Document Detail

Metabolic inertia in contracting skeletal muscle: a novel approach for pharmacological intervention in peripheral vascular disease.
MedLine Citation:
PMID:  14998419     Owner:  NLM     Status:  MEDLINE    
Peripheral vascular disease (PVD) is generally accepted to result in the failure of skeletal muscle blood flow to increase adequately at the onset of muscular work. There are currently no routine pharmacological interventions towards the treatment of PVD, however, recent Phase III trials in the USA have demonstrated the clinical potential of the phosphodiesterase III inhibitor Cilostazol for pain-free and maximal walking distances in patients with intermittent claudication. PVD is characterized by a marked reliance on oxygen-independent routes of ATP regeneration (phosphocreatine hydrolysis and glycolysis) in skeletal muscle during contraction and the rapid onset of muscular pain and fatigue. The accumulation of metabolic by-products of oxygen-independent ATP production (hydrogen and lactate ions and inorganic phosphate) has long been associated with an inhibition in contractile function in both healthy volunteers and PVD patients. Therefore, any strategy that could reduce the reliance upon ATP re-synthesis from oxygen-independent routes, and increase the contribution of oxygen-dependent (mitochondrial) ATP re-synthesis, particularly at the onset of exercise, might be expected to improve functional capacity and be of considerable therapeutic value. Historically, the increased contribution of oxygen-independent ATP re-synthesis to total ATP generation at the onset of exercise has been attributed to a lag in muscle blood flow limiting oxygen delivery during this period. However, recent evidence suggests that limited inertia is present at the level of oxygen delivery, whilst considerable inertia exists at the level of mitochondrial enzyme activation and substrate supply. In support of this latter hypothesis, we have reported on a number of occasions that activation of the pyruvate dehydrogenase complex, using pharmacological interventions, can markedly reduce the dependence on ATP re-synthesis from oxygen-independent routes at the onset of muscle contraction. This review will focus on these findings and will highlight the pyruvate dehydrogenase complex as a novel therapeutic target towards the treatment of peripheral vascular disease, or any other disease state where premature muscular fatigue is prevalent due to metabolite accumulation.
P L Greenhaff; S P Campbell-O'Sullivan; D Constantin-Teodosiu; S M Poucher; P A Roberts; J A Timmons
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  British journal of clinical pharmacology     Volume:  57     ISSN:  0306-5251     ISO Abbreviation:  Br J Clin Pharmacol     Publication Date:  2004 Mar 
Date Detail:
Created Date:  2004-03-04     Completed Date:  2004-04-16     Revised Date:  2013-06-09    
Medline Journal Info:
Nlm Unique ID:  7503323     Medline TA:  Br J Clin Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  237-43     Citation Subset:  IM    
School of Biomedical Sciences, Centre for Integrated Systems Biology and Medicine, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK.
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MeSH Terms
Acetyl Coenzyme A / metabolism
Muscle Contraction / drug effects*
Muscle, Skeletal / blood supply,  drug effects*,  metabolism
Peripheral Vascular Diseases / drug therapy*
Pyruvate Dehydrogenase Complex / metabolism
Reg. No./Substance:
0/Pyruvate Dehydrogenase Complex; 72-89-9/Acetyl Coenzyme A

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