Effect of fasudil on macrovascular disorder-induced endothelial dysfunction.
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.
Shah
Dhvanit I
DI
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147 002 Punjab, India.
Singh
Manjeet
M
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000503:physiopathology; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D009566:Nitrates; D009573:Nitrites; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D017392:Thiobarbituric Acid Reactive Substances; D014665:Vasodilator Agents; D013481:Superoxides; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; C515768:Cyba protein, rat; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D000109:Acetylcholine; C049347:fasudil