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http://dx.doi.org/10.1016/j.niox.2013.03.001
OVERVIEW
Not long ago, nitrite and nitrate were thought to be biologically inert. However, recent discoveries have shown that nitrate is converted tonitrite by oral bacteria and nitrite is converted to nitric oxide, preferentially under hypoxic conditions. Basic studies aimed at understand-ing mechanisms for nitrite action in physiology and their failure in disease have exploded in the past few years. Increasing nitric oxidebioavailability could have many beneficial effects in various conditions: increasing blood flow, reducing platelet activation and thrombosis,and reducing inflammation. Moreover, these basic studies have been translated into clinical trials aimed at treating a variety of diseasesincluding systemic hypertension, pulmonary hypertension, peripheral artery disease, sickle cell disease, peripheral artery disease, myocar-dial infarction and others.
Thus, the understanding of nitrite and nitrate has quickly evolved to our current understanding that they are likely to play important rolesin physiology; their dysfunction contributes to pathology in a variety of diseases; and they have fantastic therapeutic potential in a varietyof diseases.
‘‘The role of nitrite and nitrate in physiology, pathophysiology, and therapeutics’’, the fifth bi-annual conference held on this topic, will providea setting to debate key issues and active current controversies. In addition, discussions will also involve dosing schedules, pharmacoki-netics, and new breakthroughs in understanding basic mechanisms which influence all aspects of the field and catalyze translation totherapy.
We thank you for your participation in this conference.
Daniel Kim-Shapiro, PhDWake Forest University
Mark T. Gladwin, MDUniversity of Pittsburgh
ACKNOWLEDGEMENTS
Sponsors
The Organizing Committee gratefully acknowledges the support from the following:
� University of Pittsburgh-� Vascular Medicine Institute� Department of Surgery� Department of Pharmacology
� Wake Forest University� The Karolinska Institute, Stockholm� Heinrich Heine University Düsseldorf
Education Grant
� Society for Free Radical Biology and Medicine (SFRBM)
PROGRAM
Saturday May 4, 2013
7:30 AM Registration and Refreshments
8:00 AM Welcome and Opening RemarksMark T. Gladwin, MD
Session 1: Human Nitrite and Nitrate TransportSession Chairs: Jon Lundberg, MD, PhD and Nigel Benjamin, FMedSc
Now that it has been clearly established that both nitrate and nitrite are major reservoirs for NO bioactivity and regulate important bio-logical processes such as blood flow and blood pressure, it becomes critical to understand how these anions are transported and stored.This session will provide new insights into this area of active new research. Topical questions and controversies to be addressed: (1) Howdo nitrite and nitrate get into cells or across membranes, (2) How is nitrate actively transported, (3) How is transport to the mitochondriacontrolled, (4) Is there subcellular storage of nitrate and nitrite and how does this occur?
8:10–8:30 AM Rakesh P. Patel, PhDOverview and Topical Questions
8:30–8:50 AM Indu S. Ambudkar, PhD, MScA New Saline Nitrate Transporter is Identified and Defective in Human Salla Disease
8:50–9:10 AM Christine Yuen-Yi Hon, PharmDPharmacokinetics of Nitrite and Nitrate at Rest and Exercise
9:10–9:30 AM Open Slot–TBD
9:30–9:40 AM Hot Topic–abstract presentation–TBD
9:40–10:00 AM Speakers Panel Q AModerators: Nigel Benjamin, FMedSci and Jon Lundberg, MD, PhD
10:00–10:20 AM Refreshment Break
Session 2: Mechanisms of Nitrite and Nitrate BioactivationSession Chairs: Daniel Kim-Shapiro, PhD and Jack R. Lancaster, PhD
Topical questions and controversies: (1) What bacteria are responsible for reduction of nitrate to nitrite and are there other physiologicallyrelevant pathways, (2) What enzymes are likely important in reducing nitrite to NO, (3) What accounts for variation among individuals innitrate/nitrite efficacy?
10:20–10:40 AM Mark T. Gladwin, MDSummary of Pathways for Enzymatic and Non-Enzymatic Nitrite Reduction
10:40–11:00 AM Andrew Webb, BSc MBBS MRCP PhDExploration of the Role of Carbonic Anhydrase, Xanthine Oxidase and Aldehyde Oxidase in Nitrite-dependent Vasodilation
11:00–11:20 AM Kara Hughan, MDOral 15-N labeled nitrite and nitrate PK and hemodynamics
11:20–11:30 AM Nathan S. Bryan, PhDGlucose Uptake
11:30–11:40 AM Hot Topic – Markus Knipp, PhDNitrite Dismutase–A ‘‘Nitrite-Only’’ Source for NO
11:40–12:00 AM Speakers Panel Q AModerators: S. Bruce King, PhD, Patricia Dos Santos, Phd, and Jack R.Lancaster, PhD
12:10–1:30 PM Lunch
Session 3: Nitrite and Nitrate in the ClinicSession Chairs: Timothy R. Billiar, MD and David J. Lefer, PhD
There has been remarkable progress in the development of nitrate and nitrite as therapeutics over the last 12 months. Results of phase I and IItrials are soon to be available for presentation. Topical questions and controversies: (1) What are the limitations of nitrite and nitrate therapy?(2) Nitrite vs nitrate; what are the advantages and disadvantages? (3) What are the most relevant pharmacokinetic issues that translateinto treatment schedules? (4) Can nitrite be used with phosphodiesterase 5 inhibitors safely and do we have early evidence of efficacyfor the treatment of systemic and pulmonary hypertension? (5) What are new therapeutic targets for nitrite and nitrate?
1:30–1:50 PM Nigel Benjamin, FMedSciNitrate: From Bench to Bedside
1:50–2:10 PM David J. Lefer, PhDNitrite therapy in Heart Failure
2:10–2:30 PM Amrita Ahluwalia, PhDTreatment of Hypertension with Nitrate
2:30–2:50 PM Mark Gilchrist, BM, BSFailure of Nitrate in a Study as a Therapeutic for Diabetes
2:50–3:10 PM Hunter C. Champion, MD, PhD, FAHAInhaled Nitrite for Patients with PAH: Phase I and Phase IIa Efficacy Trial Results
3:10–3:30 PM Michael Frenneaux, MD BS, PhD, FRCPNitrite in MI
3:30–3:50 PM Speakers Panel Q AModerators: Timothy R. Billiar, MD, David J. Lefer, PhD andLei Xi, MD, FAHA
3:50–4:10 PM Refreshments
Session 4: New Pre-Clinical ModelsSession Chairs: Jason D. Allen, PhD and Tennille Presley, PhD
4:10–4:30 PM David Hackam, MD, PhDNitrite Therapy and Crohn’s Disease
4:30–4:50 PM Nicholas Khoo, PhDNitrate and Nitrite Therapy for Metabolic Syndrome and Pulmonary Hypertension in Pre-clinical Models
4:50–5:00 PM Hot Topic - Yen-Chun "Charly" Lai, PhDNitrite Therapy for PH Related to Metabolic Syndrome
5:00–5:20 PM Speakers Panel Q AModerators: Jason D. Allen, PhD and Tennille Presley, PhD
5:30–7:30 PM Poster session and Awards Reception
Sunday May 5, 2013
8:00 AM Registration and RefreshmentsWelcome and Opening RemarksDany Kim-Shapiro, PhD
Session 5: Mechanisms of Nitrite and Nitrate Downstream SignalingSession Chairs: Neil Hogg, PhD and Bruce Pitt, PhD
While nitrate and nitrite have clear signaling effects via primary reduction to form nitric oxide, the pathways downstream of NO and the NO-independent post-translational signaling events have not been clearly defined. Topical questions and controversies: (1) When does nitrite sig-nal via cGMP independent pathways and how does this occur? (2) What other nitrogen oxides mediate NO signaling and by what mechan-isms, (3) What proteins are modified and via what specific post-translational signaling mechanisms?
8:10–8:30 AM Neil Hogg, PhDOverview
8:30–8:50 AM Sruti Shiva, PhDcGMP-independent Nitrite Signaling Regulates Mitochondrial Biogenesis
8:50–9:10 AM Tienush Rassaf, MDNitrite Signaling by Myoglobin Regulates Hypoxic Vasodilation
9:10–9:30 AM Open Slot–TBD
9:30–9:40 AM Hot Topic–abstract presentation–TBD
9:40–10:00 AM Speakers Panel Q AModerators: Neil Hogg, PhD and Bruce Pitt, PhD
10:00–10:30 AM Refreshments
10:30–10:50 AM Marco Fazzari, PhDNitro-fatty Acids and Nitrite Signaling Pathways via Reactive Nitrogen Species
10:50–11:10 AM Alan N. Schechter, MDNitrite and Platelets
11:10–11:30 AM Open Slot–TBD
11:30–11:50 AM Open Slot–TBD
11:50–12:00 PM Hot Topic – Christine Helms, PhDPlatelet Activation in the Presence of Nitrite, Nitric Oxide and Heme
12:00–12:20 PM Speakers Panel Q AModerators: Prof. Dr. med. Malte Kelm, FESC and Bruce Freeman, PhD
12:30–2:00 PM Lunch and Poster Viewing
Session 6: Nitrite, Nitrate and BioenergeticsSession Chairs: Sruti Shiva, PhD and Christopher G. Kevil, PhD
The last year has seen an explosion of studies on the effects of nitrate on increasing exercise efficiency and performance; this has beencoupled to studies showing that nitrite increases skeletal muscle blood flow and oxygenation. These studies have lead to rapid and possiblyextreme use of these agents by professional and Olympic athletes, raising critical questions about safety and mechanisms of action. Topicalquestions and controversies: (1) What are the molecular mechanisms for nitrite’s effects on mitochondrial function and how do these trans-late (along with other mechanisms) into physiology and functional performance? (2) How do we explain differences in measured effects ofdietary nitrate on exercise performance/efficiency in different studies? (3) Are nitrate and nitrite performance enhancing drugs and werethey used excessively in the Olympic games?
2:00–2:20 PM Eddie Weitzberg, MD, PhDEffects of Nitrate on Mitochondria, Exercise Performance and Risk of MI Following CABG
2:20–2:40 PM Naomi Cermak, PhDEffect of Oral Nitrate on Performance Enhancement
2:40–3:00 PM Mattias Carlström, PharmD, PhDNO3/NO2 in Regulating Renal Function
3:00–3:20 PM Open Slot–TBD
3:20–3:30 PM Hot Topic–Cecilia Jädert, PhDPhysiological Recycling of Endogenous Nitrate by Oral Bacteria Regulates Gastric Mucus Release
3:30–3:50 PM Speakers Panel Q AModerators: Sruti Shiva, PhD and Christopher G. Kevil, PhD
3:50–4:10 PM Refreshment Break
4:10–4:45 PM Final Panel Discussion with all Sessions Chairs:Controversies and Major Questions in the FieldWhy have some trials succeeded and others failed?What is the nitrite reductase responsible for vasodilation?What are concerns for safety w/r administration of nitrite or nitrate?
4:45–5:00 PM Closing Remarks/Adjournment
5:00–5:30 PM Final Poster Review–Dismantling posters
5:30–6:00 PM Transportation to Banquet Dinner
6:00–7:00 PM Cocktails, Pittsburgh Zoo and Aquarium
7:00–9:30 PM Banquet Dinner, Pittsburgh Zoo and Aquarium
9:30 PM Return transportation from Pittsburgh Zoo and Aquarium
ORGANIZING COMMITTEE
Daniel Kim-Shapiro, PhD, Co-Chair, Wake Forest University
Mark T. Gladwin, MD, Co-Chair, University of Pittsburgh
Amrita Ahluwalia, PhD, The William Harvey Research Institute
Timothy R. Billiar, MD, University of Pittsburgh
Bruce Freeman, PhD, University of Pittsburgh
Malte Kelm, MD, FESC, University Hospital Düsseldorf
Chris G. Kevil, PhD, Louisiana State University Health Sciences Center
David J. Lefer, PhD, Emory University School of Medicine
Jon O. Lundberg, MD, PhD, The Karolinska Institute
Rakesh P. Patel, PhD, University of Alabama, School of Medicine
Bruce Pitt, PhD, University of Pittsburgh
Tennille Presley, PhD, Winston-Salem State University
Tienush Rassaf, MD, University Hospital Düsseldorf
Sruti Shiva, PhD, University of Pittsburgh
Eddie Weitzberg, MD, PhD, The Karolinska Institute
SPEAKERS AND SESSION CHAIRS
Amrita Ahluwalia, PhDThe William Harvey Research Institute, The London School of Medicine Dentistry, London, United Kingdom
Jason D. Allen, PhDPhysical Therapy Program Division of Cardiovascular Medicine, Frederick R. Cobb Non-Invasive Vascular Research Laboratory, DukeUniversity Medical Center, Durham, North Carolina
Indu S. Ambudkar, PhD, MScSecretory Physiology Section, Molecular Physiology and Therapeutics Branch, National Institute of Health/NIDCR, Bethesda, Maryland
Nigel Benjamin, FMedSciAcute Medicine and Torbay Hospital, University of Exeter and Plymouth, Exeter, United Kingdom
Timothy R. Billiar, MDDepartment of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Nathan S. Bryan, PhDThe Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center,Houston, Texas
Mattias Carlström, PharmD, PhDThe Karolinska Institute, Department of Physiology Pharmacology, Stockholm, Sweden
Naomi Cermak, PhDDepartment of Human Movement Sciences, Maastricht University Medical Centre, Maastricht, The Netherlands
Hunter C. Champion, MD, PhD, FAHAThe Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
Patricia Dos Santos, PhDDepartment of Chemistry, Wake Forest University, Winston-Salem, North Carolina
Marco Fazzari, PhDDepartment of Pharmacology Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Bruce Freeman, PhDDepartment Pharmacology Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Michael Frenneaux, MB BS, PhD, FRCPDepartment of Cardiovascular Physiology/Circulation, School of Medicine and Dentistry, University of AberdeenAberdeen, United Kingdom
Mark Gilchrist, BM, BSNIHR Exeter Clinical Research Facility, University of Exeter Medical School, Royal Devon Exeter Foundation NHS Trust, Exeter, UnitedKingdom
Mark T. Gladwin, MDThe Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
David Hackam, MD, PhDDepartment of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
Neil Hogg, PhDDepartment of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin
Christine (Yuen-Yi) Hon, PharmDClinical Pharmacokinetic Research Laboratory, Department of Health and Human Services, Bethesda, Maryland
Kara Hughan, MDDivision of Pediatric Endocrinology, University of Pittsburgh, Pittsburgh, Pennsylvania
Prof. Dr. med. Malte Kelm, FESCDivision of Cardiology, Pulmonary Diseases, Vascular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany
Chris G. Kevil, PhDDepartments of Pathology and Cellular and Molecular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana
Nicholas Khoo, PhDDepartment of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
Daniel B. Kim-Shapiro, PhDTranslational Science Center, Department of Physics, Wake Forest University, Winston-Salem, North Carolina
S. Bruce King, PhDDepartment of Chemistry, Wake Forest University, Winston-Salem, North Carolina
Jack R. Lancaster, Jr, PhDCenter for Free Radical Biology, Departments of Cell, Developmental, and Integrative Biologyand Environmental Health Sciences, The University of Alabama Birmingham, Birmingham, Alabama
David J. Lefer, PhDCardiothoracic Research Laboratory, Division of Cardiothoracic Surgery, Department of Surgery, Emory University, Emory University Schoolof Medicine, Atlanta, Georgia
Jon Lundberg, MD, PhDDepartment of Physiology and Pharmacology, The Karolinska Institute, Stockholm, Sweden
Rakesh P. Patel, PhDDepartment of Pathology, University of Alabama, School of Medicine, Birmingham, Alabama
Bruce R. Pitt, PhDDepartment of Environmental Occupational Health, University of Pittsburgh Graduate School Public Health, Pittsburgh, Pennsylvania
Tennille Presley, PhDDepartment of Chemistry, Winston Salem State University, Winston-Salem, North Carolina
Tienush Rassaf, MDDivision of Cardiology, Pulmonary Diseases, Vascular Medicine , University Hospital Düsseldorf, Düsseldorf, Germany
Alan N. Schechter, MDMolecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH,Bethesda, Maryland
Sruti Shiva, PhDDepartment of Pharmacology Chemical Biology, The Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
Dr Andrew Webb, BSc MBBS MRCP PhDKing’s College London, Department of Clinical Pharmacology, St. Thomas’ Hospital, London, United Kingdom
Eddie Weitzberg, MD, PhDDepartment of Physiology and Pharmacology, Karolinska University Hospital, Stockholm, Sweden
Lei Xi, MD, FAHADivision of Cardiology, Virginia Commonwealth University, Richmond, Virginia
EXHIBITORS
James White Drinks, LtdContact: Lawrence MallinsonTelephone: +0208 7723477 Web site: www.jameswhite.co.ukEmail: [email protected]: Whites Fruit Farm, Ashbocking, Ipswich, IP6 9JS, United Kingdom
GE Analytical Instruments, Inc.Contact: Tonya N Ambrose, Marketing Communications SpecialistTelephone: 720 622 0216 Web site: www.geinstruments.comEmail: [email protected]: 6060 Spine Road, Boulder, CO 80301
LOGISTICS
DATES and TIMES
Saturday, May 4, 2013
7:30 am–8:00 am Registration and Refreshments8:00 am–5:30 pm Scientific Sessions5:30 pm–7:30 pm Poster Reception
Sunday, May 5, 2013
7:30 am–8:00 am Registration and Refreshments8:00 am–5:00 pm Scientific Sessions6:00 pm–9:30 pm Banquet Dinner
VENUE
The University Club123 University PlacePittsburgh, PA [email protected]
