Acute vasodilator effects of Rho-kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide

Patrick J McNamara; Prashanth Murthy; Crystal Kantores; Lilian Teixeira; Doreen Engelberts; Todd van Vliet; Brian P Kavanagh; Robert P Jankov

doi:10.1152/ajplung.00234.2007

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Acute vasodilator effects of Rho-kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide

Journal article

Peer reviewed

Acute vasodilator effects of Rho-kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide

Patrick J McNamara, Prashanth Murthy, Crystal Kantores, Lilian Teixeira, Doreen Engelberts, Todd van Vliet, Brian P Kavanagh and Robert P Jankov

American journal of physiology. Lung cellular and molecular physiology, Vol.294(2), pp.L205-213

02/2008

DOI: 10.1152/ajplung.00234.2007

PMID: 18032699

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Abstract

Pulmonary hypertension (PHT) in neonates is often refractory to the current best therapy, inhaled nitric oxide (NO). The utility of a new class of pulmonary vasodilators, Rho-kinase (ROCK) inhibitors, has not been examined in neonatal animals. Our objective was to examine the activity and expression of RhoA/ROCK in normal and injured pulmonary arteries and to determine the short-term pulmonary hemodynamic (assessed by pulse wave Doppler) effects of ROCK inhibitors (15 mg/kg ip Y-27632 or 30 mg/kg ip fasudil) in two neonatal rat models of chronic PHT with pulmonary vascular remodeling (chronic hypoxia, 0.13 Fi(O(2)), or 1 mg.kg(-1).day(-1) ip chronic bleomycin for 14 days from birth). Activity of the RhoA/ROCK pathway and ROCK expression were increased in hypoxia- and bleomycin-induced PHT. In both models, severe PHT [characterized by raised pulmonary vascular resistance (PVR) and impaired right ventricular (RV) performance] did not respond acutely to inhaled NO (20 ppm for 15 min) or to a single bolus of a NO donor, 3-morpholinosydnonimine hydrochloride (SIN-1; 2 mug/kg ip). In contrast, a single intraperitoneal bolus of either ROCK inhibitor (Y-27632 or fasudil) completely normalized PVR but had no acute effect on RV performance. ROCK-mediated vasoconstriction appears to play a key role in chronic PHT in our two neonatal rat models. Inhibitors of ROCK have potential as a testable therapy in neonates with PHT that is refractory to NO.

Vasodilator Agents - therapeutic use

Nitric Oxide - pharmacology

Hypertension, Pulmonary - physiopathology

rhoA GTP-Binding Protein - metabolism

Nitric Oxide - therapeutic use

rho-Associated Kinases - antagonists & inhibitors

Lung - enzymology

Bleomycin

Vascular Resistance - drug effects

Hypertension, Pulmonary - drug therapy

Ventricular Function, Right - drug effects

Nitric Oxide Donors - pharmacology

Hypertension, Pulmonary - enzymology

Amides - pharmacology

Animals, Newborn

Lung - pathology

Enzyme Inhibitors - pharmacology

Administration, Inhalation

Rats

Macrophages - cytology

Enzyme Activation - drug effects

Nitric Oxide - administration & dosage

Enzyme Inhibitors - therapeutic use

Rats, Sprague-Dawley

Cell Movement - drug effects

Animals

Lung - drug effects

Hypoxia

Macrophages - drug effects

Pyridines - pharmacology

Lung - blood supply

Details

Title: Subtitle: Acute vasodilator effects of Rho-kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide
Creators: Patrick J McNamara - Department of Newborn and Developmental Paediatrics, Sunnybrook Health Sciences Centre, 76 Grenville Street, Toronto, Ontario, Canada
Prashanth Murthy
Crystal Kantores
Lilian Teixeira
Doreen Engelberts
Todd van Vliet
Brian P Kavanagh
Robert P Jankov
Resource Type: Journal article
Publication Details: American journal of physiology. Lung cellular and molecular physiology, Vol.294(2), pp.L205-213
DOI: 10.1152/ajplung.00234.2007
PMID: 18032699
ISSN: 1040-0605
eISSN: 1522-1504
Grant note: 87702 / Canadian Institutes of Health Research 84290 / Canadian Institutes of Health Research
Language: English
Date published: 02/2008
Academic Unit: Stead Family Department of Pediatrics; Neonatology; Internal Medicine
Record Identifier: 9984093469302771

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