Passos Gabriela Reolon, de Jesus Antunes Natalícia, de Oliveira Mariana G, da Costa José Luiz, Schenka André Almeida, Fregonesi Adriano, Antunes Edson, Mónica Fabiola Zakia
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, Sao Paulo, Brazil.
Campinas Poison Control Center (CIATOX), School of Medical Sciences, University of Campinas (Unicamp), Campinas, Sao Paulo, Brazil.
World J Urol. 2025 Sep 9;43(1):546. doi: 10.1007/s00345-025-05929-2.
To evaluate the impact of MRP inhibition by MK571 on prostate hypercontractility in diet-induced obesity, based on the hypothesis that this intervention enhances intracellular cAMP and cGMP signaling.
Adult C57BL/6 mice were divided into three groups: (i) lean, (ii) obese, and (iii) obese + MK571 (5 mg/kg/day, 14 days). The prostate was isolated for immunohistochemistry, biochemistry and functional assays. Electrical field stimulation (EFS) and concentration-response curves to the α1-adrenoceptor agonist phenylephrine or the nitric oxide donor sodium nitroprusside were performed with or without MK571 (20 µM, 30 min), guanylyl or adenylyl cyclase inhibitors (ODQ and SQ22,536, respectively), or the leukotriene receptor antagonist montelukast.
MRP4 and MRP5 were detected in the prostate. In vitro, phenylephrine-and EFS-induced contractions were significantly higher in prostates from obese mice compared to lean mice. Adding MK571 to the myograph chamber significantly reduced the contractile responses and improved relaxation in obese mice, reaching similar responses to those of the lean group. These effects of MK571 were inhibited by co-incubation with ODQ and SQ22536, but not by montelukast. Additionally, treating obese mice for 14 days reversed prostate hypercontractility. Obese mice exhibited significantly lower intracellular levels of cGMP compared to lean, while cAMP levels were similar. However, MK571 treatment significantly increased both cyclic nucleotides, restoring cGMP levels close to those in lean mice.
Our findings highlight that inhibiting MRPs promotes the accumulation of cGMP in the prostate, ultimately enhancing smooth muscle relaxation.
基于MK571抑制多药耐药相关蛋白（MRP）可增强细胞内环磷酸腺苷（cAMP）和环磷酸鸟苷（cGMP）信号传导这一假设，评估MK571对饮食诱导肥胖中前列腺过度收缩的影响。
将成年C57BL/6小鼠分为三组：（i）瘦小鼠组，（ii）肥胖小鼠组，（iii）肥胖+MK571组（5毫克/千克/天，共14天）。分离前列腺进行免疫组织化学、生物化学和功能测定。在有或无MK571（20微摩尔，30分钟）、鸟苷酸环化酶或腺苷酸环化酶抑制剂（分别为ODQ和SQ22536）或白三烯受体拮抗剂孟鲁司特的情况下，进行电场刺激（EFS）以及对α1肾上腺素能受体激动剂去氧肾上腺素或一氧化氮供体硝普钠的浓度-反应曲线测定。
在前列腺中检测到MRP4和MRP5。在体外，与瘦小鼠相比，肥胖小鼠前列腺中去氧肾上腺素和EFS诱导的收缩明显更高。向肌动描记器小室中添加MK571可显著降低肥胖小鼠的收缩反应并改善舒张，达到与瘦小鼠组相似的反应。MK571的这些作用在与ODQ和SQ22536共同孵育时受到抑制，但不受孟鲁司特抑制。此外，对肥胖小鼠进行14天治疗可逆转前列腺过度收缩。与瘦小鼠相比，肥胖小鼠细胞内cGMP水平显著降低，而cAMP水平相似。然而，MK571治疗可显著增加两种环核苷酸，使cGMP水平恢复至接近瘦小鼠的水平。
我们的研究结果表明，抑制MRP可促进前列腺中cGMP的积累，最终增强平滑肌舒张。
