Tawara Shunsuke, Fukumoto Yoshihiro, Shimokawa Hiroaki
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
J Cardiovasc Pharmacol. 2007 Aug;50(2):195-200. doi: 10.1097/FJC.0b013e31806befe6.
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 microg/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.
肺动脉高压（PH）是一种致命疾病，其特征为内皮功能障碍、血管平滑肌细胞过度收缩和增殖以及炎症细胞迁移，目前尚未开发出令人满意的治疗方法。我们之前已经证明，长期抑制小GTP酶Rho的效应器Rho激酶，可改善大鼠中野百合碱诱导的PH和小鼠缺氧诱导的PH。我们还报道过，前列环素及其口服类似物贝前列素钠（BPS）在体外可能对Rho激酶缺乏直接抑制作用，这表明Rho激酶抑制剂与BPS联合治疗对PH有效。在本研究中，我们在大鼠中野百合碱诱导的PH模型中探讨了这一点。雄性Sprague-Dawley大鼠皮下注射中野百合碱（60 mg/kg）。它们在接受或不接受Rho激酶抑制剂法舒地尔（30 mg/kg/天）、BPS（200 μg/kg/天）或两种药物联合治疗的情况下维持3周。与每种单一疗法相比，联合治疗在改善PH、右心室肥大和肺中层厚度方面表现出更显著的效果，且无任何不良反应。法舒地尔的血浆浓度不受BPS影响。这些结果表明，Rho激酶抑制剂与前列环素联合治疗对PH具有进一步的有益作用。
