Intratracheal Administration of Benzbromarone Attenuates Pulmonary Vascular Remodeling and Improves Survival in Rats with Monocrotaline-Induced Pulmonary Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disorder characterized by sustained elevation of pulmonary arterial pressure due to pulmonary vascular remodeling. The resulting increase in pulmonary vascular resistance leads to right ventricular hypertrophy and, ultimately, right heart failure. Although several PAH-targeted therapies have been developed, the prognosis of patients with PAH remains unsatisfactory. In the present study, we investigated the therapeutic potential of benzbromarone, a uricosuric drug clinically used to treat hyperuricemia and gout, in an experimental rat model of pulmonary hypertension (PH). Because intravenous and subcutaneous administration of benzbromarone has previously been reported to improve experimental PH, we evaluated the therapeutic effects of intratracheal (i.t.) administration of benzbromarone and compared its efficacy with that of intraperitoneal (i.p.) administration in rats with monocrotaline (MCT)-induced PH. Benzbromarone (10 mg/kg/d) was administered via either the i.p. or i.t. route. MCT treatment markedly increased right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling. Both i.p. and i.t. administration of benzbromarone attenuated these pathological changes. Furthermore, benzbromarone improved survival in MCT-induced PH rats regardless of the administration route. Overall, the therapeutic efficacy of benzbromarone was comparable between the two administration routes. In conclusion, i.t. administration of benzbromarone effectively ameliorates experimental PH and may represent a promising drug-repositioning strategy for pulmonary delivery in the treatment of PAH.