title: Prostacyclin does not inhibit rho-kinase: an implication for the treatment of pulmonary hypertension.
abstract: Primary pulmonary hypertension continues to be a fatal disease. We have recently demonstrated that long-term inhibition of Rho-kinase, an effector of the small GTPase Rho, is effective for the treatment of pulmonary hypertension (PH) in rats and humans. Prostacyclin has been clinically used for the treatment of PH with moderate success. However, it remains to be examined whether Rho-kinase inhibition is involved in its beneficial effects on PH. In an ELISA assay, neither prostacyclin nor its oral analogue, beraprost sodium, inhibited Rho-kinase even at higher concentrations (10(-7) to 10(-5) M, 100 to 10,000 times higher than their clinical concentrations), whereas specific Rho-kinase inhibitors, fasudil and hydroxyfasudil, markedly (approximately 95%) inhibited the Rho-kinase activity at 10(-5) M (near their clinical concentrations). Beraprost sodium did not significantly suppress serotonin-induced vascular smooth muscle cell (VSMC) contractions or Rho-kinase activity of the rat aorta without endothelium, as evaluated by the extent of phosphorylation of the ERM family, a substrate of Rho-kinase, whereas hydroxyfasudil markedly suppressed the VSMC contractions and Rho-kinase activity. These results indicate that prostacyclin lacks direct inhibitory effect on Rho-kinase and suggest that combination therapy with prostacyclin and a Rho-kinase inhibitor could exert further beneficial effects on PH.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan.
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Abe
authors.forename: Keiko
authors.initials: K
authors.lastname: Morikawa
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Hizume
authors.forename: Toyokazu
authors.initials: T
authors.lastname: Uwatoku
authors.forename: Keiji
authors.initials: K
authors.lastname: Oi
authors.forename: Minoru
authors.initials: M
authors.lastname: Seto
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ikegaki
authors.forename: Toshio
authors.initials: T
authors.lastname: Asano
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology; D054460:rho-Associated Kinases
chemical_list: D000959:Antihypertensive Agents; D047908:Intracellular Signaling Peptides and Proteins; D010975:Platelet Aggregation Inhibitors; D012701:Serotonin; C048081:beraprost; D011464:Epoprostenol; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases