Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension

摘要

Pulmonary hypertension (PH) is characterised by progressive elevation of pulmonary artery pressure and pulmonary vascular resistance. Pathohistological findings have demonstrated that PH is associated with abnormal vascular structures, including medial and/or intimal hypertrophy, concentric or eccentric intimal fibrosis, obstruction in the arterial lumen, and aneurysmal dilatation. Patients with PH are currently treated with anticoagulant agents, vasodilators including continuous intravenous prostacyclin (pros-taglandin I_2) and oral sildenafil or bosentan, and in end stage, with lung transplantation, when applicable. Endothelial dysfunction of pulmonary arteries and enhanced pulmonary vasoconstriction contribute to the development of PH. Endothelial nitric oxide synthase (eNOS) expression is reduced in patients with PH and therefore nitric oxide inhalation and sildenafil are useful for those patients. However, more effective treatments remain to be developed. We have recently demonstrated that Rho-kinase is substantially involved in the pathogenesis of a wide range of cardiovascular disease. Rho-kinase suppresses myosin phosphatase activity by phosphorylating the myosin binding subunit of the enzyme and thus augments vascular smooth muscle cell (VSMC) contraction at a given intracellular calcium concentration. Indeed, we have demonstrated that a Rho-kinase inhibitor, fasudil, suppresses abnormal hyper-constriction of forearm and coronary arteries in animals and humans. Moreover, we have recently demonstrated that Rho-kinase inhibition increases eNOS expression and decreases inflammatory cell migration or anigiotensin II induced mRNA expression of monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1 in vivo and in vitro. Our in vivo study also indicated that long term oral treatment with fasudil notably ameliorates monocrotaline induced PH and pulmonary vascular lesions in rats. In the present study, we thus examined the acute vasodilatory effects of pulmonary circulation by intravenous administration of fasudil in patients with severe PH.