title: Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats.
abstract: Vascular remodeling, rather than vasoconstriction, is believed to account for high vascular resistance in severe pulmonary arterial hypertension (PAH). We have found previously that acute Rho kinase inhibition nearly normalizes PAH in chronically hypoxic rats that have no occlusive neointimal lesions. Here we examined whether Rho kinase-mediated vasoconstriction was also important in a rat model of severe occlusive PAH. Adult rats were exposed to chronic hypoxia ( approximately 10% O(2)) after subcutaneous injection of the vascular endothelial growth factor receptor inhibitor SUGEN 5416. Hemodynamic measurements were made in anesthetized rats after 2 weeks of hypoxia (early group) and 3 weeks of hypoxia plus 2 weeks of normoxia (late group). Both groups developed PAH, with greater severity in the late group. In the early group, intravenous fasudil was more effective than intravenous bradykinin, inhaled NO, or intravenous iloprost in reducing right ventricular systolic pressure. Despite more occlusive vascular lesions, fasudil also markedly reduced right ventricular systolic pressure in late-stage rats. Blood-perfused lungs from late-stage rats showed spontaneous vasoconstriction, which was reversed partially by the endothelin A receptor blocker BQ123 and completely by fasudil or Y-27632. Phosphorylation of MYPT1, a downstream target of Rho kinase, was increased in lungs from both groups of rats, and fasudil (intravenous) reversed the increased phosphorylation in the late group. Thus, in addition to structural occlusion, Rho kinase-mediated vasoconstriction is an important component of severe PAH in SUGEN 5416/hypoxia-exposed rats, and PAH can be significantly reduced in the setting of a severely remodeled lung circulation if an unconventional vasodilator is used.
authors.affiliation: Cardiovascular Pulmonary Research Laboratory and Division of Pulmonary Sciences and Critical Care Medicine, Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262, USA. masahiko.oka@uchsc.edu
authors.forename: Masahiko
authors.initials: M
authors.lastname: Oka
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Homma
authors.forename: Laimute
authors.initials: L
authors.lastname: Taraseviciene-Stewart
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Morris
authors.forename: Donatas
authors.initials: D
authors.lastname: Kraskauskas
authors.forename: Nana
authors.initials: N
authors.lastname: Burns
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
authors.forename: Ivan F
authors.initials: IF
authors.lastname: McMurtry
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D065130:Endothelin A Receptor Antagonists; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology*; D000860:Hypoxia; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D009924:Organ Culture Techniques; D010456:Peptides, Cyclic / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011651:Pulmonary Artery / Q000201:enzymology / Q000503:physiopathology*; D011758:Pyrroles; D051381:Rats; D017207:Rats, Sprague-Dawley; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D054460:rho-Associated Kinases
chemical_list: D065130:Endothelin A Receptor Antagonists; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D010456:Peptides, Cyclic; D011758:Pyrroles; D014665:Vasodilator Agents; C116890:Semaxinib; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D040301:Vascular Endothelial Growth Factor Receptor-2; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D043263:Myosin-Light-Chain Phosphatase; C490372:PPP1R12A protein, human; C049347:fasudil; C072247:cyclo(Trp-Asp-Pro-Val-Leu)