title: Fasudil improves the endothelial dysfunction in the aorta of spontaneously hypertensive rats.
abstract: We investigated the effects of fasudil, a Rho kinase inhibitor, in the endothelial dysfunction of aortas from spontaneously hypertensive rats (SHRs). SHRs were divided in three groups; intraperitoneally (i.p.) vehicle-treated SHRs (SHR), SHRs treated with fasudil 3 mg/kg i.p. (Fas3), and SHRs treated with fasudil 10 mg/kg i.p. (Fas10). Vehicle-treated Wistar rats were used as normo-tensive control group. After a six-week-treatment, blood pressure and heart rate were measured by the tail cuff method. Afterwards animals were sacrificed and aortas were examined in vitro by organ bath studies to evaluate the contraction and relaxation ability. Rho kinase activity, myosin light chain (MLC), phosphorylated MLC (phospho-MLC), eNOS, phospho-eNOS protein expression and eNOS mRNA levels were evaluated. SHR demonstrated a significant hypercontractility and impaired relaxation compared to the control. Fasudil 10mg/kg significantly corrected the hypercontractility, restored the relaxation, and significantly decreased the mean arterial blood pressure, while no change observed in the systolic blood pressure. Rho kinase activity was significantly higher in the SHR, and was significantly inhibited by the high dose of fasudil. There was a slight up-regulation in the MLC, and phospho-MLC protein levels in the SHR. eNOS and phospho-eNOS protein levels were significantly lower in the SHR, and this abnormality was significantly normalized by fasudil treatment. No significant difference was observed in the eNOS gene expression. This study suggests that fasudil by inhibiting the Rho kinase activity normalizes the eNOS expression and phosphorylation and ameliorates the endothelial dysfunction induced by hypertension in the SHR model.
authors: Division of Molecular Pharmacology, Department of Pathophysiological and Therapeutic Science, Tottori University School of Medicine, 86 Nishimachi, Yonago 683-8503, Japan. ghiotina@gmail.com
authors: Panagiota
authors: P
authors: Tsounapi
authors: Motoaki
authors: M
authors: Saito
authors: Kazuyuki
authors: K
authors: Kitatani
authors: Fotios
authors: F
authors: Dimitriadis
authors: Fumiya
authors: F
authors: Ohmasa
authors: Shogo
authors: S
authors: Shimizu
authors: Yukako
authors: Y
authors: Kinoshita
authors: Atsushi
authors: A
authors: Takenaka
authors: Keisuke
authors: K
authors: Satoh
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018994:Myosin Light Chains / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D018994:Myosin Light Chains; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D052250:Nitric Oxide Synthase Type III; D054460:rho-Associated Kinases; C049347:fasudil