs as potential biomarkers in coronary artery calcification. Biomedical & Health Research Pump-Priming Funds grant, University of Surrey, 2011-2015 (£638,000) HASTE Foundation. Title: Improving detection and characterising the fundamental basis of atrial fibrillation. I am the Lead on the investigative research component (Dr E Leatham is lead on the clinical component and Prof CH Fry the manager of both components)
- 2008-2010 (£147,280; PI: R Jabr, Co-I: CH Fry). Title: The role of calcineurin in regulating action potential propagation in normal and hypertrophied myocardium through connexin43 dephosphorylation. Funded by British Heart Foundation
- 2009-2012 (€300,000; PI: CH Fry; Co-I, R Jabr). Title: Combatting Incontinence: InComb-EU Framework 7.
- 1999-2000 (£80,000- PI R Jabr). Title: Contractile and electrophysiological properties of cardiac ventricular myocytes in spontaneously hypertensive rats before and during development of hypertension, 1999. Funded by Kuwait University.
Invited research lectures
- 2012 Centre for Cardiovascular investigation; Faculty of Medicine; University of La Plata. Title: The differential role of calcineurin isoforms in the cardiovascular system.
- 2011 Physiological Society Meeting, Oxford, July, 2011 Title: Inter-relationship between conduction velocity, intracellular Ca2+ and gap junction resistance in ventricular myocardium
- 2011 University of Surrey, FHMS, research day, 'Hot topics in cardiovascular research'. Title: Cellular mechanisms for cardiac arrhythmogenesis.
- 2010 Pfizer, sandwich, UK. Title: Role of calcineurin in overactive bladder.
- 2010 The FP7 mid-term meeting, UK. Title: Use of the dielectrophoresis technique for selective cell sorting of bladder urothelial cells.
- 2009 The European Society of Cardiology, Munich, Germany. Title: Calcineurin nuclear import.
- 2009 The Marie Curie- Nuclear Receptors Biology Meeting, UK. Title: Role of nuclear calcineurin in the heart.
- 2008 UK Gap Junction meeting, University of Surrey, UK. Title: Calcineurin slows conduction velocity during rapid pacing in guinea pig papillary muscle.
Postgraduate research supervision
I currently supervise three PhD students at University of Surrey. I'm also a co-supervisor for one PhD student in Biochemical Engineering division; Faculty of Engineering & Physical Sciences, and one PhD student in Dept of Biochemistry & Physiology, University of Surrey.
2010-present Line manager for three postdoctoral fellows. Two financed from HASTE project and one from currently funded BHF project grant.
Completed postgraduate research projects I have supervised
Postgraduate research students
- 2009-2013 Supervised three MSc Toxicology students
- 2009-2012 Supervised MSc Erasmus students (University of Milan)
- 2009-2011 Mentor for PhD/MD/MSc students in Clinical Medicine Division at The Postgraduate Medical School, University of Surrey
- 2007-2008 Co-supervised MD/PhD student at NHLI, Imperial College London
- 2009-2010 Line managed postdoctoral fellow, funded by BHF project grant
- 2000-2008 Trained/co-supervised several postdoctoral fellows at UCL/King's College London and Imperial College London (NHLI)
Module organiser for BMS1032 Physiology 1 module (15 credits; Level 4)
Module organiser for BMS2038 Physiology 2 module (15 credits; Level 5)
Undergrad Physiology teaching:Cardiovascular system; Renal physiology; body fluids and electrolytes; acid-base balance; female reproductive system and pregnancy; Physiology practicals.
- Receptors and intracellular signalling pathways for undergraduate/ postgraduate modules including: L5 BMS2035, MSc Toxicology, MSc Nutrition Medicine, MSc Health and Clinical Sciences
- Cardiovascular toxicity for MSc Toxicology.
Aims Bladder wall stretch increases tissue tension and releases adenosine 5'‐triphosphate (ATP) as part of a transduction process to sense bladder filling. Aging is associated with bladder fibrosis to produce a stiffer bladder wall: this may augment ATP release and contribute to age‐dependent urgency. Muscarinic agonists also release ATP and present a potential target for antimuscarinic agents, but its age‐dependency is unknown. This study aimed, in young and old mice, to: (a) quantify the relationship between bladder wall stiffness and stretch‐dependent ATP release and; (b) characterize muscarinic agonist‐dependent release. Methods ATP release from young (9‐12 weeks) and aged (24 months) mouse bladder wall was measured in vitro, with a luciferin‐luciferase assay, after stretch or carbachol exposure. Bladder wall stiffness, measured simultaneously during stretch, was compared to histological proportions of connective tissue and detrusor muscle. Results With young mice, stretch‐activated ATP release required an intact mucosa and was positively associated with wall stiffness. ATP release by carbachol was about four‐fold greater compared to stretch. With aged mice: ATP release varied a hundred‐fold and no association with stiffness; carbachol release diminished; connective tissue and mucosa thickness increased. Conclusions With young mice, stretch, or muscarinic agonists potently induce bladder wall ATP release. Stretch‐dependent release is proportional to bladder wall stiffness, independent of the extent of stretch. With aged mice dependence of stretch‐activated ATP release with stiffness was lost. The huge variability of release suggests that aged mice do not form a homogenous cohort and may underlie the heterogeneity in bladder filling sensations.
Aim To review evidence for novel drug targets that can manage overactive bladder (OAB) symptoms. Methods A think tank considered evidence from the literature and their own research experience to propose new drug targets in the urinary bladder to characterize their use to treat OAB. Results Five classes of agents or cellular pathways were considered. (a) Cyclic nucleotide–dependent (cyclic adenosine monophosphate and cyclic guanosine monophosphate) pathways that modulate adenosine triphosphate release from motor nerves and urothelium. (b) Novel targets for β3 agonists, including the bladder wall vasculature and muscularis mucosa. (c) Several TRP channels (TRPV1, TRPV4, TRPA1, and TRPM4) and their modulators in affecting detrusor overactivity. (d) Small conductance Ca2+‐activated K+ channels and their influence on spontaneous contractions. (e) Antifibrosis agents that act to modulate directly or indirectly the TGF‐β pathway—the canonical fibrosis pathway. Conclusions The specificity of action remains a consideration if particular classes of agents can be considered for future development as receptors or pathways that mediate actions of the above mentioned potential agents are distributed among most organ systems. The tasks are to determine more detail of the pathological changes that occur in the OAB and how the specificity of potential drugs may be directed to bladder pathological changes. An important conclusion was that the storage, not the voiding, phase in the micturition cycle should be investigated and potential targets lie in the whole range of tissue in the bladder wall and not just detrusor.
Introduction The following is a report on the proceedings of the 2019 International Consultation on Incontinence‐Research Society nocturia think tank (NTT). Objectives The objectives of the 2019 NTT were as follows: (a) to evaluate the role of urothelium in the pathophysiology of nocturia; (b) to determine whether nocturia is a circadian disorder; (c) to discuss the role of melatonin in nocturia; (d) to consider ambulatory urodynamic monitoring in evaluating patients with nocturia; (e) to explore studies of water handling in human compartments utilizing heavy water; and (f) to explore whether basic science is the key to understanding the treatment options for diminished bladder capacity in patients with nocturia. Methods A compendium of discussions of the role of experimental science in understanding the pathophysiology of nocturia is described herein. Results and Conclusions Translational science will play an increasing role in understanding the pathophysiology of nocturia, which may result in improved treatment strategies.
Background and Purpose. To characterise the molecular mechanisms that determine variability of atropine‐resistance of nerve‐mediated contractions in human and guinea‐pig detrusor smooth muscle Experimental Approach. Atropine‐resistance of nerve‐mediated contractions, and the role of P2X1 receptors, was measured in isolated preparations from guinea‐pigs and also humans with or without overactive bladder syndrome, from which the mucosa was removed. Nerve‐mediated ATP release was measured directly with amperometric ATP‐sensitive electrodes. Ecto‐ATPase activity of guinea‐pig and human detrusor samples was measured in vitro by measuring the concentration‐dependent rate of ATP breakdown. The transcription of ecto‐ATPase subtypes in human samples was measured by qPCR. Key Results Atropine resistance was greatest in guinea‐pig detrusor, absent in human tissue from normally‐functioning bladders and intermediate in human overactive bladder. Greater atropine resistance correlated with reduction of contractions by the ATP‐diphospho‐hydrolase apyrase, directly implicating ATP in their generation. E‐NTPDase‐1 was the most abundantly transcribed ecto‐ATPase of those tested and transcription was reduced in tissue from human overactive, compared to normal, bladders. E‐NTPDase‐1 enzymatic activity was inversely related to the magnitude of atropine resistance. Nerve‐mediated ATP release was continually measured and varied with stimulation frequency over the range 1‐16 Hz. Conclusion and Implications Atropine‐resistance in nerve‐mediated detrusor contractions is due to ATP release and its magnitude is inversely related to E‐NTPDase‐1 activity. ATP is released under different stimulation conditions compared to acetylcholine that implies different routes for their release
A loss of ability of cells to undergo apoptosis (programmed cell death, whereby the cell ceases to function and destroys itself) is commonly associated with cancer, and many anti-cancer interventions aim to restart the process. Consequently, the accurate quantification of apoptosis is essential in understanding the function and performance of new anti-cancer drugs. Dielectrophoresis has previously been demonstrated to detect apoptosis more rapidly than other methods, and is low-cost, label-free and rapid, but has previously been unable to accurately quantify cells through the apoptotic process because cells in late apoptosis disintegrate, making cell tracking impossible. In this paper we use a novel method based on light absorbance and multi-population tracking to quantify the progress of apoptosis, benchmarking against conventional assays including MTT, trypan blue and Annexin-V. Analyses are performed on suspension and adherent cells, and using two apoptosis-inducing agents. IC50 measurements compared favourably to MTT and were superior to trypan blue, whilst also detecting apoptotic progression faster than Annexin-V.
Temperature compensation and period determination by casein kinase 1 (CK1) are conserved features of eukaryotic circadian rhythms, whereas the clock gene transcription factors that facilitate daily gene expression rhythms differ between phylogenetic kingdoms. Human red blood cells (RBCs) exhibit temperature-compensated circadian rhythms, which, because RBCs lack nuclei, must occur in the absence of a circadian transcription-translation feedback loop. We tested whether period determination and temperature compensation are dependent on CKs in RBCs. As with nucleated cell types, broad-spectrum kinase inhibition with staurosporine lengthened the period of the RBC clock at 37°C, with more specific inhibition of CK1 and CK2 also eliciting robust changes in circadian period. Strikingly, inhibition of CK1 abolished temperature compensation and increased the Q10 for the period of oscillation in RBCs, similar to observations in nucleated cells. This indicates that CK1 activity is essential for circadian rhythms irrespective of the presence or absence of clock gene expression cycles.
To measure the effect of external heating on bladder wall contractile function, histological structure and expression of proteins related to tissue protection and apoptosis. Material and Methods In vitro preparations of bladder wall and ex vivo perfused pig bladders were heated from 37 to 42°C, 46 and 50°C for 15 min. Isolated preparations were heated by radiant energy and perfused bladders were heated by altering perfusate temperature. Spontaneous contractions or pressure variations were recorded, as well as responses to the muscarinic agonist carbachol or motor nerve excitation in vitro during heating. Tissue histology in control and after heating was analysed using haematoxylin and eosin staining and 40-6-diamidino-2- phenylindole (DAPI) nuclear labelling. The effects of heating on protein expression levels of (i) heat shock proteins HSP27- pSer82 and inducible-HSP70 and (ii) caspase-3 and its downstream DNA-repair substrate poly-[ADP-ribose] polymerase (PARP) were measured. Results Heating to 42°C reduced spontaneous contractions or pressure variations by ~70%; effects were fully reversible. There were no effects on carbachol or nerve-mediated responses. Tissue histology was unaffected by heating, and expression of heat shock proteins as well as caspase-3 and PARP were also unaltered. A TRPV1 antagonist had no effect on the reduction of spontaneous activity. Heating to 46°C had a similar effect on spontaneous activity and also reduced the carbachol contracture. Urothelial structure was damaged, caspase-3 levels were increased and inducible- HSP70 levels declined. At 50°C evoked contractions were abolished, the urothelium was absent and heat shock proteins and PARP expression was reduced with raised caspase-3 expression. Conclusions Heating to 42°C caused a profound, reversible and reproducible attenuation of spontaneous activity, with no tissue damage and no initiation of apoptosis pathways. Higher temperatures caused tissue damage and activation of apoptotic mechanisms. Mild heating offers a novel approach to reducing bladder spontaneous activity.
Electrical correlates of the physiological state of a cell, such as membrane conductance and capacitance, as well as cytoplasm conductivity, contain vital information about cellular function, ion transport across the membrane, and propagation of electrical signals. They are, however, difficult to measure; gold-standard techniques are typically unable to measure more than a few cells per day, making widespread adoption difficult and limiting statistical reproducibility. We have developed a dielectrophoretic platform using a disposable 3D electrode geometry that accurately (r2>0.99) measures mean electrical properties of populations of ~20,000 cells, by taking parallel ensemble measurements of cells at 20 frequencies up to 45 MHz, in (typically) ten seconds. This allows acquisition of ultra-high-resolution (100-point) DEP spectra in under two minutes. Data acquired from a wide range of cells – from platelets to large cardiac cells - benchmark well with patch-clamp-data. These advantages are collectively demonstrated in a longitudinal (same-animal) study of rapidly-changing phenomena such as ultradian (2-3 hour) rhythmicity in whole blood samples of the common vole (Microtus arvalis), taken from 10 µl tail-nick blood samples and avoiding sacrifice of the animal that is typically required in these studies.
Atrial fibrillation (AF) is the commonest sustained arrhythmia globally and results in significantly increased morbidity and mortality including a fivefold risk of stroke. Paroxysmal atrial fibrillation (PAF) constitutes approximately half of all AF cases and is thought to represent an early stage of the disease. This intermittent form of atrial arrhythmia can be a challenge to identify and as a result many affected individuals are not prescribed appropriate antithrombotic therapy and hence are at risk of stroke and thromboembolism. Despite these adverse outcomes there have been relatively few diagnostic advances in the field since the introduction of the Holter monitor in 1949. This review aims to establish the available evidence for electrophysiological, molecular, and morphological biomarkers to improve the detection of PAF with reference to the underlying mechanisms for the condition.
Circadian rhythms organize many aspects of cell biology and physiology to a daily temporal program that depends on clock gene expression cycles in most mammalian cell types. However, circadian rhythms are also observed in isolated mammalian red blood cells (RBCs), which lack nuclei, suggesting the existence of post-translational cellular clock mechanisms in these cells. By using electrophysiological and pharmacological approaches, we show that human RBCs display circadian regulation of membrane conductance and cytoplasmic conductivity that depends on the cycling of cytoplasmic K+ levels. Using pharmacological intervention and ion replacement, we show that inhibition of K+ transport abolishes RBC electrophysiological rhythms. Our results suggest that in the absence of conventional transcription cycles, RBCs maintain a circadian rhythm in membrane electrophysiology through dynamic regulation of K+ transport.
Introduction Posterior urethral valves (PUV) is the most common cause of congenital bladder outflow obstruction with persistent lower urinary tract and renal morbidities. There is a spectrum of functional bladder disorders ranging from hypertonia to bladder underactivity, but the aetiology of these clinical conditions remains unclear. Aims and objectives We tested the hypothesis that replacement of detrusor muscle with non-muscle cells and excessive deposition of connective tissue is an important factor in bladder dysfunction with PUV. We used isolated detrusor samples from children with PUV and undergoing primary or secondary procedures in comparison to age-matched data from children with functionally normal bladders. In vitro contractile properties, as well as passive stiffness, were measured and matched to histological assessment of muscle and connective tissue. We examined if a major pathway for fibrosis was altered in PUV tissue samples. Methods Isometric contractions were measured in vitro in response to either stimulation of motor nerves to detrusor or exposure to cholinergic and purinergic receptor agonists. Passive mechanical stiffness was measured by rapid stretching of the tissue and recording changes to muscle tension. Histology measured the relative amounts of detrusor muscle and connective tissue. Multiplex quantitative immunofluorescence labelling using five epitope markers was designed to determine cellular pathways, in particular the Wnt-signalling pathway, responsible for any changes to excessive deposition of connective tissue. Results and Discussion PUV tissue showed equally reduced contractile function to efferent nerve stimulation or exposure to contractile agonists. Passive muscle stiffness was increased in PUV tissue samples. The smooth muscle:connective tissue ratio was also diminished and mirrored the reduction of contractile function and the increase of passive stiffness. Immunofluorescence labelling showed in PUV samples increased expression of the matrix metalloproteinase, MMP-7; as well as cyclin-D1 expression suggesting cellular remodelling. However, elements of a fibrosis pathway associated with Wnt-signalling were either reduced (β-catenin) or unchanged (c-Myc). The accumulation of extracellular matrix, containing collagen, will contribute to the reduced contractile performance of the bladder wall. It will also increase tissue stiffness that in vivo would lead to reduced filling compliance. Conclusions Replacement of smooth muscle with fibrosis is a major contributory factor in contractile dysfunction in the hypertonic PUV bladder. This suggests that a potential strategy to restore normal contractile and filling properties is development of the effective use of antifibrotic agents.
Paroxysmal atrial fibrillation (PAF) is the most common cardiac arrhythmia, conveying a stroke risk comparable to persistent AF. It poses a significant diagnostic challenge given its intermittency and potential brevity, and absence of symptoms in most patients. This pilot study introduces a novel biomarker for early PAF detection, based upon analysis of sinus rhythm ECG waveform complexity. Sinus rhythm ECG recordings were made from 52 patients with ( n = 28) or without ( n = 24) a subsequent diagnosis of PAF. Subjects used a handheld ECG monitor to record 28-second periods, twice-daily for at least 3 weeks. Two independent ECG complexity indices were calculated using a Lempel-Ziv algorithm: R-wave interval variability (beat detection, BD) and complexity of the entire ECG waveform (threshold crossing, TC). TC, but not BD, complexity scores were significantly greater in PAF patients, but TC complexity alone did not identify satisfactorily individual PAF cases. However, a composite complexity score ( h -score) based on within-patient BD and TC variability scores was devised. The h -score allowed correct identification of PAF patients with 85% sensitivity and 83% specificity. This powerful but simple approach to identify PAF sufferers from analysis of brief periods of sinus-rhythm ECGs using hand-held monitors should enable easy and low-cost screening for PAF with the potential to reduce stroke occurrence.
Electrical correlates of the physiological state of a cell, such as membrane conductance and capacitance, as well as cytoplasm conductivity, contain vital information about cellular function, ion transport across the membrane, and propagation of electrical signals. They are, however, difficult to measure; gold-standard techniques are typically unable to measure more than a few cells per day, making widespread adoption difficult and limiting statistical reproducibility. We have developed a dielectrophoretic platform using a disposable 3D electrode geometry that accurately (r2 > 0.99) measures mean electrical properties of populations of ~20,000 cells, by taking parallel ensemble measurements of cells at 20 frequencies up to 45 MHz, in (typically) ten seconds. This allows acquisition of ultra-high-resolution (100-point) DEP spectra in under two minutes. Data acquired from a wide range of cells – from platelets to large cardiac cells - benchmark well with patch-clamp-data. These advantages are collectively demonstrated in a longitudinal (same-animal) study of rapidly-changing phenomena such as ultradian (2–3 hour) rhythmicity in whole blood samples of the common vole (Microtus arvalis), taken from 10 µl tail-nick blood samples and avoiding sacrifice of the animal that is typically required in these studies.
Temperature compensation and period determination by casein kinase 1 (CK1) are conserved features of eukaryotic circadian rhythms, whereas the clock gene transcription factors that facilitate daily gene expression rhythms differ between phylogenetic kingdoms. Human red blood cells (RBCs) exhibit temperature compensated circadian rhythms which, since RBCs lack nuclei, must occur in the absence of a circadian transcription-translation feedback loop. We tested whether period determination and temperature compensation are dependent on casein kinases in RBCs. As with nucleated cell types, broad spectrum kinase inhibition with staurosporine lengthened the period of the RBC clock at 37°C, with more specific inhibition of CK1 and CK2 also eliciting robust changes in circadian period. Strikingly, inhibition of CK1 abolished temperature compensation and increased the Q10 for the period of oscillation in RBCs, similar to observations in nucleated cells. This indicates that CK1 activity is essential for circadian rhythms irrespective of the presence or absence of clock gene expression cycles.
Spinal cord transection (SCT) leads to an increase of spontaneous contractile activity in the isolated bladder that is reminiscent of an overactive bladder syndrome in patients with similar damage to the central nervous system. An increase of interstitial cell number in the suburothelial space between the urothelium and detrusor smooth muscle layer occurs in SCT bladders and these cells elicit excitatory responses to purines and pyrimidines such as ATP, ADP and UTP. We have investigated the hypothesis that these agents underlie the increase of spontaneous activity. Rats underwent lower thoracic spinal cord transection and their bladder sheets or strips, with intact mucosa except where specified, used for experiments. Isometric tension was recorded and propagating Ca2+ and membrane potential (Em) waves recorded by fluorescence imaging using photodiode arrays. SCT bladders were associated with regular spontaneous contractions (2.9±0.4 min-1); ADP, UTP and UDP augmented the amplitude but not their frequency. With strips from such bladders, a P2Y6-selective agonist (PSB0474) exerted similar effects. Fluorescence imaging of bladder sheets showed that ADP or UTP increased the conduction velocity of Ca2+/Em waves that were confined to regions of the bladder wall with an intact mucosa. When transverse bladder sections were used, Ca2+/Em waves originated in the suburothelial space and propagated to the detrusor and urothelium. Analysis of wave propagation showed that the suburothelial space exhibited properties of an electrical syncitium. These experiments are consistent with the hypothesis that P2Y-receptor agonists increase spontaneous contractile activity by augmenting functional activity of the cellular syncitium in the suburothelial space.
To measure the relative transcription of adenosine receptor subtypes and the contractile effects of adenosine and selective receptor-subtype ligands on detrusor smooth muscle from patients with neuropathic overactive (NDO) and stable bladders and also from guinea-pigs. Contractile function was measured at 37°C in vitro from detrusor smooth muscle strips. Contractions were elicited by superfusate agonists or by electrical field stimulation. Adenosine-receptor (A1, A2A, A2B, A3) transcription was measured by RT-PCR. Adenosine attenuated nerve-mediated responses with equivalent efficacy in human and guinea-pig tissue (pIC50 3.65–3.86); the action was more effective at low (1–8 Hz) compared to high (20– 40 Hz) stimulation frequencies in human NDO and guinea-pig tissue. With guinea-pig detrusor the action of adenosine was mirrored by the A1/A2-agonist N-ethylcarboxamido adenosine (NECA), partly abolished in turn by the A2B-selectve antagonist alloxazine, as well as the A1-selective agonist N6- cyclopentyladenosine (CPA). With detrusor from stable human bladders the effects of NECA and CPA were much smaller than that of adenosine. Adenosine also attenuated carbachol contractures, but mirrored by NECA (in turn blocked by alloxazine) only in guinea-pig tissue. Adenosine receptor subtype transcription was measured in human detrusor and was similar in both groups, except reduced A2A levels in overactive bladder. Suppression of the carbachol contracture in human detrusor is independent of A-receptor activation, in contrast to an A2B-dependent action with guinea-pig tissue. Adenosine also reduced nerve-mediated contractions, by an A1- dependent action suppressing ATP neurotransmitter action.
An actionpotential is a transient depolarization of the membrane potential of excitable cells. They serve two main functions: to transmit and encode information, and to initiate cellular events such as muscular contraction. In this article actionpotentials generated in nerves will be the focus of attention. An actionpotential results from a transient change to the properties of the cell membrane, from a state where it is much more permeable to K+ than Na+, to a reversal of these permeability properties. Thus during the actionpotential an influx of Na+ is responsible for the rapid depolarization and an efflux of K+ causes repolarization. This ionic basis of the actionpotential can be predicted from the Nernst equation and is illustrated in the text. Changes to membrane ionic permeability are due to the opening and closing of voltage-gated ion channels, and the properties of such channels explain additional phenomena such as refractoriness, threshold and cellular excitability. Actionpotentials conduct with a finite velocity along nerve axons, and the actual velocity depends on a number of factors that include: fibre radius, temperature, functional ion channel number and the presence of a myelin sheath. The physical basis of conduction is explained by the local circuit hypothesis. Synaptic transmission of an actionpotential is explained in terms of excitatory post-synaptic potential (EPSP) generation at the post-synaptic membrane. The facility by which post-synaptic actionpotential may be developed is explained in terms of temporal and spatial summation as well as the influence of inhibitory transmitters.
Background—We tested the hypothesis that alterations to action potential conduction velocity (CV) and conduction anisotropy in left ventricular hypertrophy are associated with topographical changes to gap-junction coupling and intracellular conductance by measuring these variables in the same preparations. Methods and Results—Left ventricular papillary muscles were excised from aortic-banded or sham-operated guinea-pig hearts. With intracellular stimulating and recording microelectrodes, CV was measured in 3 dimensions with simultaneous conductance mapping with subthreshold stimuli and correlated with quantitative histomorphometry of myocardial architecture and connexin 43 distribution. In hypertrophied myocardium, CV in the longitudinal axis was smaller and transverse velocity was greater compared with control; associated with similar differences of intracellular conductance, consistent with more cell contacts per cell (5.7±0.2 versus 8.1±0.5; control versus hypertrophy), and more intercalated disks mediating side-to-side coupling (8.2±0.2 versus 10.2±0.4 per cell). Intercalated disk morphology and connexin 43 immunolabelling were not different in hypertrophy. Hypertrophied preparations showed local submillimeter (≈250 μm) regions with slow conduction and low intracellular conductance, which, although not affecting CV on the millimeter scale, were consistent with discontinuities from increased microscopical connective tissue content. Conclusions—With myocardial hypertrophy, altered longitudinal and transverse CV, and greater nonuniformity of CV anisotropy correspond to changes of intracellular conductance. These are associated with alteration of myocardial architecture, specifically the topography of cell–cell coupling and gap-junction connectivity.
T-type Ca channels are widely expressed throughout the urinary and male genital tracts, generally alongside L-type Ca channels. The use of pharmacological blockers of these channels has suggested functional roles in all regions, with the possible exception of the ureter. Their functional expression is apparent not just in smooth muscle cells but also in interstitial cells that lie in close proximity to muscle, nerve and epithelial components of these tissues. Thus, T-type Ca channels can contribute directly to modulation of muscle function and indirectly to changes of epithelial and nerve function. T-type Ca channel activity modulates phasic contractile activity, especially in conjunction with Ca -activated K channels, and also to agonist-dependent responses in different tissues. Upregulation of channel density occurs in pathological conditions associated with enhanced contractile responses, e.g. overactive bladder, but it is unclear if this is causal or a response to the pathological state. Moreover, T-type Ca channels may have a role in the development of prostate tumours regulating the secretion of mitogens from neuroendocrine cells. Although a number of selective channel blockers exist, their relative selectivity over L-type Ca channels is often low and makes evaluation of T-type Ca channel function in the whole organism difficult. © 2014 Springer-Verlag.
Cardiac arrhythmias are associated with raised intracellular [Ca2+] and slowed action potential conduction caused by reduced gap junction (GJ) electrical conductance (Gj). Ventricular GJs are composed of connexin proteins (Cx43), with Gj determined by Cx43 phosphorylation status. Connexin phosphorylation is an interplay between protein kinases and phosphatases but the precise pathways are unknown. We aimed to identify key Ca2+-dependent phosphorylation sites on Cx43 that regulate cardiac gap junction conductance and action potential conduction velocity. We investigated the role of the Ca2+-dependent phosphatase, calcineurin. Intracellular [Ca2+] was raised in guinea-pig myocardium by a low-Na solution or increased stimulation. Conduction velocity and Gj were measured in multicellular strips. Phosphorylation of Cx43 serine residues (S365 and S368) and of the intermediary regulator I1 at threonine35 was measured by Western blot. Measurements were made in the presence and absence of inhibitors to calcineurin, I1 or protein phosphatase-1 and phosphatase-2. Raised [Ca2+]i decreased Gj, reduced Cx43 phosphorylation at S365 and increased it at S368; these changes were reversed by calcineurin inhibitors. Cx43-S368 phosphorylation was reversed by the protein kinase C inhibitor chelerythrine. Raised [Ca2+]i also decreased I1 phosphorylation, also prevented by calcineurin inhibitors, to increase activity of the Ca2+-independent phosphatase, PPI. The PP1 inhibitor, tautomycin, prevented Cx43-365 dephosphorylation, Cx43-S368 phosphorylation and Gj reduction in raised [Ca2+]i. PP2A had no role. Conduction velocity was reduced by raised [Ca2+]i and reversed by calcineurin inhibitors. Reduced action potential conduction and Gj in raised [Ca2+] are regulated by calcineurin-dependent Cx43-S365 phosphorylation, leading to Cx43-S368 dephosphorylation. The calcineurin action is indirect, via I1 dephosphorylation and subsequent activation of PP1.
1 Gray RP, Dhillon P, Jacques A, Walker JM, Jabr RI, Marston S, Peters NS, McKenna W, Fry CH (2014). Electromechanical properties of isolated myocardium from patients with hypertrophic obstructive cardiomyopathy. Circulation (Arrhythmias and Electrophysiology) - under revision.
2 Fry CH, Gray RP, Dhillon PS, Jabr RI, Patel PM, Peters NS (2014). Relationship between intracellular conductance, action potential conduction, gap junction topology and tissue architecture in guinea-pig left ventricular hypertrophy. Circulation (Arrhythmias and Electrophysiology) - under revision
3 Dhillon PS, Chowdhury RA, Patel PM, Jabr R, Momin AU, Vecht J, Gray R, Shipolini A, Fry CH, Peters NS. (2014) Relationship between connexin expression and gap-junction resistivity in human atrial myocardium. Circulation (Arrhythmias and Electrophysiology):1: 7: 321-329.
4 Fry CH and Jabr RI. (2014) T-type Ca2+ channels and the urinary and male genital tracts. Pflügers Archives - European Journal of Physiology: 466: 781-789.
5 Paul MA, Mesquita RF, Jabr R, Marber MS, Brain SD, Mahadeo VB, Heads RJ (2014). Protein kinase-C epsilon regulates cardiac fibroblast phenotype by transcriptional co-operation with calcineurin via TLR4 and COX-2. Molecular and Cellular Biology; 34: 574-594
6 Dhillon PD, Gray R, Kojodjojo P, Jabr R, Chowdhury R, Fry CH, Peters NS (2013). The relationship between gap junction conductance and conduction velocity in mammalian myocardium. Circulation Electrophysiology and Arrhythmias: 6: 1208-1214.
7 Fahmi A, Smart N, Punn A, Jabr R, Marber M, Heads R (2013). p42/p44-MAPK and PI3K are Sufficient for IL-6 Family Cytokines/gp130 to Signal to Hypertrophy and Survival in Cardiomyocytes in the Absence of JAK/STAT Activation. Cell Signalling: 25: 898-909.
8 Fry CH, Salvage SC, Manazza A, Dupont E, Labeed FH, Hughes MP, Jabr RI (2012). Cytoplasm resistivity of mammalian atrial myocardium determined by dielectrophoresis and impedance methods. Biophysical Journal: 103: 2287-2294.
9 Fry CH, Young JS, Jabr RI, McCarthy C, Ikeda Y, Kanai AJ (2012). Modulation of spontaneous activity in the overactive bladder - the role of P2Y agonists. American Journal of Physiology, Renal Physiology: 302: F1447-1454.
10 Wyndaele JJ, Gammie A, Bruschini H, De Wachter S, Fry CH, Jabr RI, Kirschner-Hermanns R, Madersbacher H (2011). Bladder compliance what does it represent: can we measure it, and is it clinically relevant? Neurourology and Urodynamics: 30: 714-722.
11 Fry CH, Sadananda P, Wood DN, Thiruchelvam N, Jabr RI, Clayton R (2011). Modeling the urinary tract - computational, physical, and biological methods. Neurourology and Urodynamics: 30: 692-699.
12 Fry CH, Jabr RI. (2010) The action potential and nervous conduction. Surgery Feb.
13 Cook AR, Bardswell SC, Pretheshan S, Dighe K, Kanaganayagam GS, Jabr RI, Merkle S, Marber MS, Engelhardt S, Avkiran M (2009). Paradoxical resistance to myocardial ischemia and age-related cardiomyopathy in NHE1 transgenic mice: a role for ER stress? Journal of Molecular and Cellular Cardiology; 46: 225-233.
14. Jabr RI, Gorog DA, Tanno M, Fisher SG, Cao XB, Bellahcene M, Dighe K, Kabir AM, Quinlan RA, Kato K, Gaestel M, Marber MS, Heads RJ (2009). MAPKAPK-2 modulates p38-MAPK localisation and small heat shock protein phosphorylation, but does not mediate the injury associated with p38-MAPK activation during myocardial ischemia. Cell Stress and Chaperons; 14: 477-489.
15. Jabr RI, Wilson AJ, Riddervold MH, Jenkins AH, Perrino BA, Clapp LH (2007). Nuclear translocation of calcineurin Aß but not Aα by platelet-derived growth factor in rat aortic smooth muscle. American Journal of Physiology, Cell Physiology 2007: 292: C2213-2225.
16. Obasanjo-Blackshire K, Mesquita RS, Jabr RI, Molkentin J, Marber MS, Xia Y and Heads RJ (2006). Calcineurin regulates NFAT-dependent iNOS expression and protection of cardiomyocytes: co-operation with Src tyrosine kinase. Cardiovascular Research: 71: 672-683.
17. Clapp LC, Jabr RI (2003). The BK channel: protective or detrimental in genetic hypertension? Circulation Research 2003: 93: 893-895.
18. Jabr RI, Wilson AJ, Clapp LH (2000). Calcium modulation of vascular smooth muscle ATP-sensitive K+ channels: Role of protein phosphatase-2B. Circulation Research: 87: 1019-1025.
19. Jabr RI, Yamazaki J, Hume JR (2000). Lysophosphatidylcholine triggers intracellular calcium release and activation of non-selective cation channels in renal arterial smooth muscle cells. Pflügers Archives; 439: 495-500.
20. Jabr RI, Toland H, Gelband CH, Wang XX, Hume JR (1997). Prominent role of sarcoplasmic reticulum Ca2+ stores in canine hypoxic pulmonary vasoconstriction. British Journal of Pharmacology: 122: 21-30.
21. Aiello ER, Jabr RI, Cole WC (1995). Arrhythmias and delayed recovery of cardiac action potential during reperfusion after ischemia: Role of oxygen radical-induced no-reflow phenomenon. Circulation Research: 77: 153-162.
22. Jabr RI, Cole WC (1995). Oxygen-derived free radical stress activates non-selective cation current in guinea-pig ventricular myocytes: Role of sulfhydryl groups. Circulation Research: 76: 812-824.
23. Jabr RI, Cole WC (1993). Alterations in electrical activity and membrane ionic currents induced by intracellular exposure of guinea-pig ventricular myocytes to oxy-radical stress. Circulation Research: 72: 1229-1244.
24. Jabr RI, Braveny P, Juggi JS (1988). Recovery of the conduction system from ischemic arrest and cardioplegia in perfused rat heart. Canadian Journal of Cardiology: 4: 90-96
Abstracts-Presented in national and international conferences:
2013Qasem AH, Fry CH, Mahmoudi M, Jabr RI. Assessment of Gap Junction Communication between Human Umbilical Vein Endothelial Cells and Monocytes In Response To Tumour Necrosis Factor (TNF-α). Presented in 1) British Society for Cardiovascular Research & Atherosclerosis Society (London, June 2013); and 2) International Unions of Physiological Society (IUPS) Congress, Birmingham, July 2013.
Waheed A, Salvage SC, Orlowski A, Fry CH, Michael A, Aiello A, Jabr RI. Low-Na increases ventricular gap junction resistivity and phosphorylation levels of connexion 43 at Serine 368: Possible synergistic interaction between calcineurin and protein kinase C. Presented in 1) International Society for Heart Research , The world Congress, San Diego, USA, July 2013; and 2) International Unions of Physiological Society (IUPS) Congress, Birmingham, July 2013.
Clayton J, Kitney D, Hague T, Talstaya A, Fry CH, Jabr RI. Modulation of urinary bladder smooth muscle contractility and mucosal ATP release by inhibition of intracellular protein phosphatases. International Unions of Physiological Society (IUPS) Congress, Birmingham, July 2013.
Kitney D, Hague T, Jabr RI, Fry CH. The influence of heating (37-50C) on spontaneous contractile activity of isolated bladder preparations. Presented in 1) International Unions of Physiological Society (IUPS) Congress, Birmingham, July 2013 and 2) ICS, Spain, August 2013.
2012Salvage SC, Roberts M, Fry CH, Jabr RI. Low Na+ solution increases gap junction resistivity and connexin 43 phosphorylation at serine 368 in guinea pig atrial myocardium: a role for calcineurin. Physiological Society meeting, Edinburgh, UK, July 2012.
2011Manazza A, Salvage S, Fry CH, Jabr RI. Measurement of myocardial sarcoplasmic resistivity by dielectrophoresis and impedance analysis. Physiological Society meeting, Oxford, 2011 as well as the European working group on cardiac cellular electrophysiology group , Oslo, Norway, 2011.
Salvage S, Dillon PS, Fry CH, Jabr RI. Interrelationship between conduction velocity, intracellular Ca2+ and gap junctions. Physiological Society meeting, Oxford, 2011 as well as the European working group on cardiac cellular electrophysiology group , Oslo, Norway, 2011.
2009Lin Y-C, Fry CH, Jabr RI. Modulation of staircase response in mouse myocardium by isoprenaline Physiological Society meeting (Dublin, 2009)
Jabr RI, Fry CH. Calcineurin slows myocardial action potential conduction during rapid pacing by increasing intercellular resistivity. American Heart Association (North American section; Baltimore, 2009)
Fry CH, Gray R, Dillon P, Jabr RI. Electrophysiological properties of human myocardium from hypertrophic cardiomyopathy. American Heart Association (North American section; Baltimore, 2009)
Dhillon PS, Gray R, Kojodjojo P, Jabr RI, Chowdhury RA, Fry CH, Peters NS. The Relationship Between Gap Junction Conductance and Conduction Velocity in Intact Myocardium Authors: Circulation 2009.
2007Jabr RI, Gray R, Patel PM, Peters NS, Fry C H. Calcinuerin slows the conduction velocity in isolated guinea-pig papillary muscle. Abstract submitted to the European Cardiac Arrhythmias Society Congress to be held in Marseille, France, April 2007.
Chowdhury R, Inuabasi L, Jabr R, Nicholson Thomas DM, Hall MC, Kirubakaran S, Dhillon P, Garratt CJ, Peters NS. Multiple anatomical changes in a goat model of atrial fibrillation are associated with conduction velocity abnormalities at 3 months. Abstract submitted to the Heart Rhythm Society, the 28th Annual Scientific Sessions to be held in Denver, Colorado May 2007.
2006Jabr RI, Gorog DA, Bellahcene M, Dighe K, Marber MS. MAPKAPK-2 does not mediate the injury associated with P38-MAPK activation during myocardial ischaemia: Possible role of nuclear translocation of phosphorylated P38-MAPK. Heart, 2006:92(1), no.017.
2005Mesquita RS, Jabr RI, Marber MS, Heads.RJ. Calcineurin and Protein Kinase C Regulate cyclooxygenase-2 expression in the heart. Presented in the 2nd Annual Symposium of the American Heart Association Council on Basic Cardiovascular Sciences-Targeting Heart Failure: New Science, NewTools, New Strategies Keystone, CO, USA, 2005.
Jabr RI, Gorog DA, Bellahcene M, Dighe K, Marber MS. MAPKAPK-2 does not mediate the injury associated with P38-MAPK activation during myocardial ischaemia. J Mol Cell Cardiol, 2005:38(6), no.90.
2004Jabr RI, Perrino B, Clapp LH: Nuclear translocation of calcineurin A ß isoform in response to platelet-derived growth factor in cultured rat aortic smooth muscle cells. Biophysical J, Feb 2004
2001Jabr RI, Wilson AW, Perrino BA, Clapp LH: Characterisation of calcineurin in rat aortic smooth muscle. Journal of Physiology, Bristol, 5-7 September, 2001: 536P.
Jabr RI, Wilson AW, Clapp LH: Ca2+ modulates vascular smooth muscle KATP channels via protein phosphatase-2B. Biophysical Journal 2001:80:627a.
2000Wilson AW, Jabr RI Clapp LH: Modulation of Glibenclamide-sensitive background K+ current by extracellular Ca2+ in isolated rat aortic smooth muscle cells. Journal of Physiology (London) 2000: 525P, 77P.
1999Al-Saeedi F, Juggi JS, Jabr RI, Al-Zaid NS: Intracellular kinetics of activator Ca2+ after ischemic preconditioning as determined by force-frequency relationship. J Mol Cell Cardiol, May 1999.
Ghadanfer E.A., Juggi JS, Jabr RI, Al-Zaid NS: Effect of preconditioning temperature on cardioprotection during global ischemia-reperfusion. J Mol Cell Cardiol, May 1999.
Jabr RI, Juggi JS, Joseph S, Barac-Nieto M: An increase in myocardial shortening velocity precedes arterial hypertension in spontaneously hypertensive rats. J Mol Cell Cardiol, May 1999.
1997Jabr RI, Hume JR: Effects of lysophosphatidylcholine on membrane currents in renal artery smooth muscle cells. Circulation 1997:94(8), pp1I-353, 2060.
Jabr RI, Hume JR: Prominent role of sarcoplasmic reticulum Ca2+ stores in canine hypoxic pulmonary vasoconstriction. Biophysical Journal 1997:72(2), pp. A184.
1996Jabr RI, Ahn DS, Hume JR: Characterization of three types of delayed rectifier potassium channels in canine pulmonary artery smooth muscle cells. Biophysical Journal Feb 1996:70(2), pp. A188.
1995Cole WC, Jabr RI, Aiello AE, Morales E: Cardiac non-selective cation current activated by oxy-radical stress and lysophosphatidylcholine: Voltage-dependence and block by Ni2+. Biophysical Journal 1995:68:A210.
1994Aiello EA, Jabr RI, Cole WC: Cardiac action potential shortening and arrhythmias during reperfusion after ischemia: Role of coronary vasoconstriction due to oxy-radical stress. Biophysical Journal 1994:66:A83.
Jabr RI, Cole WC: Oxygen-derived free -radical stress activates non-selective cation current in guinea-pig ventricular myocytes: Role of sulfhydryl groups. Biophysical Journal1994:66:A434.
Jabr RI, Leblanc N, Cole WC: Abnormal Ca2+ release activates Ca2+ -activated K+ channels in rabbit coronary myocytes during oxygen radicals stress. International Symposium on Resistance Arteries, Vermont, USA,1994.
1993Jabr RI, Cole WC: Oxygen radicals stimulates Na+/Ca2+ exchange and non-selective cation currents in guinea-pig ventricular myocytes. Biophysical Journal 1993:64:A397: 227.
1992Sigurdsson S, Jabr RI, Miller AL, Stephens NL, Cole WC: Whole-cell and single channel K+ currents in isolated canine bronchial smooth muscle cells. Biophysical Journal 1992:61:A251: 1446.
Jabr RI, Leblanc N, Cole WC: Abnormal sarcoplasmic reticulum (SR) Ca2+ release may mediate activation of Ca2+-dependent K+ current in coronary myocytes during oxygen-radical stress. Biophysical Journal 1992:61: A433: 2490.
1991Jabr RI, Cole WC: Effects of oxygen radicals on electrical activity and membrane currents in heart are mediated by abnormal Ca2+ release from sarcoplasmic reticulum. Circulation 1991:2:II-283; 1127.
1990Cole WC, McPherson CD, Jabr RI, Miller AL: Alterations in action potentials and contraction associated with perfusion of guinea-pig right ventricle: Protection by oxy-radical scavengers. Journal of Molecular and Cellular Cardiology 1990:22(suppl 1):S40.
Jabr RI, Cole WC: Alterations in electrical activity and membrane ionic currents after exposure of guinea-pig ventricular myocytes to oxy-radical. Journal of Molecular and Cellular Cardiology 1990:22(suppl 1):S35.
1987Jabr RI, Braveny P, Juggi JS: Preservation of the conduction system during ischemic heart arrest and cardioplegia. PACE 1987:10(3):598.
1986Braveny P, Juggi JS, Jabr RI: Post-arrest electrical instability of perfused rat heart. Journal of Molecular and Cellular Cardiology 1986:18(suppl 21): 274.