The multidrug resistance protein inhibitor, MK571 inhibits the hypercontractility state in prostate from obese mice.

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: Our findings highlight that inhibiting MRPs promotes the accumulation of cGMP in the prostate, ultimately enhancing smooth muscle relaxation.