Novel agonist of adenosine receptor induces relaxation of corpus cavernosum in guinea pigs: an in vitro and in vivo study.
OBJECTIVE
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.


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Departamento de Cirurgia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Victor J G
VJG
Moura
Departamento de Farmacologia, Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Allan K N
AKN
Alencar
Departamento de Cirurgia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Jorge de Albuquerque
JA
Calasans-Maia
Departamento de Farmacologia, Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Jaqueline Soares
JS
da Silva
Departamento de Farmacologia, Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Carlos A M
CAM
Fraga
Departamento de Farmacologia, Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Gisele
G
Zapata-Sudo
Departamento de Farmacologia, Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Eliezer J
EJ
Barreiro
Departamento de Farmacologia, Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address: rtsudo@icb.ufrj.br.
Roberto Takashi
RT
Sudo
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D004357:Drug Synergism; D006168:Guinea Pigs; D006835:Hydrazones / Q000494:pharmacology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D010413:Penis / Q000187:drug effects* / Q000502:physiology*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000494:pharmacology*
C000596271:3,4-dimethoxyphenyl-N-methylbenzoylhydrazide; D001549:Benzamides; D006835:Hydrazones; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D000068677:Sildenafil Citrate