Abstract
Chronic inhibition of Rho-kinase has been recently implicated in retardation of atherogenesis induced by high-fat diet in low-density lipoprotein receptor deficient (LDLR-/-) mice. However, it remains to be examined whether long-term Rho-kinase inhibition will reduce vascular dysfunction in this model. LDLR-/- mice on a high-fat diet were treated either with saline (LDLR-/-) or with the Rho-kinase inhibitor Fasudil (HA1077, 5-Isoquinolinesulfonyl homopiperazine, 100 mg/kg/day by gavage, LDLR-/- +Fasudil) for 10 weeks. Fasudil-treatment normalized endothelial function (measured by means of endothelium-dependent vasorelaxation) in LDLR-/- +Fasudil, to the level of controls (C57BL/6J). No tolerance toward Rho-kinase inhibition has been detected in Fasudil-treated animals. We conclude that long-term Rho-kinase inhibition normalizes endothelial function without development of tolerance.
MeSH terms
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives*
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
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Acetylcholine / pharmacology
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Animals
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Aorta, Thoracic / drug effects
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Aorta, Thoracic / physiology
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Dietary Fats / administration & dosage
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Dose-Response Relationship, Drug
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Endothelium, Vascular / drug effects*
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Endothelium, Vascular / physiopathology
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In Vitro Techniques
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Intracellular Signaling Peptides and Proteins
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Phenylephrine / pharmacology
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Potassium Chloride / pharmacology
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Protein Kinase Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Receptors, LDL / deficiency
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Receptors, LDL / genetics*
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Time Factors
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Vasoconstrictor Agents / pharmacology
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Vasodilation / drug effects
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Vasodilator Agents / pharmacology
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rho-Associated Kinases
Substances
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Dietary Fats
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Intracellular Signaling Peptides and Proteins
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Protein Kinase Inhibitors
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Receptors, LDL
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Vasoconstrictor Agents
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Vasodilator Agents
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Phenylephrine
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Potassium Chloride
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
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Protein Serine-Threonine Kinases
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rho-Associated Kinases
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Acetylcholine
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fasudil