Novel Agonist of Adenosine Receptor Induces Relaxation of Corpus Cavernosum in Guinea Pigs: An In Vitro and In Vivo Study

Abstract

To test the relaxation effect of a new adenosine receptor agonist N-acylhydrazone derivative, 3,4-dimethoxyphenyl-N-methyl-benzoylhydrazide (LASSBio-1359), on in vitro and in vivo preparation of corpus cavernosum (CC), and its interaction with type-5 phosphodiesterase enzyme inhibitor, sildenafil. For in vitro study, an increasing concentration of LASSBio-1359 was added in the solution at the plateau isometric tension recording of isolated guinea pig CC induced by phenylephrine (30 μM). Concentration-response curve was repeated in the presence of A2A receptor antagonist, ZM 241385 (10 μM). Sildenafil-induced CC relaxing effect was compared with that of LASSBio-1359. Isobolographic analysis was performed to identify possible synergistic interaction between LASSBio-1359 and sildenafil. For in vivo study, blood pressure response in the CC of guinea pig was measured after administration of LASSBio-1359 (10 mg/kg intravenously) or sildenafil (10 mg/kg intravenously). LASSBio-1359 caused relaxation of phenylephrine-induced contraction of isolated CC in a concentration-dependent manner (IC50 = 10.1 ± 1.8 μM), which was shifted to the right in the presence of ZM 241385 (IC50 = 27.1 ± 1.4 μM; P <.05). Isobolographic analysis showed synergistic interaction between LASSBio-1359 and sildenafil. As sildenafil, LASSBio-1359 increased blood pressure oscillation in the CC confirming its systemic efficacy. CC relaxing effects induced by the adenosine A2A receptor agonist, LASSBio-1359, demonstrated in vitro and in vivo experimental protocols, represent a promise therapeutic option for the treatment of erectile dysfunction. Synergistic interaction of LASSBio-1359 with sildenafil suggests a combined use to reach a higher population of patients with erectile dysfunction.