Parasympathetic overdrive as a cause of overactive bladder in a high-fat-diet-induced obesity mouse model

Overactive bladder (OAB) is a highly prevalent condition characterized by urinary urgency that negatively affects quality of life. Because obesity and metabolic syndrome (MetS) are known as major risk factors for OAB, we explored the mechanisms underlying obesity-/MetS-associated OAB using a high-fat-diet (HFD)-induced obesity mouse model. Four-week-old male C57BL6 mice were subjected to either a HFD (60 kcal% fat) or a normal diet (ND, 10 kcal% fat). Cystometry and bladder afferent activity recordings in anaesthetized mice, isometric tension recordings in detrusor smooth muscle (DSM) strips and intravesical pressure recordings in isolated whole bladders were performed after 12 weeks of ND or HFD feeding. Bladder morphology was examined using histochemistry. HFD mice exhibited a MetS phenotype characterized by abdominal obesity, hyperglycaemia and insulin resistance. HFD mice developed enlarged non-voiding contractions (NVCs) during bladder filling associated with enhanced afferent activity. Both were attenuated by intravenous administration of atropine (1 mg/kg) or pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), a P2X purinoceptor antagonist (10 mg/kg), or by bilateral pelvic nerve transection. In ND mice these drugs attenuated NVCs but not afferent activity. Spontaneous or nerve-evoked DSM contractions or transient pressure increases in isolated whole bladders were unaltered in HFD mice. DSM thickness, collagen deposition or parasympathetic nerve density in HFD bladders was unaltered. Thus the OAB phenotype in HFD mice appears to primarily results from the increased parasympathetic neural activity during the bladder storage phase. These results provide the basis of the clinical effectiveness of anti-muscarinic agents on OAB as well as the enhanced purinergic transmission in OAB patients known as 'atropine resistance'. KEY POINTS: High-fat-diet (HFD)-induced obese mice exhibiting metabolic syndrome phenotype display overactive bladder (OAB) phenotype characterized by enlarged non-voiding contractions (NVCs) associated with bladder afferent overactivity. Both enlarged NVCs and afferent overactivity in HFD mice are reversed by intravenous administration of atropine or the P2X receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), or by bilateral pelvic nerve transection. Detrusor muscle strip contractility, corresponding spontaneous pressure increases in isolated whole bladder and bladder morphology are unaltered in HFD mice. The OAB phenotype in HFD-induced obese mice primarily results from excessive parasympathetic activity during the bladder storage phase. These findings provide a basis for the clinical effectiveness of anti-muscarinic drugs on bladder storage symptoms as well as the relevance of enhanced purinergic transmission in OAB patients known as 'atropine resistance'.