title: Role of phosphodiesterases in adult-onset pulmonary arterial hypertension.
abstract: Pulmonary arterial hypertension (PAH) is characterized by increased mean pulmonary artery pressure (mPAP) due to vasoconstriction and structural changes in the small pulmonary arteries (PAs); proliferation of pulmonary artery smooth muscle cells (PASMCs) contributes to the remodeling. The abnormal pathophysiology in the pulmonary vasculature relates to decreased cyclic nucleotide levels in PASMCs. Phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP, thereby PDE inhibitors are effective in vasodilating the PA and decreasing PASMC proliferation. Experimental studies support the use of PDE3, PDE5, and PDE1 inhibitors in PAH. PDE5 inhibitors such as sildenafil are clinically approved to treat different forms of PAH and lower mPAP, increase functional capacity, and decrease right ventricular hypertrophy, without decreasing systemic arterial pressure. New evidence suggests that the combination of PDE inhibitors with other therapies for PAH may be beneficial in treating the disease. Furthermore, inhibiting PDEs in the heart and the inflammatory cells that infiltrate the PA may offer new targets to reduce right ventricular hypertrophy and inhibit inflammation that is associated with and contributes to the development of PAH. This chapter summarizes the advances in the area and the future of PDEs in PAH.
authors.affiliation: Department of Pharmacology and Department of Medicine, BSB 3073, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA 92093-0636, USA. fmurray@ucsd.edu
authors.forename: F
authors.initials: F
authors.lastname: Murray
authors.forename: M R
authors.initials: MR
authors.lastname: Maclean
authors.forename: P A
authors.initials: PA
authors.lastname: Insel
mesh_terms: D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000502:physiology; D065627:Familial Primary Pulmonary Hypertension; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology*; D009712:Nucleotides, Cyclic / Q000502:physiology; D058987:Phosphodiesterase 3 Inhibitors / Q000627:therapeutic use; D058986:Phosphodiesterase 5 Inhibitors / Q000627:therapeutic use; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000502:physiology*
chemical_list: D009712:Nucleotides, Cyclic; D058987:Phosphodiesterase 3 Inhibitors; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1