Acute combination therapy with Sildenafil and Brain Natriuretic Peptide attenuates monocrotaline (MCT)‐induced pulmonary hypertension (PH) in rats

Abstract

Background: PH is a lethal disease characterized by changes in pulmonary vascular structure and function. We hypothesized that combination therapy using sildenafil (SILD) and brain natriuretic peptide (BNP) synergistically attenuates PH while minimizing systemic effects compared to monotherapies. Methods: Adult male SD rats were injected (SC) with MCT (n=36, 50mg/kg). After 5 weeks, under anesthesia, the rats were instrumented to measure mean arterial pressure (MAP) and right ventricular systolic pressure (RVSP) during infusions of vehicle, SILD (85 mcg/kg/min, IV), and BNP (50 and 100 ng/kg/min, IV) alone and in combination. Results: Vehicle infusions did not alter hemodynamic variables. SILD alone decreased RVSP (17±5.6%, P=0.01) and decreased MAP (4±4.7%, P=NS). BNP alone at 50 and 100 ng/kg/min decreased RVSP (28±5.3%; 27±2.9%, both P<0.001) and MAP (8.7±5.3%; 14±4.1%, P=NS, P=0.006). Combination therapy with SILD and BNP (100 ng/kg/min) lowered RVSP (27±3.2%, P<0.001) and increased systemic effect (−21±3.1%, P<0.001). Conclusions: Combination SILD and BNP attenuates MCT-induced PH compared with monotherapies while causing additive systemic side effects. At the tested doses, BNP and SILD monotherapies are preferred options. Further studies are needed to determine the efficacy of lower dose combination therapy before testing in humans. Research supported by Scios Corporation.