Modulation of soluble guanylate cyclase-cyclic guanosine monophosphate (sGC-cGMP) pathway by hydrogen sulphide (H2S) in experimental Cystitis

Abstract

Interstitial Cystitis or Bladder Pain Syndrome (IC/BPS) is a chronic painful inflammatory disease, which affects 2-17% of the world population, and is characterized by pelvic pressure, voiding urgency and frequency. Although the mechanisms that leads to its development are not well established, it is known that both the expression of the subunits of the soluble Guanylate Cyclase enzyme (sGC) and the intracellular concentration of cyclic guanosine monophosphate (cGMP) is reduced in the bladder tissue of mice with cystitis, indicating an oxidized state (Fe3 +) of sGC. It is considered that the new gaseous mediator, hydrogen sulfide (H2S), favors the conversion of (Fe3+) from sGC to its reduced state (Fe2+), thus been able to regulate the GCs-cGMP pathway and the effects promoted by Nitric Oxide (NO). Considering that the intracellular concentration of cGMP is reduced in IC/BPS, given the inactivity of the oxidized state of GCs, it is plausible to suggest that therapy with H2S donors would restore the activity of the GCs-cGMP complex. This project aims to: I) to characterize functional, inflammatory and nociceptive parameters in the experimental model of IC/BPS induced by cyclophosphamide (CYP) in C57Bl/6 mice of both sexes, as well as to evaluate the pharmacological influence of different classes of H2S donors (slow [GYY4137] and hybrid with non-steroidal anti-inflammatory drug [ATB-352]); II) assess whether the chemical deletion of endogenous H2S, via treatment with a synthesis inhibitor (aminooxyacetate acid), enhances the functional, inflammatory and nociceptive changes observed in the IC/BPS murine model; III) investigate the functional activity (relaxing or contractile) of H2S donors molecules or H2S synthesis inhibitor in isolated organ (urethra and bladder) of naive mice and with IC/BPS and, IV) characterize the intracellular signaling pathway involved in the activation of the sGCs-cGMP complex and the correlation with the production of H2S and the main enzymes involved in its synthesis (cystathionine gamma-lyase, cystathionine beta synthase) in tissues (bladder, urethra) of mice with IC/BPS submitted to pharmacological treatments with H2S donors (or synthesis inhibitor). It is believed that the knowledge from this project will contribute to a better understanding of the mechanisms involved in IC/BPS, in addition to stimulating new therapeutic potential for IC/BPS. (AU)