Effects of Silodosin, an α_1A-Adrenoceptor Antagonist, and Distigmine, an Acetylcholinesterase Inhibitor, and Their Combined Effects on Impaired Voiding Function in Zucker Diabetic Fatty Rats

Abstract

Background/Aims: To evaluate the effects of silodosin (α_1A-adrenoceptor antagonist) and distigmine (acetylcholinesterase inhibitor), alone or in combination, on voiding dysfunction in Zucker diabetic fatty (ZDF) rats, a type 2 diabetes model, by pressure flow study. Methods: Male ZDF rats were anesthetized with urethane and a catheter was implanted into the bladder through the dome. Saline was continuously infused into the bladder at 6 ml/h to induce the micturition reflex. Intravesical pressure and micturition volume were recorded continuously and various urodynamic parameters were calculated using a waveform analysis system. Results: Increased bladder capacity, residual volume, and urethral resistance and decreased maximum detrusor contraction velocity and urine flow rate, considered to be detrusor underactivity-like symptoms, were observed in ZDF rats. Although both silodosin and distigmine improved impaired voiding function, administration of both drugs in combination was more effective than either drug alone. Conclusions: ZDF rats showed symptoms suggestive of detrusor underactivity, and silodosin tended to ameliorate these symptoms in ZDF rats. These results suggested that an α_1A-adrenoceptor antagonists may be effective against the voiding disorder accompanying not only bladder outlet obstruction but also deficiency of bladder function. Moreover, combined administration of an α_1A-adrenoceptor antagonist with an acetylcholinesterase inhibitor may have additive efficacy in clinical use.

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

“…Among T2DM models with high blood glucose levels, expected to lead to major diuresis, ZDF rats, Akita mice, and db/db mice have been tested in cystometric studies. Similar to the T1DM models, ZDF rats exhibited increased BC and PVR and a markedly reduced voiding efficiency . Acute administration of the α 1A ‐adrenoceptor antagonist silodosin did not markedly alter these three parameters, and the acetylcholinesterase inhibitor distigmine had inconclusive effects; combination of silodosin and distigmine, however, reduced BC and PVR and increased voiding efficiency.…”

“…Similar to the T1DM models, ZDF rats exhibited increased BC and PVR and a markedly reduced voiding efficiency. 25 Acute administration of the α 1A -adrenoceptor antagonist silodosin did not markedly alter these three parameters, and the acetylcholinesterase inhibitor distigmine had inconclusive effects; combination of silodosin and distigmine, however, reduced BC and PVR and increased voiding efficiency. Akita mice also exhibited an elevated BC and PVR, irrespective whether they had undergone extended infusion with angiotensin II.…”

Effects of Distigmine on the Mechanical Activity of Urinary Bladder Smooth Muscle

“…In recent years, however,ONO-8055,anagonistoftheprostanoidEP 2 and EP 3 receptors, was reported to be effective in a radical hysterectomy-induced underactive monkey bladder model. 27) Thus, prostanoid receptor-related drugs may prove to be efficacious therapeutic agents for the management of underactive bladder.…”

“…In recent years, distigmine efficacy was validated with various animal disease models. [27][28][29] The therapeutic effect of distigmine in the management of urinary disorders is explained by its ChE inhibition. This mechanism enhances the contractile force of the urinary bladder smooth muscle (UBSM) by increasing the concentration of acetylcholine (ACh) in the synaptic cleft between the parasympathetic nerve terminal and the UBSM.…”

Pathophysiology of the underactive bladder

“…This DM model is relatively guaranteed the experimental reproducibility with higher glucose blood level, but simultaneously needs to pay attention to the differentiation from the influence of polyuria, which can be distinguished by sucrose-induced polyuria animal model [ 63 ]. Moreover, genetical DM animals have long been used and recognized as mild DM model, which may be similar to type II DM in human [ 79 80 81 82 83 ].…”