Protective effects of hydrogen sulfide pretreatment on cyclophosphamide-induced bladder dysfunction in rats via suppression of bladder afferent nerves

Cyclophosphamide (CYP), a broad-spectrum anticancer drug, causes serious side effects, such as haemorrhagic cystitis (HC). Hydrogen sulfide (H2S), an endogenous gasotransmitter, has physiological properties, including anti-inflammation, anti-oxidation, and neuromodulation. In this study, we investigated the effects of NaHS (H2S donor) pretreatment on bladder dysfunction in CYP-treated rats. Male Wistar rats were intraperitoneally pre-treated with NaHS (3 or 10 mu mol/kg) or vehicle once daily for 7 days before cystometry, and CYP (150 mg/kg) or saline was intraperitoneally administered 2 days before cystometry. After cystometry, the bladder tissues were collected for haematoxylin and eosin staining. In some rats, capsaicin (CAP), which can desensitise CAP-sensitive afferent nerves, was subcutaneously injected at 125 mg/kg 4 days before cystometry. CYP reduced intercon-traction intervals (ICI) and bladder compliance (Comp) and increased the number of non-voiding contractions (NVCs) compared with the saline-treated control group. NaHS pretreatment dose-dependently improved the CYP-induced these changes. In bladder tissues, CYP increased histological scores of neutrophil infiltration, haemor-rhage, and oedema, while NaHS had no effect on these CYP-induced changes. CAP showed a tendency to suppress CYP-induced changes in ICI. NaHS-induced improvement in CYP-induced changes in urodynamic parameters were not detected in CAP-treated rats. These findings suggest that NaHS pretreatment prevented bladder dysfunction in CYP-treated rats by suppressing CAP-sensitive bladder afferent nerves, but not by suppressing bladder inflammation. Therefore, H2S represents a new candidate as a protective drug for bladder dysfunction induced by HC, a side effect of CYP chemotherapy.

Automated summary

In this study, it was found that hydrogen sulfide pretreatment can prevent bladder dysfunction caused by cyclophosphamide treatment by suppressing the activity of bladder afferent nerves, rather than by inhibiting bladder inflammation. Therefore, hydrogen sulfide may be a new candidate as a protective drug for bladder dysfunction induced by cyclophosphamide chemotherapy.