Effects of combined therapy with a Rho-kinase inhibitor and prostacyclin on monocrotaline-induced pulmonary hypertension in rats

Shunsuke Tawara, Yoshihiro Fukumoto, Hiroaki Shimokawa

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)

Abstract

Pulmonary hypertension (PH) is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells, and migration of inflammatory cells, for which no satisfactory treatment has yet been developed. We have previously demonstrated that long-term inhibition of Rho-kinase, an effector of the small GTPase Rho, ameliorates monocrotaline-induced PH in rats and hypoxia-induced PH in mice. We also have reported that prostacyclin and its oral analogue, beraprost sodium (BPS), may lack direct inhibitory effect on Rho-kinase in vitro, suggesting that combination therapy with a Rho-kinase inhibitor and BPS is effective for the treatment of PH. In this study, we addressed this point in monocrotaline-induced PH model in rats. Male Sprague-Dawley rats were given a subcutaneous injection of monocrotaline (60 mg/kg). They were maintained with or without the treatment with a Rho-kinase inhibitor, fasudil (30 mg/kg/day), BPS (200 μg/kg/day), or a combination of both drugs for 3 weeks. The combination therapy, when compared with each monotherapy, showed significantly more improvement in PH, right ventricular hypertrophy, and pulmonary medial thickness without any adverse effects. Plasma concentrations of fasudil were not affected by BPS. These results suggest that combination therapy with a Rho-kinase inhibitor and prostacyclin exerts further beneficial effects on PH.

Original languageEnglish
Pages (from-to)195-200
Number of pages6
JournalJournal of cardiovascular pharmacology
Volume50
Issue number2
DOIs
Publication statusPublished - 2007 Aug

Keywords

  • Beraprost sodium
  • Fasudil
  • Monocrotaline
  • Pulmonary hypertension
  • Rho-kinase

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

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