Pharmacological targets for pulmonary vascular disease: vasodilation versus anti-remodelling.
Two gross mechanisms of pathology are central to pulmonary arterial hypertension - increased pulmonary vascular tone and remodelling of the pulmonary arteries. These pathologies can be caused by a variety of aberrant processes, and combine to cause an increase in pulmonary vascular resistance and consequent right ventricular hypertrophy, eventually leading to dysfunction and death. Current therapeutic strategies have focused on altering the vasoconstrictive elements of the disease. Whilst improvements in life expectancy have been observed, current therapies have not managed to halt or reverse progression of the disease. Here we discuss said unmet medical need and postulate as to the impact on disease anti-remodelling therapy might provide. The mechanisms of remodelling in pulmonary arterial hypertension are reviewed, and leading examples of potential targets within such mechanisms are discussed.
Thomas
Matthew
M
Novartis Institutes for Biomedical Research, Respiratory Disease Area, Horsham, UK. matthew.thomas@novartis.com
D000818:Animals; D018450:Disease Progression; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D051880:Receptors, Notch / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D010982:Platelet-Derived Growth Factor; D015221:Potassium Channels; D051880:Receptors, Notch; D018125:Receptors, Transforming Growth Factor beta; D012701:Serotonin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D020742:rhoA GTP-Binding Protein