Document Detail


Analysis of responses to the Rho-kinase inhibitor Y-27632 in the pulmonary and systemic vascular bed of the rat.
MedLine Citation:
PMID:  20435851     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Responses to the Rho kinase inhibitor Y-27632 were investigated in the anesthetized rat. Under baseline conditions intravenous injections of Y-27632 decreased pulmonary and systemic arterial pressures and increased cardiac output. The decreases in pulmonary arterial pressures were enhanced when baseline tone was increased with U-46619, and under elevated tone conditions Y-27632 produced similar percent decreases in pulmonary and systemic arterial pressures. Injections of Y-27632 prevented and reversed the hypoxic pulmonary vasoconstrictor response. The increase in pulmonary arterial pressure in response to ventilation with a 10% O(2)-90% N(2) gas mixture was not well maintained during the period of hypoxic exposure. Treatment with the nitric oxide (NO) synthase (NOS) inhibitor nitro-l-arginine methyl ester (l-NAME) increased pulmonary arterial pressure and prevented the decline or fade in the hypoxic pulmonary vasoconstrictor response. The hypoxic pulmonary vasoconstrictor response was reversed by Y-27632 in control and in l-NAME-treated animals. The Rho kinase inhibitor attenuated increases in pulmonary arterial pressures in response to intravenous injections of serotonin, angiotensin II, and Bay K 8644. Y-27632, sodium nitrite, and BAY 41-8543, a guanylate cyclase stimulator, decreased pulmonary and systemic arterial pressures and vascular resistances in monocrotaline-treated rats. These data suggest that Rho kinase is involved in the regulation of baseline tone and in the mediation of pulmonary vasoconstrictor responses. The present data suggest that the hypoxic pulmonary vasoconstrictor response is modulated by the release of NO that mediates the nonsustained component of the response in the anesthetized rat. These data suggest that Rho kinase and NOS play important roles in the regulation of vasoconstrictor tone in physiological and pathophysiological states and that monocrotaline-induced pulmonary hypertension can be reversed by agents that inhibit Rho kinase, generate NO, or stimulate soluble guanylate cyclase.
Authors:
David B Casey; Adeleke M Badejo; Jasdeep S Dhaliwal; James L Sikora; Alex Fokin; Neel H Golwala; Anthony J Greco; Subramanyam N Murthy; Bobby D Nossaman; Albert L Hyman; Philip J Kadowitz
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-04-30
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  299     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-06-17     Completed Date:  2010-07-06     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H184-92     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Health Sciences Center, Tulane University School of Medicine, 1430 Tulane Ave., New Orleans, LA 70112, USA.
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MeSH Terms
Descriptor/Qualifier:
Amides / administration & dosage,  pharmacology*
Animals
Anoxia / drug therapy*,  enzymology,  physiopathology
Antihypertensive Agents / administration & dosage,  pharmacology*
Blood Pressure / drug effects
Cardiac Output / drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Enzyme Activation
Enzyme Activators / pharmacology
Enzyme Inhibitors / pharmacology
Guanylate Cyclase / metabolism
Hemodynamics / drug effects*
Hypertension, Pulmonary / chemically induced,  drug therapy*,  enzymology,  physiopathology
Injections, Intravenous
Male
Monocrotaline
Nitric Oxide / metabolism
Nitric Oxide Synthase / antagonists & inhibitors,  metabolism
Protein Kinase Inhibitors / administration & dosage,  pharmacology*
Pulmonary Circulation / drug effects*
Pyridines / administration & dosage,  pharmacology*
Rats
Rats, Sprague-Dawley
Receptors, Cytoplasmic and Nuclear / metabolism
Time Factors
Vascular Resistance
Vasoconstriction / drug effects
Vasoconstrictor Agents / pharmacology
Vasodilator Agents / pharmacology*
rho-Associated Kinases / antagonists & inhibitors*,  metabolism
Grant Support
ID/Acronym/Agency:
HL-62000/HL/NHLBI NIH HHS; HL-77412/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Amides; 0/Antihypertensive Agents; 0/Enzyme Activators; 0/Enzyme Inhibitors; 0/Protein Kinase Inhibitors; 0/Pyridines; 0/Receptors, Cytoplasmic and Nuclear; 0/Vasoconstrictor Agents; 0/Vasodilator Agents; 10102-43-9/Nitric Oxide; 138381-45-0/Y 27632; 315-22-0/Monocrotaline; EC 1.14.13.39/Nitric Oxide Synthase; EC 2.7.11.1/rho-Associated Kinases; EC 4.6.1.2/Guanylate Cyclase; EC 4.6.1.2/soluble guanylyl cyclase
Comments/Corrections

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