title: Vasodilatory effect of a novel Rho-kinase inhibitor, DL0805-2, on the rat mesenteric artery and its potential mechanisms.
abstract: OBJECTIVE
  In the present study, we investigated the vasodilatory effect of a novel scaffold Rho-kinase inhibitor, DL0805-2, on isolated rat arterial rings including mesenteric, ventral tail, and renal arteries. We also examined the potential mechanisms of its vasodilatory action using mesenteric artery rings.
  
  
  METHODS
  A DMT multiwire myograph system was used to test the tension of isolated small arteries. Several drugs were employed to verify the underlying mechanisms.
  
  
  RESULTS
  DL0805-2 (10(-7)-10(-4) M) inhibited KCl (60 mM)-induced vasoconstriction in three types of small artery rings (pEC50: 5.84 ± 0.03, 5.39 ± 0.03, and 5.67 ± 0.02 for mesenteric, renal, and ventral tail artery rings, respectively). Pre-incubation with DL0805-2 (1, 3, or 10 μM) attenuated KCl (10-60 mM) and angiotensin II (AngII; 10(-6) M)-induced vasoconstriction in mesenteric artery rings. The relaxant effect on the rat mesenteric artery was partially endothelium-dependent (pEC50: 6.02 ± 0.05 for endothelium-intact and 5.72 ± 0.06 for endothelium-denuded). The influx and release of Ca(2+) were inhibited by DL0805-2. In addition, the increased phosphorylation levels of myosin light chain (MLC) and myosin-binding subunit of myosin phosphatase (MYPT1) induced by AngII were blocked by DL0805-2. However, DL0805-2 had little effect on K(+) channels.
  
  
  CONCLUSIONS
  The present results demonstrate that DL0805-2 has a vasorelaxant effect on isolated rat small arteries and may exert its action through the endothelium, Ca(2+) channels, and the Rho/ROCK pathway.
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors.forename: Tian-Yi
authors.initials: TY
authors.lastname: Yuan
authors.forename: Yu
authors.initials: Y
authors.lastname: Yan
authors.forename: Yu-Jie
authors.initials: YJ
authors.lastname: Wu
authors.forename: Xiao-Na
authors.initials: XN
authors.lastname: Xu
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Xiao-Zhen
authors.initials: XZ
authors.lastname: Jiao
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.forename: Lian-Hua
authors.initials: LH
authors.lastname: Fang
authors.forename: Guan-Hua
authors.initials: GH
authors.lastname: Du
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology*; D018994:Myosin Light Chains / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects; D011189:Potassium Chloride / Q000037:antagonists & inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007191:Indazoles; D018994:Myosin Light Chains; C000598341:N-(1H-indazol-5-yl)-1-(4-methylbenzyl)pyrrolidine-3-carboxamide; D015221:Potassium Channels; D047428:Protein Kinase Inhibitors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000804:Angiotensin II; D011189:Potassium Chloride; D054460:rho-Associated Kinases; D043263:Myosin-Light-Chain Phosphatase; D002118:Calcium