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.