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Updated: Jun 18, 2026
Murine Prostate Micro-dissection and Surgical Castration
Published on: May 11, 2016
The multidrug resistance protein inhibitor, MK571 inhibits the hypercontractility state in prostate from obese mice
Gabriela Reolon Passos1, Natalícia de Jesus Antunes2, Mariana G de Oliveira1
1Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, Sao Paulo, Brazil.
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.
Insights
Inhibiting multidrug resistance-associated protein (MRP) with MK571 reversed prostate hypercontractility in obese mice by increasing cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) levels.
Area of Science:
- Urology
- Pharmacology
- Obesity Research
Background:
- Diet-induced obesity is linked to prostate hypercontractility.
- Multidrug resistance-associated proteins (MRPs) are implicated in smooth muscle function.
- Intracellular cyclic nucleotide signaling pathways (cAMP and cGMP) regulate smooth muscle tone.
Purpose of the Study:
- To investigate the effect of MRP inhibition using MK571 on prostate hypercontractility in diet-induced obesity.
- To determine if MK571 enhances intracellular cAMP and cGMP signaling in the prostate.
- To explore the therapeutic potential of MRP inhibition for obesity-related prostate dysfunction.
Main Methods:
- Adult C57BL/6 mice were grouped into lean, obese, and obese+MK571 treatments.
- Prostate tissues were analyzed using immunohistochemistry, biochemistry, and functional assays.
- In vitro and in vivo studies involved electrical field stimulation (EFS), receptor agonist/antagonist treatments, and cyclic nucleotide measurements.
Main Results:
- Obese mice exhibited significantly higher prostate contractions compared to lean mice.
- MK571 treatment significantly reduced prostate contractions and improved relaxation in obese mice, restoring levels similar to lean mice.
- MK571 treatment increased both cAMP and cGMP levels in obese mice, with cGMP restoration being particularly notable.
Conclusions:
- MRP inhibition, specifically with MK571, effectively reverses prostate hypercontractility in diet-induced obesity.
- The mechanism involves promoting the accumulation of cGMP, leading to enhanced smooth muscle relaxation.
- Targeting MRPs represents a potential therapeutic strategy for managing prostate dysfunction associated with obesity.
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