title: Role of Rho-kinase signaling and endothelial dysfunction in modulating blood flow distribution in pulmonary hypertension.
abstract: Rho-kinase-mediated vasoconstriction and endothelial dysfunction are considered two primary instigators of pulmonary arterial hypertension (PAH). However, their contribution to the adverse changes in pulmonary blood flow distribution associated with PAH has not been addressed. This study utilizes synchrotron radiation microangiography to assess the specific role, and contribution of, Rho-kinase-mediated vasoconstriction and endothelial dysfunction in PAH. Male adult Sprague-Dawley rats were injected with saline (Cont-rats) or monocrotaline (MCT-rats) 3 wk before microangiography was performed on the left lung. We assessed dynamic changes in vessel internal diameter (ID) in response to 1) the Rho-kinase inhibitor fasudil (10 mg/kg iv); or 2) ACh (3 μg · kg⁻¹ · min⁻¹), sodium nitroprusside (SNP, 5 μg · kg⁻¹ · min⁻¹), and N(ω)-nitro-l-arginine methyl ester (l-NAME, 50 mg/kg iv). We observed that MCT-rats had fewer vessels of the microcirculation compared with Cont-rats. The fundamental result of this study is that fasudil improved pulmonary blood flow distribution and reduced pulmonary pressure in PAH rats, not only by dilating already-perfused vessels (ID > 100 μm), but also by restoring blood flow to vessels that had previously been constricted closed (ID < 100 μm). Endothelium-dependent vasodilation was impaired in MCT-rats primarily in vessels with an ID < 200 μm. Moreover the vasoconstrictor response to l-NAME was accentuated in MCT-rats, but only in the 200- to 300-μm vessels. These results highlight the importance of Rho-kinase-mediated control and endothelial control of pulmonary vascular tone in PAH. Indeed, an effective therapeutic strategy for treating PAH should target both the smooth muscle Rho-kinase and endothelial pathways.
authors.affiliation: Dept. of Physiology, Univ. of Otago, Dunedin, New Zealand. daryl.schwenke@stonebow.otago.ac.nz
authors.forename: Daryl O
authors.initials: DO
authors.lastname: Schwenke
authors.forename: James T
authors.initials: JT
authors.lastname: Pearson
authors.forename: Takashi
authors.initials: T
authors.lastname: Sonobe
authors.forename: Hatsue
authors.initials: H
authors.lastname: Ishibashi-Ueda
authors.forename: Akito
authors.initials: A
authors.lastname: Shimouchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
authors.forename: Keiji
authors.initials: K
authors.lastname: Umetani
authors.forename: Mikiyasu
authors.initials: M
authors.lastname: Shirai
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000792:Angiography; D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008168:Lung / Q000098:blood supply* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D016686:Monocrotaline; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D009599:Nitroprusside; D016686:Monocrotaline; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D000109:Acetylcholine; C049347:fasudil; D019331:NG-Nitroarginine Methyl Ester