Effect of Inorganic Nitrite on Cardiac and Skeletal Muscle: Physiology, Pharmacology and Therapeutic Potential
Lead Research Organisation:
University of East Anglia
Department Name: Norwich Medical School
Abstract
Consumption of green vegetables and beetroot increases the concentration in the bloodstream of a chemical called nitrite. Recent evidence suggests that when the cncentration of this chemical is increased by dietary means muscle works more efficiently and requires less oxygen. We will investigate why this occurs. Heart muscle is another type of muscle and we will investigate whether nitrite has a similar effect in heart muscle. Finally we will investigate whether this can be exploited as a treatment in conditions such as blockage of the arteries of the leg and the heart.
Technical Summary
Until recently considered a relatively inert metabolite of nitric oxide, there is now emerging evidence that nitrite can exert very important effects, some of which occur at concentrations close to physiological levels. Amongst these, recent studies indicate that modestly increasing plasma nitrite by dietary means increases the metabolic efficiency of skeletal muscle during exercise. The mechanism responsible is unclear but may involve an effect on the mitochondrial electron transport chain. It is not known whether nitrite exerts similar effects on cardiac muscle. This programme grant comprises a series of mechanistic and clinical studies to 1. Evaluate the mechanism(s) responsible for increased metabolic efficiency in skeletal muscle when plasma nitrite is increased 2. Assess whether nitrite exerts similar effects in cardiac muscle 3. Assess the potential clinical application of these effects for therapeutic purposes. This will include the treatment of intermittent claudication (reversible ischaemia of limb skeletal muscle during exercise), stable angina (reversible ischaemia of cardiac muscle) and heart failure (a syndrome in which reduced cardiac energetic status plays an important pathophysiological role). The applicants bring together a mix of clinical, physiological, pharmacological and molecular skills and the design of the programme ensures strong integration between the clinical and mechanistic studies.
Publications
Arif S
(2015)
Role of aldehyde dehydrogenase in hypoxic vasodilator effects of nitrite in rats and humans.
in British journal of pharmacology
Ashmore T
(2015)
Nitrate enhances skeletal muscle fatty acid oxidation via a nitric oxide-cGMP-PPAR-mediated mechanism.
in BMC biology
Bailey JC
(2014)
Pharmacology and therapeutic role of inorganic nitrite and nitrate in vasodilatation.
in Pharmacology & therapeutics
Bentley R
(2014)
Dietary nitrate reduces skeletal muscle oxygenation response to physical exercise: a quantitative muscle functional MRI study.
in Physiological reports
Borgognone A
(2018)
Nitrite circumvents platelet resistance to nitric oxide in patients with heart failure preserved ejection fraction and chronic atrial fibrillation.
in Cardiovascular research
Cortese-Krott M
(2016)
Inorganic sulfur-nitrogen compounds: from gunpowder chemistry to the forefront of biological signaling
in Dalton Transactions
Cortese-Krott MM
(2015)
Key bioactive reaction products of the NO/H2S interaction are S/N-hybrid species, polysulfides, and nitroxyl.
in Proceedings of the National Academy of Sciences of the United States of America
Cumpstey AF
(2019)
Pushing arterial-venous plasma biomarkers to new heights: A model for personalised redox metabolomics?
in Redox biology
Dautov RF
(2013)
The nitric oxide redox sibling nitroxyl partially circumvents impairment of platelet nitric oxide responsiveness.
in Nitric oxide : biology and chemistry
Durham T
(2020)
Chemistry, pharmacology, and cellular uptake mechanisms of thiometallate sulfide donors.
in British journal of pharmacology
Feelisch M
(2020)
Long-lasting blood pressure lowering effects of nitrite are NO-independent and mediated by hydrogen peroxide, persulfides, and oxidation of protein kinase G1a redox signalling.
in Cardiovascular research
Gorman S
(2015)
Can skin exposure to sunlight prevent liver inflammation?
in Nutrients
Loudon BL
(2016)
Present and future pharmacotherapeutic agents in heart failure: an evolving paradigm.
in British journal of pharmacology
Maassen H
(2022)
Nitric oxide and long-term outcomes after kidney transplantation: Results of the TransplantLines cohort study.
in Nitric oxide : biology and chemistry
Maher A
(2013)
Impact of chronic congestive heart failure on pharmacokinetics and vasomotor effects of infused nitrite The vascular effects of intra-arterial nitrite in heart failure patients
in British Journal of Pharmacology
Nagasaka Y
(2018)
Pharmacological preconditioning with inhaled nitric oxide (NO): Organ-specific differences in the lifetime of blood and tissue NO metabolites.
in Nitric oxide : biology and chemistry
Ntessalen M
(2020)
Inorganic nitrate and nitrite supplementation fails to improve skeletal muscle mitochondrial efficiency in mice and humans.
in The American journal of clinical nutrition
Ntessalen M
(2020)
Reply to TA Schiffer et al.
in The American journal of clinical nutrition
Ormerod JO
(2017)
Human Second Window Pre-Conditioning and Post-Conditioning by Nitrite Is Influenced by a Common Polymorphism in Mitochondrial Aldehyde Dehydrogenase.
in JACC. Basic to translational science
Ormerod JO
(2015)
Short-term intravenous sodium nitrite infusion improves cardiac and pulmonary hemodynamics in heart failure patients.
in Circulation. Heart failure
Schwarz K
(2017)
Inorganic Nitrate in Angina Study: A Randomized Double-Blind Placebo-Controlled Trial.
in Journal of the American Heart Association
Schwarz K
(2014)
The breathing heart - mitochondrial respiratory chain dysfunction in cardiac disease.
in International journal of cardiology
Schwarz K
(2016)
A randomized double-blind placebo-controlled crossover trial of sodium nitrate in patients with stable angina INAS.
in Future cardiology
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