Monotherapy with tolterodine or mirabegron is insufficient for ameliorating cyclophosphamide-induced bladder overactivity in rats

Abstract

Monotherapy continues to be the most common pharmacological treatment option for patients with overactive bladder (OAB), despite evidence indicating that it may have inferior efficacy compared to combination therapy. This seems to be especially true for patients with concomitant cystitis. The current study examined the effects of monotherapy with either the antimuscarinic tolterodine or the β3 agonist mirabegron on bladder overactivity induced by bladder inflammation. Further, the possible involvement of nitric oxide (NO) was studied. For this purpose, rats were pretreated with either drug for 10 days. Bladder inflammation was induced by intraperitoneal injection with cyclophosphamide, with saline serving as control. Micturition parameters were assessed in a metabolic cage. Meanwhile, urine samples were collected and further analysed for NO content. After 16 h, the animals were euthanized, and their bladders were excised and examined immunohistochemically for signs of inflammation. Cyclophosphamide treatment led to bladder overactivity and obvious signs of inflammation. Neither treatment with tolterodine nor mirabegron could significantly alleviate the induced overactivity or the observed inflammation. Further, while induction of inflammation led to a significant increase in NO production, neither drug seemed to act by further enhancing its production. On the contrary, treatment with either tolterodine or mirabegron significantly decreased NO production in cyclophosphamide treated rats. Considering previous findings showing significant improvement by combination therapy, the current study indirectly implies this as the superior treatment option. Further studies are needed to verify the involvement, or lack thereof, of NO in the mechanism of action of drugs used to treat OAB.