| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Pediatric Heart Lung Center and Sections of 1Neonatology and 2Pulmonary Medicine, Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado
Submitted 5 December 2005 ; accepted in final form 19 June 2006
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 has not been studied in the fetal lung. 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, Y-27632 (15–500 µg) and HA-1077 (500 µg), in chronically prepared 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 mmHg·ml–1·min–1 (P < 0.01) at the highest dose tested without lowering systemic arterial pressure. Despite brief infusions, Y-27632-induced pulmonary vasodilation was sustained for 50 min. 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 nitro-L-arginine (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 Y-27632 (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 NO synthase inhibition. We speculate that Rho kinase plays an essential role in the normal fetal pulmonary circulation and that Rho kinase inhibitors may provide novel therapy for neonatal pulmonary hypertension.
Y-27632; fasudil; nitric oxide; persistent pulmonary hypertension of the newborn; newborn
This article has been cited by other articles:
|
|
 |
|
  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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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 | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
