Prostacyclin does not inhibit Rho-kinase: An implication for the treatment of pulmonary hypertension

Kohtaro Abe, Keiko Morikawa, Takatoshi Hizume, Toyokazu Uwatoku, Keiji Oi, Minoru Seto, Ichiro Ikegaki, Toshio Asano, Kozo Kaibuchi, Hiroaki Shimokawa

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 hydroxy-fasudil, markedly (∼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.

Original languageEnglish
Pages (from-to)120-124
Number of pages5
JournalJournal of Cardiovascular Pharmacology
Volume45
Issue number2
DOIs
Publication statusPublished - 01-02-2005
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

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