title: Sustained therapeutic hypercapnia attenuates pulmonary arterial Rho-kinase activity and ameliorates chronic hypoxic pulmonary hypertension in juvenile rats.
abstract: Sustained therapeutic hypercapnia prevents pulmonary hypertension in experimental animals, but its rescue effects on established disease have not been studied. Therapies that inhibit Rho-kinase (ROCK) and/or augment nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling can reverse or prevent progression of chronic pulmonary hypertension. Our objective in the present study was to determine whether sustained rescue treatment with inhaled CO(2) (therapeutic hypercapnia) would improve structural and functional changes of chronic hypoxic pulmonary hypertension. Spontaneously breathing pups were exposed to normoxia (21% O(2)) or hypoxia (13% O(2)) from postnatal days 1-21 with or without 7% CO(2) (Pa(CO(2)) elevated by ∼25 mmHg) or 10% CO(2) (Pa(CO(2)) elevated by ∼40 mmHg) from days 14 to 21. Compared with hypoxia alone, animals exposed to hypoxia and 10% CO(2) had significantly (P < 0.05) decreased pulmonary vascular resistance, right-ventricular systolic pressure, right-ventricular hypertrophy, and medial wall thickness of pulmonary resistance arteries as well as decreased lung phosphodiesterase (PDE) V, RhoA, and ROCK activity. Rescue treatment with 10% CO(2), or treatment with a ROCK inhibitor (15 mg/kg ip Y-27632 twice daily from days 14 to 21), also increased pulmonary arterial endothelial nitric oxide synthase and lung NO content. In contrast, cGMP content and cGMP-dependent protein kinase (PKG) activity were increased by exposure to 10% CO(2), but not by ROCK inhibition with Y-27632. In vitro exposure of pulmonary artery smooth muscle cells to hypercapnia suppressed serum-induced ROCK activity, which was prevented by inhibition of PKG with Rp-8-Br-PET-cGMPS. We conclude that sustained hypercapnia dose-dependently inhibited ROCK activity, augmented NO-cGMP-PKG signaling, and led to partial improvements in the hemodynamic and structural abnormalities of chronic hypoxic PHT in juvenile rats. Increased PKG content and activity appears to play a major upstream role in CO(2)-induced suppression of ROCK activity in pulmonary arterial smooth muscle.
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
authors.forename: Gary
authors.initials: G
authors.lastname: Peng
authors.forename: Julijana
authors.initials: J
authors.lastname: Ivanovska
authors.forename: Crystal
authors.initials: C
authors.lastname: Kantores
authors.forename: Todd
authors.initials: T
authors.lastname: Van Vliet
authors.forename: Doreen
authors.initials: D
authors.lastname: Engelberts
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kavanagh
authors.forename: Masahiro
authors.initials: M
authors.lastname: Enomoto
authors.forename: Jaques
authors.initials: J
authors.lastname: Belik
authors.forename: Amish
authors.initials: A
authors.lastname: Jain
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McNamara
authors.forename: Robert P
authors.initials: RP
authors.lastname: Jankov
mesh_terms: D000818:Animals; D002245:Carbon Dioxide / Q000008:administration & dosage / Q000627:therapeutic use*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000201:enzymology; D000860:Hypoxia / Q000188:drug therapy* / Q000201:enzymology; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D002245:Carbon Dioxide; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D054460:rho-Associated Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D020742:rhoA GTP-Binding Protein