University of Pittsburgh Department of Cell Biology
  • Research

    A central goal of Dr. Salama's laboratory is to elucidate the mechanisms responsible for the initiation and termination of cardiac arrhythmias. An important step towards that end is to better understand the electrophysiology and function of the normal mammalian heart. To achieve these goals, they have developed the use of voltage-sensitive dyes and high temporal and spatial resolution optical techniques to map patterns of action potential (AP) propagation and repolarization. These novel methods are used to elucidate of the mechanisms that generate spatial heterogeneities of AP durations and the interplay between dispersion of repolarization (DOR) and anisotropic conduction velocities (CV). Several parameters play a role in producing non-uniformities of repolarization: the anisotropy of fiber structure is now found to influence DOR as well as CV and spatial heterogeneities of ionic channel expression and of AP duration restitution following a change in heart rate. Another related issue is to map AP propagation transmurally from endocardium to epicardium to elucidate the role of M-cells as (midwall cells) which may provide reentry pathways by forming a barrier of abrupt DOR. Animal models for cardiac arrhythmias include: acute ischemia in the guinea pig heart and 2 rabbit models of the long QT syndrome (LQTS). A number of mechanisms are being investigated as factors that promote arrhythmias in the LQTS: elevation of extracellular K+, sympathetic stimulation, and the role of spontaneous Ca2+ oscillation from the sarcoplasmic reticulum. Mapping spatial heterogeneities of intracellular Ca2+ transients in mammalian hearts using Ca2+ indicator dyes and imaging techniques. Once the normal heterogeneities of Ca2+ are determined, changes in Ca2+ transients will be analyzed in a wide range of physiological conditions to determined parameter that modulate Ca2+ transients. This laboratory has been at the forefront of the investigation of the role of sulfhydryl oxidation-reduction as a mechanisms to regulate Ca2+ release from the sarcoplasmic reticulum (SR). They are continuing this line of work in very exciting direction. 1) We have found that nitric oxide (NO) and NO donors nitrosylate regulatory thiols on the SR Ca2+ release channel (e.g., ryanodine receptor) resulting in channel opening and release of Ca2+ from the SR. This mechanism seems to play a key role in Ca2+ homeostasis in striated muscles. 2) We recently found that the actions of NO can be reversed by thioredoxin, thioredoxin reductase, a thiol redox regulatory mechanism in mammalian cells which is linked to NAPDH metabolism.

  • Publications

    1. Berkich D, Salama G, LaNoue KF. Mitochondrial membrane potentials in ischemic hearts Archives of Biochem & Biophys (in press)
    2. London L, Baker LC, Petkova-Kirova P, Nerbonne JM, Choi B-K, and Salama G. Dispersion of Repolarization and Refractoriness are Determinants of Arrhythmia Phenotype in Transgenic Mice with long QT J. Physiol. (London) 578: 115-129, 2007
    3. Mantravadi R, Gabris B, Liu T, Choi B-R, de Groat W, G. Ng A, and Salama G. Autonomic Nerve Stimulation reverses Ventricular Repolarization Sequence in Rabbit Hearts, Circulation Research, 100:72-80, 2007.
    4. Choi B-K, Liu T, and Salama G. Low Osmolarity Transforms Ventricular Fibrillation from complex to highly organized, with a dominant high frequency source, Heart Rhythm, 3(10): 1210-1220, 2006
    5. Choi B-R, Liu T, and Salama G. Calcium Transients influence Action Potential Amplitudes in Ventricular Fibrillation. IEEE Engineering in Medicine and Biology Society (EMBS): 12: 231-234, 2006
    6. Hwang S, Choi B-R, and Salama G. Monte Carlo Simulation of 3D Mapping of Cardiac Electrical Activity with Spinning Slit Confocal Optics. IEEE Engineering in Medicine and Biology Society (EMBS) 12: 184-188, 2006.
    7. Petkova-Kirova PS, Gursoy E, Mehdi H, London B and Salama G. Electrical Remodeling of Cardiac Myocytes from Mice with Heart Failure due to the over-expression of Tumor Necrosis Factor . Am J Physiol. Heart Circ Physiol. 290(5):H2098-107, 2006.
    8. Salama G, Arrhythmia Genesis: Aberrations of Voltage or Ca2+ Cycling? Heart Rhythm 31 (1):67-70, 2006.
    9. Tallini NY, Ohkura M, Choi B-R, Ji G, Imoto K, Doran R, Lee J, Plan P, Wilson J, Xin H.B, Robbins J, Salama G, Nakai J, and Kotlikoff MI, Imaging Cellular Signals in the Heart in Vivo: Cardiac Signaling Mice Expressing the High Signal Ca2+ Indicator GCaMP2 PNAS 103(12):4753-4758, 2006.
    10. Choi, B-R, Liu, T and Salama, G. Fiber Orientation Modulates Wave Kinetics in Ventricular Fibrillation J Cardiovascular Electrophysiology 14:851-860, 2003.
    11. Ivanova J, Salama G, Clancy RM, Schor NF, Nylander KD, Stoyanovsky DA. Formation of Nitroxyl and Hydroxyl Radical in Solution of sodium Trioxodinitrate: Effects of pH and Cytotoxicity J Biol Chem 2003 Aug 14
    12. Choi B-R, Burton F and Salama G. Cytosolic Ca2+ Triggers Early Afterdepolarizations and Torsade de Pointes in Rabbits with type 2 Long QT Syndrome. J Physiol. (London), 543.2: 615-631, 2002.
    13. Choi, B-R, Nho, W, Liu, T and Salama, G. Lifespan of Fibrillation Events, Circ Res 91:339-345, 2002.
    14. Drici, M-D, Baker, F, Plan, P, Barhanin, J, Romey, G, and Salama G. Mice Display Gender differences in Halothane-Induced Polymorphic Ventricular Tachycardia. Circulation 106:497-503, 2002.
    15. Baker LC, London B, Choi, B-R, Koren G, Salama G. Enhanced dispersion of repolarization and refractoriness in transgenic mouse hearts promotes reentrant ventricular tachycardia. Circulation Research 86:396-407, 2000.
    16. Choi B-R, and Salama G. Simultaneous maps of optical action potentials and Ca2+ transients in guinea pig hearts: mechanisms underlying concordant alternans. J Physiol (London) 529.1: 171-188, 2000.
    17. Choi B-R, and Salama G. Optical mapping of the rabbit atrio-ventricular node reveals discontinuities of propagation from atrial to nodal cells. Am. J. Physiol. 43(Heart Cir. Physiol 3):H829-H845; 1998.
    18. Stoyanovsky D, Murphy T, Anno PR, Kim Y-M, and Salama G. Nitric Oxide activates skeletal and cardiac ryanodine receptors. Cell Calcium 21: 19-29, 1997.
    19. Salama G, Efimov IR, and Kanai A. Subthreshold stimulation of the Purkinje system interrupts ventricular tachycardia as monitored with voltage-sensitive dyes and imaging techniques. Circ. Res. 74: 1-16, 1994.
    20. Blasdel G and Salama G. Voltage-sensitive dyes reveal a modular organization in monkey striate cortex. Nature 321: 579-585, 1986.
    21. Salama G, and Morad M. Merocyanine 540, as an optical probe of transmembrane electrical activity in the heart. Science 191:485-487, 1976.


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