Synergistic interaction between a PDE5 inhibitor (sildenafil) and a new adenosine A2A receptor agonist (LASSBio-1359) improves pulmonary hypertension in rats.

Allan K Alencar,Carlos M Fraga,Sabrina T Martinez,Fábio I Carvalho,Eliezer J Barreiro,Gisele Zapata-Sudo,Jorge A Calasans-Maia,Roberto T Sudo,Ananssa M Silva,Michael Bader

doi:10.1371/journal.pone.0195047

Allan K Alencar, Carlos M Fraga + Show 8 more

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https://doi.org/10.1371/journal.pone.0195047

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Abstract

IntroductionPulmonary hypertension (PH) is characterized by enhanced pulmonary vascular resistance, which causes right ventricle (RV) pressure overload and results in right sided heart failure and death. This work investigated the effectiveness of a combined therapy with PDE5 inhibitor (PDE5i) and a new adenosine A2A receptor (A2AR) agonist in mitigating monocrotaline (MCT) induced PH in rats.MethodsAn in vitro isobolographic analysis was performed to identify possible synergistic relaxation effect between sildenafil and LASSBio 1359 in rat pulmonary arteries (PAs). In the in vivo experiments, PH was induced in male Wistar rats by a single intraperitoneal injection of 60 mg/kg MCT. Rats were divided into the following groups: control (saline injection only), MCT + vehicle, MCT + sildenafil, MCT + LASSBio 1359 and MCT + combination of sildenafil and LASSBio 1359. Fourteen days after the MCT injection, rats were treated daily with oral administration of the regimen therapies or vehicle for 14 days. Cardiopulmonary system function and structure were evaluated by echocardiography. RV systolic pressure and PA endothelial function were measured.ResultsIsobolographic analysis showed a synergistic interaction between sildenafil and LASSBio 1359 in rat PAs. Combined therapy with sildenafil and LASSBio 1359 but not monotreatment with low dosages of either sildenafil or LASSBio 1359 ameliorated all of PH related abnormalities in cardiopulmonary function and structure in MCT challenged rats.ConclusionsThe combination of sildenafil and LASSBio 1359 has a synergistic interaction, suggesting that combined use of these pharmacological targets may be an alternative to improve quality of life and outcomes for PH patients.

Highlights

Pulmonary hypertension (PH) is characterized by enhanced pulmonary vascular resistance, which causes right ventricle (RV) pressure overload and results in right sided heart failure and death
Isobolographic analysis showed a synergistic interaction between sildenafil and LASSBio 1359 in rat pulmonary arteries (PAs)
Pulmonary hypertension (PH) is a vasculopathy of the cardiopulmonary system, which may lead to right ventricle (RV) dysfunction, decompensated heart failure, and significant reduction of life expectancy [1, 2]

Summary

Methods

An in vitro isobolographic analysis was performed to identify possible synergistic relaxation effect between sildenafil and LASSBio 1359 in rat pulmonary arteries (PAs). Male Wistar rats were obtained from the Animal Facility of the Institute of Biomedical Sciences at Universidade Federal do Rio de Janeiro and were maintained at 20 ± 3 ̊C under a 12 hour light/dark cycle, with water and standard rat chow offered ad libitum. The experimental procedures were submitted and approved by the Animal Care and Use Committee at Universidade Federal do Rio de Janeiro (Permit # DFBCICB059).”. LASSBio-1359 was synthesized by Laboratorio de Avaliacão e Sıntese de Substancias Bioativas (LASSBio) at Universidade Federal do Rio de Janeiro, Brazil. MCT was synthesized by Laboratorio de Quımica at Universidade Federal Fluminense (Rio de Janeiro, Brazil), and it was dissolved in 1 N HCl, neutralized with 0.5 N NaOH, and diluted with phosphate-buffered saline.

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