Inhibition of multidrug resistance proteins by MK571 restored the erectile function in obese mice through cGMP accumulation

Author(s)

de Oliveira, Mariana Goncalves ; Passos, Gabriela Reolon ; de Gomes, Erick de Toledo ; Leonardi, Guilherme Ruiz ; Zapparoli, Adriana ; Antunes, Edson ; Monica, Fabiola Zakia

• Document type: Journal article
• Source: ANDROLOGY; v. 11, n. 3, p. 10-pg., 2022-11-25.

Abstract

BackgroundIntracellular levels of cyclic nucleotides can also be controlled by the action of multidrug resistance protein types 4 (MRP4) and 5 (MRP5). To date, no studies evaluated the role of their inhibition in an animal model of erectile dysfunction (ED). ObjectivesTo evaluate the effect of a 2-week treatment with MK571, an inhibitor of the efflux of cyclic nucleotides in the ED of obese mice. Materials and methodsMice were divided in three groups: (i) lean, (ii) obese, and (iii) obese + MK571. The corpus cavernosum (CC) were isolated, and concentration-response curves to acetylcholine (ACh), sodium nitroprusside (SNP), and tadalafil in addition to electrical field stimulation (EFS) were carried out in phenylephrine pre-contracted tissues. Expression of ABCC4 and ABCC5, intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), the protein levels for pVASP(Ser157) and pVASP(Ser239), and the intracavernous pressure (ICP) were also determined. The intracellular and extracellular (supernatant) ratios in CC from obese and lean stimulated with a cGMP-increasing substance (BAY 58-2667) in the absence and presence of MK571 (20 mu M, 30 min) were also assessed. ResultsThe treatment with MK571 completely reversed the lower relaxing responses induced by EFS, ACh, SNP, and tadalafil observed in obese mice CC in comparison with untreated obese mice. Cyclic GMP and p-VASP(Ser239) expression were significantly reduced in CC from obese groups. MK571 promoted a sixfold increase in cGMP without interfering in the protein expression of p-VASP(Ser239). Neither the cAMP levels nor p-VASP(Ser157) were altered in MK571-treated animals. The ICP was similar to 50% lower in obese than in the lean mice; however, the treatment with MK571 fully reversed this response. Expressions of ABCC4 and ABCC5 were not different between groups. The intra/extracellular ratio of cGMP was similar in CC from obese and lean mice stimulated with BAY 58-2667. ConclusionsThe MRPs inhibition by MK571 favored the accumulation of cGMP in the smooth muscle cells, thus improving the smooth muscle relaxation and the erectile function in obese mice. (AU)

• FAPESP's process: 18/09765-3 - Voiding and prostatic dysfunction in middle-aged rats and obese mice: focus on NADPH oxidase (NOX)
• Grantee: Mariana Gonçalves de Oliveira Taranto
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/21880-2 - Characterization of the periprostatic adipose tissue and its effect in the functional activity of the prostate from obese mice treated or not with mirabgron, a beta-3 adrenoceptor agonist.
• Grantee: Fabíola Taufic Monica Iglesias
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/15175-1 - Modulation of soluble guanylate cyclase and the intracellular levels of cyclic nucleotides in the lower urinary tract and prostate
• Grantee: Edson Antunes
• Support Opportunities: Research Projects - Thematic Grants