Long term Rho-kinase inhibition ameliorates endothelial dysfunction in LDL-Receptor deficient mice.
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.
Steioff
Kerstin
K
Sanofi-Aventis Pharma GmbH, Therapeutic Department Cardiovascular Diseases, Industriepark Höchst, 65926 Frankfurt am Main, Germany.
Rütten
Hartmut
H
Busch
Andreas E
AE
Plettenburg
Oliver
O
Ivashchenko
Yuri
Y
Löhn
Matthias
M
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D004041:Dietary Fats / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics*; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D054460:rho-Associated Kinases
D004041:Dietary Fats; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011973:Receptors, LDL; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; D011189:Potassium Chloride; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D000109:Acetylcholine; C049347:fasudil