Dados do Trabalho

Título

Probenecid increased the relaxation induced by cyclic guanosine monophosphate-augmenting substances in isolated corpus cavernosum from rats

Resumo

Introduction: Erectile dysfunction (ED) is a common male sexual dysfunction characterized by the consistent or recurrent inability to attain and maintain an erection sufficient for satisfactory sexual performance, significantly impacting quality of life. Drug repurposing is a strategy that aims to redirect substances approved on the clinical settings for new therapeutic indications. Probenecid, a drug indicated for the treatment of gout is known for inhibiting multidrug resistance proteins (MRPs), organic anion transporters (OATs) and pannexin-1 as well as for activating transient receptor potential cation channel (TRPV2). The therapeutic concentration of probenecid is in the range of 0.1-1 mM. Aim: To evaluate the effect of probenecid in the relaxing responses induce by different agents in corpus cavernosum (CC) from rat . Methods: Experiments were conducted on isolated CC from rats. Concentration-response curves (CRCs) were carried out and the potency (pEC50) and maximal response values (Emax) were determined. Approval by the Ethic Committee (CEUA/UNICAMP: 6369-1/2023). Results: Probenecid relaxed the CC of rats with an Emax of, approximately, 50%. This response was significantly reduced in the presence of inhibitors of soluble guanylyl cyclase (ODQ, 100 μM, 26.8 ± 4.3 %, n=4, P<0.01) and eNOS (L-NAME, 100 μM, 24.2 ± 7.0 %, n=4, P<0.01) and significantly increased in the presence of phosphodiesterases inhibitor (IBMX, 100 μM, 93.3 ± 10.1 %, n=4, P<0.05). However, in the presence of adenylyl cyclase inhibitor (SQ 22,536, 100 μM) no alteration in the pharmacological parameters was observed. We also observed that probenecid (1 mM; 30 min) increased the relaxing responses induced by acetylcholine (Emax: 46.5 ± 6.7 % vs 70.5 ± 8.0 %, n=4, P<0.01) and the nitric-oxide donor, sodium nitroprusside (SNP, Emax: 75.3 ± 5.8 % vs 96.2 ± 4.4 %, n=4, P<0.01). Moreover, a significant potentiation in the relaxing response induced by tadalafil (pEC50: 3.69 ± 0.17 vs 4.30 ± 0.19; n=4, P<0.05) and SNP (pEC50: 5.21 ± 0.14 vs 5.52 ± 0.20; n=4, P<0.05) were observed in the presence of probenecid (1 mM; 30 min). Conclusion: Probenecid relaxes CC and enhances responses to key relaxant agents, possibly through the inhibition of MRPs, thus leading to greater intracellular levels of cGMP. Further studies are needed to elucidate these mechanisms and evaluate the efficacy in animal models of ED and in human CC.

Palavras Chave

probenecid; corpus cavernosum; ERECTILE FUNCTION