title: The effect of first-in-class small molecule RhoA inhibitor, HL07, on the phenylephrine-induced artery contraction.
abstract: The RhoA/ROCK inhibitors have emerged as a new promising treatment for cardiovascular diseases. Recently, we first reported a series of first-in-class small molecular RhoA inhibitors and a chemical compound named HL07 showed high RhoA inhibition activities. In this study, we aimed to explore the pharmacological effect and possible mechanism of HL07 on agonists-induced vasoconstriction. Results showed that 1) in rat thoracic aorta (TA) rings, HL07(0∼180 µmol/L) effectively inhibited phenylephrine (PE)-induced contraction in concentration-dependent manner , whereas the half maximal inhibitory concentration (IC(50)) being 156.93 µmol/L, while it produced weak inhibition on high-K(+)-induced contraction. Furthermore, in the presence of nifedipine and thapsigargin (Nif/TSG), HL07 had a comparable degree of inhibition on PE-induced contraction with IC(50)=149.52 µmol/L; especially at the concentration (0∼150 µmol/L), the inhibition was greater than the inhibition in absence of Nif/TSG (P < 0.01). In addition, HL07 displayed greater inhibition on pulmonary artery (PA) rings (IC(50)=134.97 µmol/L) than on TA rings. 2) HL07 potently blocked RhoA activation stimulated by PE in concentration-dependent manner in human cerebrovascular smooth muscle cells (HBVSMCs), when HL07 at 10, 2, 0.25 µmol/L, the corresponding inhibition rates were 64 ± 5%, 42 ± 7%, 31 ± 5%, respectively; and at the same concentrations, HL07 had no significant effect on RhoA mRNA level. 3) In HBVSMCs, RhoA activity was increased by pre-incubating with GNP, but HL07 showed inhibitory effect on this tendency. These results indicate that HL07 produces significant inhibitory effects on PE-induced vascular smooth muscle contraction. The inhibitory effects of HL07 were mainly contributed to its inhibition on RhoA/Rho-kinase pathway through blocking RhoA activation, and the binding affinities of HL07 for RhoA preference over the GNP might be responsible for the inhibition of HL07 on RhoA activity.
authors.affiliation: Department of Clinical Pharmacology Research Lab, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Deng
authors.forename: Sheng
authors.initials: S
authors.lastname: Ma
authors.forename: Lin
authors.initials: L
authors.lastname: Xue
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.forename: Wei-liang
authors.initials: WL
authors.lastname: Zhu
authors.forename: Hua-liang
authors.initials: HL
authors.lastname: Jiang
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Li-yan
authors.initials: LY
authors.lastname: Miao
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D002934:Cinnamates / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D010656:Phenylephrine / Q000008:administration & dosage / Q000494:pharmacology; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019284:Thapsigargin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000008:administration & dosage / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors*
chemical_list: C579119:3-(3-(quinoxalin-3-ylamino)phenyl)acrylic acid; D002934:Cinnamates; D011810:Quinoxalines; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D019284:Thapsigargin; D020742:rhoA GTP-Binding Protein; D009543:Nifedipine