Emerging therapies for the treatment of pulmonary hypertension.
Current treatment of pulmonary arterial hypertension, which includes the use of prostacyclins, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors, either alone or in combination, often leads to improvements in functional capacity and modest decreases in pulmonary artery pressure. Disappointingly, however, two recent meta-analysis reviewing the controlled trials in pulmonary arterial hypertension, using these three agents, demonstrated little or no increase in survival. Importantly, however, increasing knowledge of the cellular and molecular basis of pulmonary arterial hypertension has led to the development of new agents aimed at either reversing sustained vasoconstriction or stopping/reversing the abnormal cell and extracellular matrix accumulation that, in combination, obstruct pulmonary blood flow and ultimately cause right heart failure. Rho kinase inhibitors, vasodilator peptides (such as vasoactive intestinal peptide and adrenomedullin), and endothelial nitric oxide synthase coupling agents (cicletanine) have been shown sometimes to exert potent pulmonary vasodilatory effects in animal models and in pilot studies in humans. Tyrosine kinase inhibitors (platelet-derived growth factor and epidermal growth factor receptor inhibitors), multikinase inhibitors (tyrosine kinase and serine/threonine kinase), elastase inhibitors, metabolic modulators (e.g., dichloroacetate), survivin inhibitors, and HMG-COA reductase inhibitors have been shown to reverse pulmonary hypertension in rodent models of pulmonary hypertension through inhibition of cell proliferation and induction of apoptosis. Early success in human pulmonary arterial hypertension with tyrosine kinase inhibitors has appeared in case reports. Furthermore, anti-inflammatory/immunomodulatory agents (thiazolidinedinones, rapamycin, cyclosporine, and STAT3 inhibitors) have been demonstrated to be effective at reducing vascular remodeling in animal models. Collectively, these studies are exciting and open potential new avenues for treatment. Caution should be exercised, however, as many agents, which are successful at preventing or reversing pulmonary arterial hypertension in currently used animal models, do not result in similar long-term success in the treatment of human pulmonary arterial hypertension.
Stenmark
Kurt R
KR
Developmental Lung Biology Laboratory, University of Colorado-Denver, Aurora, CO, USA. kurt.stenmark@ucdenver.edu
Rabinovitch
Marlene
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D019001:Nitric Oxide Synthase / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D014660:Vasoactive Intestinal Peptide; C038068:cicletanine; D019001:Nitric Oxide Synthase; D054460:rho-Associated Kinases