Rho kinase activation maintains high pulmonary vascular resistance in the ovine fetal lung

Am J Physiol Lung Cell Mol Physiol. 2006 Nov;291(5):L976-82. doi: 10.1152/ajplung.00512.2005. Epub 2006 Jun 30.

Abstract

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 microg) and HA-1077 (500 microg), 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 x ml(-1) x 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • Amides / pharmacology
  • Animals
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Female
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lung / blood supply*
  • Lung / embryology*
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / metabolism
  • Nitroarginine / pharmacology
  • Pregnancy
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*
  • Pulmonary Circulation / drug effects
  • Pulmonary Circulation / physiology
  • Pyridines / pharmacology
  • Sheep
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Vascular Resistance / drug effects
  • Vascular Resistance / physiology*
  • rho-Associated Kinases

Substances

  • Amides
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • Pyridines
  • Y 27632
  • Nitroarginine
  • Nitric Oxide
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Nitric Oxide Synthase
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases
  • fasudil