Therapeutic targets in pulmonary arterial hypertension.
Pulmonary arterial hypertension is a progressive, fatal disease. Current treatments including prostanoids, endothelin-1 (ET-1) antagonists, and phosphodiesterase (PDE) inhibitors, have sought to address the pulmonary vascular endothelial dysfunction and vasoconstriction associated with the condition. These treatments may slow the progression of the disease but do not afford a cure. Future treatments must target more directly the structural vascular changes that impair blood flow through the pulmonary circulation. Several novel therapeutic targets have been proposed and are under active investigation, including soluble guanylyl cyclase, phosphodiesterases, tetrahydrobiopterin, 5-HT2B receptors, vasoactive intestinal peptide, receptor tyrosine kinases, adrenomedullin, Rho kinase, elastases, endogenous steroids, endothelial progenitor cells, immune cells, bone morphogenetic protein and its receptors, potassium channels, metabolic pathways, and nuclear factor of activated T cells. Tyrosine kinase inhibitors, statins, 5-HT2B receptor antagonists, EPCs and soluble guanylyl cyclase activators are among the most advanced, having produced encouraging results in animal models, and human trials are underway. This review summarises the current research in this area and speculates on their likely success.
Rhodes
Christopher J
CJ
Department of Experimental Medicine and Toxicology, Imperial College London, and National Pulmonary Hypertension Service, Hammersmith Hospital, United Kingdom.
Davidson
Alexandra
A
Gibbs
J Simon R
JS
Wharton
John
J
Wilkins
Martin R
MR
D053607:Adrenomedullin / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D052004:Bone Morphogenetic Protein Receptors / Q000187:drug effects / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology*; D003999:Dichloroacetic Acid / Q000494:pharmacology / Q000627:therapeutic use; D055808:Drug Discovery; D042783:Endothelial Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology*; D050778:NFATC Transcription Factors / Q000187:drug effects / Q000378:metabolism; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000187:drug effects; D011014:Pneumonia / Q000188:drug therapy / Q000503:physiopathology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology / Q000627:therapeutic use; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D050778:NFATC Transcription Factors; D053607:Adrenomedullin; D012701:Serotonin; D014660:Vasoactive Intestinal Peptide; D003999:Dichloroacetic Acid; D020794:Receptor Protein-Tyrosine Kinases; D054460:rho-Associated Kinases; D052004:Bone Morphogenetic Protein Receptors; D010196:Pancreatic Elastase; D006152:Cyclic GMP