Effect of zamicastat, a dopamine beta-hydroxylase inhibitor, on the monocrotaline rat model of pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a group of rare diseases characterized by elevated pulmonary arterial resistance leading to right ventricle hypertrophy and failure. Studies of PAH patients show that hyperstimulation of the sympathetic nervous system appears to contribute to the development of the condition (Velez-Roa S. et al Circulation 2004, 110:1308–1312). The aim of this study was to evaluate the effect of Zamicastat, a reversible inhibitor of dopamine β-hydroxylase (DβH; EC 1.14.17.1), on the rat monocrotaline (MCT) model of PAH. PAH model was induced in male Wistar Han rats with a subcutaneous administration of MCT (60 mg/kg). Twelve days after, when the increase in right ventricular pressure has been established, daily treatment with Zamicastat (30 mg/kg/day) was initiated and prolonged until day 27 or 25, when surviving animals were evaluated respectively for catecholamine levels or right ventricular systolic pressure. Zamicastat significantly improved the survival rate of MCT-treated animals. This was associated with a significant decrease in sympathetic activity, as shown by a reduction in noradrenaline (NE) levels in the urine and by a significant decrease in NE tissue content in the ventricles. Interestingly no effect of Zamicastat on the MCT-induced increase in right ventricle systolic pressure was observed. Therapeutic administration of Zamicastat, and consequent decrease of NE, although not altering high right ventricular pressure, is effective in significantly improving rat survival in the PAH MCT model. This suggests that the beneficial effect of Zamicastat is exerted by a mechanism other than decreasing right ventricular pressure.