Abstract 70: Novel Multi-target Compound, Agonist of Adenosine Receptor and Inhibitor of Phosphodiesterase 5, Ameliorates Monocrotaline-induced Pulmonary Hypertension in Rats

Abstract

Aims: Pulmonary hypertension (PH) is a disease that results in right ventricular (RV) dysfunction and premature death. This work investigated the effects of LASSBio-1386, a compound with dual target, activation of the adenosine A 2A receptor and inhibition of phosphodiesterase 5 in rats with monocrotaline (MCT)-induced PH. Methods and Results: Protocols were approved by Animal Care and Use Committee at Universidade Federal do Rio de Janeiro. Male Wistar rats received a single intraperitoneal injection of MCT (60 mg/kg) for PH induction. Experimental groups were: control, MCT + vehicle (DMSO), MCT + LASSBio-1386 (100 μmol/kg/day p.o.) and MCT + Sildenafil (100 μmol/kg/day p.o.). Animals were treated with vehicle or drug for 14 days after the onset of disease (n = 6 per group). Treadmill test and transthoracic echocardiography were performed to access exercise capacity and cardiac function, respectively. Right ventricular systolic pressure (RVSP) and ratio between RV and body weight (RV/BW) were analyzed. Exercise capacity (m.kg) was reduced from 1336.2 ± 82.2(control) to 479.7 ± 75.5 (MCT+ vehicle) and recovered to 1357.0 ± 87.8 and 1221.0 ± 96.8 after treatment with LASSBio-1386 and sildenafil, respectively. Pulmonary acceleration time (PAT) (ms) was reduced from 45.3 ± 0.8 (control) to 21.9 ± 0.3 in MCT + vehicle group ( P < 0.05) and restored to 42.9 ± 0.7 in MCT + LASSBio-1386 group, but it was only partially restored to 37.8 ± 1.3 (ms) in MCT + Sildenafil-treated group. RVSP (mmHg) was increased from 27.1 ± 0.7 (control) to 52.9 ± 1.5 in the PH rats and was reduced to 29.1 ± 1.0 and to 31.8 ± 0.6 after treatment with LASSBio-1386 and sildenafil. PH induced an increase of RV/BW (mg/g) from 0.62 ± 0.03 (control) to 1.81 ± 0.20 which was reduced to 0.70 ± 0.07 after administration of LASSBio-1386. Sildenafil treatment did not reverse the RV hypertrophy in PH rats (RV/BW = 1.52 ± 0.10 mg/g). Conclusions: LASSBio-1386 was effective to prevent RV dysfunction and exercise intolerance indicating important implications for ongoing clinical evaluation of multi-target drugs for the treatment of PAH.