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Publications (2)11.05 Total impact

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    ABSTRACT: Until genetic correction approaches are routinely available for treat-ment of muscular dystrophies, treatments that extend longevity and improve quality of life will be important alternatives. Based on our stud-ies of one isoform of nitric oxide synthase (nNOSb) which localizes on the Golgi with guanylyl cyclase and protein kinase G, we proposed that increasing cGMP levels by inhibition of specific phosphodiesterases (PDEs) would improve cardiac and skeletal muscle function in the mdx mouse. We examined the effect of sildenafil (Viagra), a selective inhibitor of PDE5 which is present in cardiac and diaphragm muscle. Our published results (Adamo et al., 2010, Proc. Natl. Acad. Sci. 107:19079) showed that chronic administration of sildenafil via the drinking water reduces functional deficits in the cardiac performance of aged mdx mice. Furthermore, when sildenafil treatment was started after cardiomyopathy had developed, the established symptoms were reversed within a few days. Chronic administration of sildenafil to mdx mice beginning at 3 weeks of age improved diaphragm function. At 5 months of age, diaphragms from mdx mice treated with sildenafil exhibited less Evans Blue dye uptake and markedly reduced levels of fibrosis, compared to untreated mdx diaphragms. Functional measure-ments showed an increase in specific force. Quantitative PCR analyses of pro-fibrotic and pro-inflammatory gene expression revealed that tran-script levels for TNFa and MMP-13 were upregulated in dystrophic dia-phragm. Sildenafil treatment reduced the transcripts of TNFa and MMP-13 to near normal levels. Our results suggest that sildenafil treat-ment of individuals with muscular dystrophies and other muscle fibrotic diseases may preserve muscle function and integrity.
    Neuromuscular Disorders 10/2012; 22(9-10). · 3.46 Impact Factor
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    ABSTRACT: Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy caused by mutations in the dystrophin gene. Loss of dystrophin initiates a progressive decline in skeletal muscle integrity and contractile capacity which weakens respiratory muscles including the diaphragm, culminating in respiratory failure, the leading cause of morbidity and mortality in DMD patients. At present, corticosteroid treatment is the primary pharmacological intervention in DMD, but has limited efficacy and adverse side effects. Thus, there is an urgent need for new safe, cost-effective, and rapidly implementable treatments that slow disease progression. One promising new approach is the amplification of nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signalling pathways with phosphodiesterase 5 (PDE5) inhibitors. PDE5 inhibitors serve to amplify NO signalling that is attenuated in many neuromuscular diseases including DMD. We report here that a 14-week treatment of the mdx mouse model of DMD with the PDE5 inhibitor sildenafil (Viagra(®), Revatio(®)) significantly reduced mdx diaphragm muscle weakness without impacting fatigue resistance. In addition to enhancing respiratory muscle contractility, sildenafil also promoted normal extracellular matrix organization. PDE5 inhibition slowed the establishment of mdx diaphragm fibrosis and reduced matrix metalloproteinase-13 (MMP-13) expression. Sildenafil also normalized the expression of the pro-fibrotic (and pro-inflammatory) cytokine tumour necrosis factor α (TNFα). Sildenafil-treated mdx diaphragms accumulated significantly less Evans Blue tracer dye than untreated controls, which is also indicative of improved diaphragm muscle health. We conclude that sildenafil-mediated PDE5 inhibition significantly reduces diaphragm respiratory muscle dysfunction and pathology in the mdx mouse model of Duchenne muscular dystrophy. This study provides new insights into the therapeutic utility of targeting defects in NO-cGMP signalling with PDE5 inhibitors in dystrophin-deficient muscle.
    The Journal of Pathology 05/2012; 228(1):77-87. · 7.59 Impact Factor