AJP - Lung AJP: Regulatory, Integrative and Comparative Physiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
QUICK SEARCH:   [advanced]


     

Am J Physiol Lung Cell Mol Physiol (June 30, 2006). doi:10.1152/ajplung.00512.2005
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
291/5/L976    most recent
00512.2005v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Parker, T. A.
Right arrow Articles by Abman, S. H
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Parker, T. A.
Right arrow Articles by Abman, S. H
Submitted on December 5, 2005
Accepted on June 19, 2006

Rho-kinase Activation Maintains High Pulmonary Vascular Resistance in the Ovine Fetal Lung

Thomas A. Parker1*, Gates Roe1, Theresa R Grover1, and Steven H Abman1

1 University of Colorado School of Medicine, Pediatric Heart Lung Center, Sections of Neonatology and Pulmonary Medicine, Department of Pediatrics, Denver, Colorado, United States

* To whom correspondence should be addressed. E-mail: parker.thomas{at}tchden.org.

Mechanisms that maintain high pulmonary vascular resistance (PVR) in the fetal lung are poorly understood. Activation of the rho-kinase signal transduction pathway, which promotes actin-myosin interaction in vascular smooth muscle cells, is increased in the pulmonary circulation of adult animals with experimental pulmonary hypertension. However, the role of rho-kinase in the fetal lung is unknown. We hypothesized that activation of rho-kinase contributes to elevated PVR in the fetus. To address this hypothesis, we studied the pulmonary hemodynamic effects of brief (10 min) intrapulmonary infusions of two specific rho-kinase inhibitors, Y27632 (15-500 µg) and HA-1077 (500 µg), in late-gestation fetal lambs (n=9). Y-27632 caused potent, dose-dependent pulmonary vasodilation, lowering PVR from 0.67±0.18 to 0.16±0.02 mm Hg/ml/min (p<0.01) at the highest dose tested without lowering systemic arterial pressure. Despite brief infusions, Y27632-induced pulmonary vasodilation was sustained for 50 minutes. HA-1077 caused a similar fall in PVR, from 0.39±0.03 to 0.19±0.03 (p<0.05). To study nitric oxide (NO)-rho-kinase interactions in the fetal lung, we tested the effect of rho-kinase inhibition on pulmonary vasoconstriction caused by inhibition of endogenous NO production with L-NA (15-30 mg), a selective NO synthase antagonist. L-NA increased PVR by 127±73% above baseline under control conditions, but this vasoconstrictor response was completely prevented by treatment with Y27632 (p<0.05). We conclude that the rho-kinase signal transduction pathway maintains high PVR in the normal fetal lung and that activation of the rho-kinase pathway mediates pulmonary vasoconstriction after NOS inhibition. We speculate that rho-kinase inhibitors may provide novel therapy for neonatal pulmonary hypertension.




This article has been cited by other articles:


Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
A. M. Badejo Jr., J. S. Dhaliwal, D. B. Casey, T. B. Gallen, A. J. Greco, and P. J. Kadowitz
Analysis of pulmonary vasodilator responses to the Rho-kinase inhibitor fasudil in the anesthetized rat
Am J Physiol Lung Cell Mol Physiol, November 1, 2008; 295(5): L828 - L836.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
J. Gien, G. J. Seedorf, V. Balasubramaniam, N. Tseng, N. Markham, and S. H. Abman
Chronic intrauterine pulmonary hypertension increases endothelial cell Rho kinase activity and impairs angiogenesis in vitro
Am J Physiol Lung Cell Mol Physiol, October 1, 2008; 295(4): L680 - L687.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
P. Tourneux, M. Chester, T. Grover, and S. H. Abman
Fasudil inhibits the myogenic response in the fetal pulmonary circulation
Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1505 - H1513.
[Abstract] [Full Text] [PDF]

Home page
 Postgrad. Med. J.Home page
B Wojciak-Stothard
New drug targets for pulmonary hypertension: Rho GTPases in pulmonary vascular remodelling
Postgrad. Med. J., July 1, 2008; 84(993): 348 - 353.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
P. J. McNamara, P. Murthy, C. Kantores, L. Teixeira, D. Engelberts, T. van Vliet, B. P. Kavanagh, and R. P. Jankov
Acute vasodilator effects of Rho-kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide
Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L205 - L213.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
J. S. Dhaliwal, D. B. Casey, A. J. Greco, A. M. Badejo Jr., T. B. Gallen, S. N. Murthy, B. D. Nossaman, A. L. Hyman, and P. J. Kadowitz
Rho kinase and Ca2+ entry mediate increased pulmonary and systemic vascular resistance in L-NAME-treated rats
Am J Physiol Lung Cell Mol Physiol, November 1, 2007; 293(5): L1306 - L1313.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Visit Other APS Journals Online
Copyright © 2006 by the American Physiological Society.