Abstract
The present study has been designed to investigate the effect of fasudil (Rho-kinase inhibitor) in hypercholesterolemia- and hypertension-induced endothelial dysfunction. High fat diet (8 weeks) and desoxycortisone acetate (DOCA) (40 mg.kg-1) were administered (s.c.) to rats to produce hypercholesterolemia and hypertension (mean arterial blood pressure > 120 mmHg), respectively. Endothelial dysfunction was assessed using isolated aortic ring, electron microscopy of thoracic aorta, and serum concentration of nitrite/nitrate. The expression of mRNA for p22phox and eNOS was assessed by using RT-PCR. Serum thiobarbituric acid reactive substances concentration and aortic superoxide anion concentration were estimated to assess oxidative stress. Fasudil (30 mg.kg-1, p.o.) and atorvastatin (30 mg.kg-1, p.o.) treatments markedly prevented hypercholesterolemia- and hypertension-evoked attenuation of acetylcholine-induced endothelium-dependent relaxation, impairment of vascular endothelial lining, decrease in expression of mRNA for eNOS and serum nitrite/nitrate concentration, and an increase in expression of mRNA for p22phox, superoxide anion, and serum thiobarbituric acid reactive substances. The ameliorative effect of fasudil was prevented by L-NAME. In conclusion, fasudil-induced inhibition of Rho-kinase may improve hypercholesterolemia- and hypertension-induced endothelial dysfunction.
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 / metabolism
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Aorta, Thoracic / physiopathology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / physiopathology
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Hypercholesterolemia / drug therapy*
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Hypercholesterolemia / physiopathology
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Hypertension / chemically induced
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Hypertension / drug therapy*
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Hypertension / physiopathology
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In Vitro Techniques
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Male
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NADPH Oxidases / genetics
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NADPH Oxidases / metabolism
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Nitrates / blood
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Nitric Oxide Synthase Type III / genetics
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Nitric Oxide Synthase Type III / metabolism
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Nitrites / blood
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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RNA, Messenger / analysis
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Rats
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Rats, Wistar
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Superoxides / metabolism
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Thiobarbituric Acid Reactive Substances / analysis
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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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Intracellular Signaling Peptides and Proteins
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Nitrates
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Nitrites
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Protein Kinase Inhibitors
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RNA, Messenger
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Thiobarbituric Acid Reactive Substances
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Vasodilator Agents
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Superoxides
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
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Nitric Oxide Synthase Type III
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NADPH Oxidases
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Cyba protein, rat
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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