| Analysis of responses to the Rho-kinase inhibitor Y-27632 in the pulmonary and systemic vascular bed of the rat. | |
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MedLine Citation:
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PMID: 20435851 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-04-30 |
Journal Detail:
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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:
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Created Date: 2010-06-17 Completed Date: 2010-07-06 Revised Date: 2011-08-01 |
Medline Journal Info:
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Nlm Unique ID: 100901228 Medline TA: Am J Physiol Heart Circ Physiol Country: United States |
Other Details:
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Languages: eng Pagination: H184-92 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, Health Sciences Center, Tulane University School of Medicine, 1430 Tulane Ave., New Orleans, LA 70112, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amides
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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:
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HL-62000/HL/NHLBI NIH HHS; HL-77412/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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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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