title: Rho kinase mediates right ventricular systolic dysfunction in rats with chronic neonatal pulmonary hypertension.
abstract: Chronic neonatal pulmonary hypertension frequently culminates in right ventricular (RV) failure and death. In juvenile rats, RV systolic dysfunction secondary to chronic hypoxia is rescued by systemic treatment with a Rho kinase (ROCK) inhibitor. To explore the relationship between ROCK inhibitor-mediated decreases in pulmonary vascular resistance and pressure, RV hypertrophy, and systolic dysfunction, we compared the effects of systemically administered to inhaled (pulmonary-selective) ROCK inhibitor on RV systolic function. Rat pups were exposed to air or hypoxia (13% O2) from Postnatal Days 1 to 21 and received rescue treatment with aerosolized fasudil (200 mM) for 15 minutes three times daily or intraperitoneal Y27632 (15 mg/kg twice daily) from Days 14 to 21. Chronic hypoxia differentially increased RhoA and ROCK activity in the right, but not left, cardiac ventricle. Inhaled ROCK inhibitor normalized pulmonary vascular resistance and caused regression of RV hypertrophy and pulmonary arterial wall remodeling but did not improve RV systolic dysfunction (decreased stroke volume and tricuspid annular plane systolic excursion). Systemic, but not inhaled, ROCK inhibitor normalized up-regulated ROCK and phosphodiesterase 5 activities in the right ventricle. Treatment with sildenafil (100 mg/kg/d intraperitoneally from Days 14 to 21) improved RV systolic function. Collectively, these data indicate that pressure unloading and regressed arterial and cardiac remodeling did not lead to recovery of systolic function while right ventricular ROCK activity remained increased. Right ventricle-specific up-regulation of RhoA/ROCK activity is critical to hypoxia-mediated systolic dysfunction, in part by regulating the activity of phosphodiesterase 5.
authors.affiliation: 1 Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto.
authors.forename: Kiranjot
authors.initials: K
authors.lastname: Gosal
authors.forename: Kristyn
authors.initials: K
authors.lastname: Dunlop
authors.forename: Rupinder
authors.initials: R
authors.lastname: Dhaliwal
authors.forename: Julijana
authors.initials: J
authors.lastname: Ivanovska
authors.forename: Crystal
authors.initials: C
authors.lastname: Kantores
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Desjardins
authors.forename: Kim A
authors.initials: KA
authors.lastname: Connelly
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McNamara
authors.forename: Amish
authors.initials: A
authors.lastname: Jain
authors.forename: Robert P
authors.initials: RP
authors.lastname: Jankov
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D006352:Heart Ventricles / Q000201:enzymology; D006976:Hypertension, Pulmonary / Q000150:complications / Q000188:drug therapy / Q000201:enzymology*; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects; D018497:Ventricular Dysfunction, Right / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000068677:Sildenafil Citrate; D054460:rho-Associated Kinases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D020742:rhoA GTP-Binding Protein; C049347:fasudil
keywords: Y-27632; echocardiography; fasudil; phosphodiesterase