Serotonin (5‐HT)2A/2C receptor agonist (2,5‐dimethoxy‐4‐idophenyl)‐2‐aminopropane hydrochloride (DOI) improves voiding efficiency in the diabetic rat

Abstract

ObjectivesTo examine the effects of the serotonin (5-HT)2A/2C receptor agonist (2,5-dimethoxy-4-idophenyl)-2-aminopropane hydrochloride (DOI) on micturition in rats with diabetes mellitus (DM). MethodsFemale Sprague-Dawley rats (n = 16) were divided into two groups: rats with Type 1 DM and age-matched control rats. DM was induced by i.p. injection of streptozotocin (65 mg/ kg) and detailed cystometrogram (CMG) studies were performed 8 weeks post-injection in all rats under urethane anaesthesia. The selective 5-HT2A antagonist ketanserin was administered after each DOI dose-response curve was plotted. All drugs were administered i.v. ResultsCompared with controls, comprehensive urodynamic studies showed that DM rats had a higher bladder capacity and post-void residual urine volume (PVR), and a markedly lower voiding efficiency. In DM rats, DOI (0.01-0.3 mg/kg) induced significant dose-dependent increases in micturition volume and reductions in PVR, resulting in greater voiding efficiency. CMG measurements showed a dose-dependent increase in high-frequency oscillation (HFO) activity, evidenced by an increased duration of HFOs per voiding. This correlated with the improved voiding efficiency. Ketanserin (0.1 mg/kg) partially or completely reversed the DOI-induced changes. ConclusionsThe HFOs observed in the present study seem to correlate with external urethral sphincter bursting activity during voiding. Bladder voiding efficiency was reduced in DM rats. The 5-HT2A receptor agonist can enhance HFO activity and improves voiding efficiency, and so may represent a new strategy to improve voiding efficiency after DM in experimental studies.

A systematic review of urinary bladder hypertrophy in experimental diabetes: Part 2. Comparison of animal models and functional consequences

“…Similar to voided volume in behavioral studies (see section 5.1), mean micturition volume was also increased in cystometric studies and normalized after insulin treatment . Micturition volume was also increased in Brattleboro rats .…”

“…This has been assessed more directly in cystometric studies, which have been performed in vivo in anesthetized and, in some cases, in conscious animals 34,38,39 and with isolated bladders in vitro. [40][41][42] Similar to voided volume in behavioral studies (see section 5.1), mean micturition volume was also increased in cystometric studies 29,38,39,[43][44][45][46] and normalized after insulin treatment. 29,38,47 Micturition volume was also increased in Brattleboro rats.…”

“…This was confirmed consistently in cystometric studies. 29,31,34,35,38,39,41,[44][45][46][47][48]50 Time course studies have shown that BC is increased as early as 1 week after STZ injection and does not increase substantially thereafter for up to 8 months, 34,35,50 which is in line with maximum BW at this time point. 4 Treatment with insulin largely restored BC 38,45,50 and a partial restoration was also reported with NGF gene transfer.…”

“…A greater compliance in functional studies fits the anatomical finding of reduced collagen content (see part III of series), as the latter is relevant for structural stability of the bladder. 51 While there have been exceptions in either direction, basal pressure, 38,39,45,46,48 threshold pressure, 34,35,38,39,45,48 and peak pressure 29,35,38,39,43,[45][46][47][48] were largely reported to be similar in STZ-treated and control rats. In studies where micturition pressure increased in T1DM, it was normalized by treatment with insulin.…”

“…28,34,35,38,43,44,46 PVR may worsen with duration of diabetes. 34 On the other hand, it can be normalized by treatment with insulin 38,46 or NGF gene transfer. 35 Voiding efficiency, that is, the ratio between voided volume and BC, is the flipside of PVR.…”