title: Cinaciguat, a soluble guanylate cyclase activator, augments cGMP after oxidative stress and causes pulmonary vasodilation in neonatal pulmonary hypertension.
abstract: Although inhaled NO (iNO) therapy is often effective in treating infants with persistent pulmonary hypertension of the newborn (PPHN), up to 40% of patients fail to respond, which may be partly due to abnormal expression and function of soluble guanylate cyclase (sGC). To determine whether altered sGC expression or activity due to oxidized sGC contributes to high pulmonary vascular resistance (PVR) and poor NO responsiveness, we studied the effects of cinaciguat (BAY 58-2667), an sGC activator, on pulmonary artery smooth muscle cells (PASMC) from normal fetal sheep and sheep exposed to chronic intrauterine pulmonary hypertension (i.e., PPHN). We found increased sGC α(1)- and β(1)-subunit protein expression but lower basal cGMP levels in PPHN PASMC compared with normal PASMC. To determine the effects of cinaciguat and NO after sGC oxidation in vitro, we measured cGMP production by normal and PPHN PASMC treated with cinaciguat and the NO donor, sodium nitroprusside (SNP), before and after exposure to 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, an sGC oxidizer), hyperoxia (fraction of inspired oxygen 0.50), or hydrogen peroxide (H(2)O(2)). After treatment with ODQ, SNP-induced cGMP generation was markedly reduced but the effects of cinaciguat were increased by 14- and 64-fold in PPHN fetal PASMC, respectively (P < 0.01 vs. controls). Hyperoxia or H(2)O(2) enhanced cGMP production by cinaciguat but not SNP in PASMC. To determine the hemodynamic effects of cinaciguat in vivo, we compared serial responses to cinaciguat and ACh in fetal lambs after ductus arteriosus ligation. In contrast with the impaired vasodilator response to ACh, cinaciguat-induced pulmonary vasodilation was significantly increased. After birth, cinaciguat caused a significantly greater fall in PVR than either 100% oxygen, iNO, or ACh. We conclude that cinaciguat causes more potent pulmonary vasodilation than iNO in experimental PPHN. We speculate that increased NO-insensitive sGC may contribute to the pathogenesis of PPHN, and cinaciguat may provide a novel treatment of severe pulmonary hypertension.
authors.affiliation: Pediatric Heart Lung Center, Sections of Neonatology and Pulmonary Medicine, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Chester
authors.forename: Gregory
authors.initials: G
authors.lastname: Seedorf
authors.forename: Pierre
authors.initials: P
authors.lastname: Tourneux
authors.forename: Jason
authors.initials: J
authors.lastname: Gien
authors.forename: Nancy
authors.initials: N
authors.lastname: Tseng
authors.forename: Theresa
authors.initials: T
authors.lastname: Grover
authors.forename: Jason
authors.initials: J
authors.lastname: Wright
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.forename: Steven H
authors.initials: SH
authors.lastname: Abman
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000032:analysis / Q000096:biosynthesis*; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000009:adverse effects; D007231:Infant, Newborn; D007527:Isoenzymes / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D010069:Oxadiazoles / Q000009:adverse effects; D010547:Persistent Fetal Circulation Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011247:Pregnancy; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000187:drug effects; D011810:Quinoxalines / Q000009:adverse effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D012756:Sheep; D000071756:Soluble Guanylyl Cyclase; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D001565:Benzoates; D007527:Isoenzymes; D010069:Oxadiazoles; D011810:Quinoxalines; D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; C480588:BAY 58-2667; D006861:Hydrogen Peroxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP