title: Soluble guanylate cyclase modulators blunt hyperoxia effects on calcium responses of developing human airway smooth muscle.
abstract: Exposure to moderate hyperoxia in prematurity contributes to subsequent airway dysfunction and increases the risk of developing recurrent wheeze and asthma. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic GMP (cGMP) axis modulates airway tone by regulating airway smooth muscle (ASM) intracellular Ca(2+) ([Ca(2+)]i) and contractility. However, the effects of hyperoxia on this axis in the context of Ca(2+)/contractility are not known. In developing human ASM, we explored the effects of novel drugs that activate sGC independent of NO on alleviating hyperoxia (50% oxygen)-induced enhancement of Ca(2+) responses to bronchoconstrictor agonists. Treatment with BAY 41-2272 (sGC stimulator) and BAY 60-2770 (sGC activator) increased cGMP levels during exposure to 50% O2. Although 50% O2 did not alter sGCα1 or sGCβ1 expression, BAY 60-2770 did increase sGCβ1 expression. BAY 41-2272 and BAY 60-2770 blunted Ca(2+) responses to histamine in cells exposed to 50% O2. The effects of BAY 41-2272 and BAY 60-2770 were reversed by protein kinase G inhibition. These novel data demonstrate that BAY 41-2272 and BAY 60-2770 stimulate production of cGMP and blunt hyperoxia-induced increases in Ca(2+) responses in developing ASM. Accordingly, sGC stimulators/activators may be a useful therapeutic strategy in improving bronchodilation in preterm infants.
authors.affiliation: Departments of Anesthesiology and.
authors.forename: Rodney D
authors.initials: RD
authors.lastname: Britt
authors.affiliation: Departments of Anesthesiology and.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thompson
authors.affiliation: Departments of Anesthesiology and.
authors.forename: Ine
authors.initials: I
authors.lastname: Kuipers
authors.affiliation: Departments of Anesthesiology and.
authors.forename: Alecia
authors.initials: A
authors.lastname: Stewart
authors.affiliation: Departments of Anesthesiology and.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Vogel
authors.affiliation: Departments of Anesthesiology and.
authors.forename: James
authors.initials: J
authors.lastname: Thu
authors.affiliation: Department of Pediatrics, Division of Neonatology, Rainbow Babies Children's Hospital, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Martin
authors.affiliation: Departments of Anesthesiology and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Pabelick
authors.affiliation: Departments of Anesthesiology and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; and Prakash.ys@mayo.edu.
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
mesh_terms: D001565:Benzoates / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001980:Bronchi / Q000473:pathology; D020013:Calcium Signaling; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D018496:Hyperoxia / Q000188:drug therapy* / Q000201:enzymology; D009130:Muscle, Smooth / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D010100:Oxygen / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase; D014132:Trachea / Q000473:pathology
chemical_list: C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; C528797:4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid; D001565:Benzoates; D001713:Biphenyl Compounds; D006845:Hydrocarbons, Fluorinated; D011720:Pyrazoles; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D010100:Oxygen
keywords: cGMP; calcium; lung; pediatric asthma; prematurity