title: Involvement of Rho-kinase in experimental vascular endothelial dysfunction.
abstract: The present study has been designed to investigate the effect of fasudil (Rho-kinase inhibitor) in diabetes mellitus (DM) and hyperhomocyteinemia (HHcy) induced vascular endothelial dysfunction (VED). Streptozotocin (55 mg kg(-1), i.v., once only) and methionine (1.7% w/w, p.o., daily for 4 weeks) were administered to rats to produce DM (serum glucose >140 mg dl(-1)) and HHcy (serum homocysteine >10 microM) respectively. VED was assessed using isolated aortic ring, electron microscopy of thoracic aorta, and serum concentration of nitrite/nitrate. Serum thiobarbituric acid reactive substances (TBARS) concentration was estimated to assess oxidative stress. Atorvastatin has been employed in the present study as standard agent to improve vascular endothelial dysfunction. Fasudil (15 mg kg(-1) and 30 mg kg(-1), p.o., daily) and atorvastatin (30 mg kg(-1), p.o., daily) treatments significantly attenuated increase in serum glucose and homocysteine but their concentrations remained markedly higher than sham control value. Fasudil and atorvastatin treatments markedly prevented DM and HHcy-induced (i) attenuation of acetylcholine induced endothelium-dependent relaxation, (ii) impairment of vascular endothelial lining, (iii) decrease in serum nitrite/nitrate concentration, and (iv) increase in serum TBARS. It may be concluded that fasudil prevented DM and HHcy-induced VED partially by decreasing serum glucose and homocysteine concentration due to inhibition of Rho-kinase. Moreover, inhibition of Rho-kinase by fasudil and consequent prevention of oxidative stress may have directly improved VED in diabetic and hyperhomocysteinemic rats. The Rho-kinase appears to be a pivotal target site involved in DM and HHcy-induced VED.
authors.affiliation: Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India.
authors.forename: Dhvanit I
authors.initials: DI
authors.lastname: Shah
authors.forename: Manjeet
authors.initials: M
authors.lastname: Singh
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D000069059:Atorvastatin; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D048909:Diabetes Complications / Q000628:therapy; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000628:therapy*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D006538:Heptanoic Acids / Q000494:pharmacology; D006710:Homocysteine / Q000187:drug effects / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D020138:Hyperhomocysteinemia / Q000473:pathology / Q000628:therapy*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D018384:Oxidative Stress; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin / Q000633:toxicity; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D054460:rho-Associated Kinases
chemical_list: D000903:Antibiotics, Antineoplastic; D001786:Blood Glucose; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009566:Nitrates; D009573:Nitrites; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D017392:Thiobarbituric Acid Reactive Substances; D006710:Homocysteine; D013311:Streptozocin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000069059:Atorvastatin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D000109:Acetylcholine; C049347:fasudil