A novel and selective endothelin ETA receptor antagonist YM598 prevents the development of chronic hypoxia-induced pulmonary hypertension in rats

The preventive effects of the novel and selective endotbelin ETA receptor antagonist YM598 on the development of pulmonary hypertension (PH) were investigated in chronic hypoxia-induced PH rats. Oral administration of YM598 at a dose of I mg/kg was started on the first day of chronic hypoxia exposure for 2 and 3 weeks to investigate the effects of this compound on hemodynamic and arterial blood gas variables, respectively. Cardiopulmonary organ weights were measured at the end of the 2-week administration period. Chronic hypoxia for 2 weeks induced a marked increase in pulmonary arterial pressure, right ventricular hypertrophy, and pulmonary and systemic congestion, and a decrease in right cardiac diastolic function. Repeated oral administration of YM598 significantly suppressed the increase in pulmonary arterial pressure, right ventricular hypertrophy, and pulmonary and systemic congestion. YM598 also improved the hypoxemia which was induced by 3 weeks of exposure to hypoxia. These results suggest that repeated oral administration of YM598 to rats with chronic hypoxia effectively prevented the development of PH. Oral administration of YM598 also improved hypoxemia in this model. These data strongly suggest that YM598 will be clinically useful in the treatment of patients with either primary or secondary pulmonary hypertension. (c) 2005 Elsevier Inc. All rights reserved.