Modulating cGMP to treat lung diseases.
Nitric oxide (NO) is constitutively produced in the lung by NO-synthases. The main cellular sources of lung NO production are the vascular endothelium and the airway epithelia (Bohle et al. 2000; German et al. 2000; Ide et al. 1999). Local NO production contributes to regulation of pulmonary perfusion depending on alveolar ventilation to assure optimized ventilation/perfusion distribution (Grimminger et al. 1995). NO-synthase activity is regulated on transcriptional and post-translational redox-based modulation level. The common signaling pathway of endogenous vasodilators, such as nitric oxide, prostaglandins, and natriuretic peptides, engage cyclic nucleotides (cAMP and cGMP). These second messengers are mainly produced by activation of adenylate- and guanylate-cyclases, both membrane-bound and soluble (Beavo 1995). Phosphodiesterases (PDEs) represent a superfamily of enzymes, with PDE1 through PDE11 being currently known, that inactivate cyclic AMP and cyclic GMP, with different tissue distribution and substrate specificities (Ahn et al. 1991; Von Euler and Liljestrand. 1946). Because of stabilization of these second messengers, PDE inhibitors differentially regulate levels of cAMP and/or cGMP, depending on their selectivity profile. Recently, direct activators and stimulators of the sGC have been suggested as new therapeutic tools for the treatment of lung vascular disorders that might have even higher potency than PDE inhibitors or exogenously applied NO.
Ghofrani
Hossein-Ardeschir
HA
University Hospital Giessen and Marburg GmbH, Klinikstrasse 36, Giessen, 35392, Germany. ardeschir.ghofrani@innere.med.uni-giessen.de
Grimminger
Friedrich
F
D000280:Administration, Inhalation; D000818:Animals; D002986:Clinical Trials as Topic; D006152:Cyclic GMP / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D016503:Drug Delivery Systems; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D008171:Lung Diseases / Q000188:drug therapy* / Q000503:physiopathology; D009569:Nitric Oxide / Q000008:administration & dosage / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase
D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP