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(Circulation Research. 2007;100:923.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Rho Kinase–Mediated Vasoconstriction Is Important in Severe Occlusive Pulmonary Arterial Hypertension in Rats

Masahiko Oka, Noriyuki Homma, Laimute Taraseviciene-Stewart, Kenneth G. Morris, Donatas Kraskauskas, Nana Burns, Norbert F. Voelkel, Ivan F. McMurtry

From the 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. Present address for I.F.M.: Department of Pharmacology and Center for Lung Biology at the University of South Alabama, Mobile.

Correspondence to Masahiko Oka, MD, CVP Research Laboratory, B-133, UCDHSC, 4200 E 9th Ave, Denver, CO 80262. E-mail masahiko.oka{at}uchsc.edu

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 (10% O₂) 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.

Key Words: fasudil • vasodilator • vascular remodeling • SU5416

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