Effects of TAK‐802, a novel acetylcholinesterase inhibitor, and tamsulosin, an α₁‐adrenoceptor antagonist, and their synergistic effects on the urodynamic characteristics in a guinea‐pig model of functional bladder outlet obstruction

Abstract

RESULTSContinuous intravenous infusion of phenylephrine, an a 1 -adrenoceptor agonist (1-6 m g/animal/min), dose-dependently decreased the Q max and voiding efficiency, and increased the P vesmax and P ves Q max , possibly by constricting urethral smooth muscle. In this functional urethral constriction model, both TAK-802 at 1 and 10 m g/kg and tamsulosin at 3 and 10 m g/kg (intravenously) caused increasing effects on the Q max and voiding efficiency. The effects were more apparent with combined exposure. Although the P vesmax was dose-dependently increased by TAK-802 alone, the effects were completely abolished by concomitant treatment with tamsulosin. CONCLUSIONThese results suggest that TAK-802 and tamsulosin have synergistic effects in increasing the Q max and voiding efficiency, and TAK-802 does not inhibit the decreasing effect of tamsulosin on urethral resistance. That TAK-802 increased P ves when administered alone implies that monotherapy using an acetylcholinesterase inhibitor should be withheld in patients with voiding dysfunction caused by obvious bladder outlet obstruction with benign prostatic hyperplasia, to avoid disorders of the upper urinary tracts, and it should be used with an a 1 -adrenoceptor antagonist. Whether TAK-802 combined with an a 1 -adrenoceptor antagonist confers additional clinical benefit is not yet known. KEYWORDSTAK-802, tamsulosin, acetylcholinesterase inhibitor, a 1 -adrenoceptor antagonist, urodynamics, guinea pig OBJECTIVETo investigate the effects of TAK-802, a potent acetylcholinesterase inhibitor, and tamsulosin, an a 1 -adrenoceptor antagonist, and their concomitant administration on the urodynamic characteristics in a guinea-pig model of functional bladder outlet obstruction. MATERIALS AND METHODSCystometry was performed in urethaneanaesthetized guinea pigs, and various urodynamic variables, including the maximum flow rate (Q max ), voiding efficiency, maximum intravesical pressure (P vesmax ) and intravesical pressure at Q max (P ves Q max ), were measured before and after administration of the drugs in combination and alone.

Rodent models for urodynamic investigation

“…On the other hand, thicker catheters may cause irritation in small bladders, but are more resistant to damage due to biting and to occlusion, and also are less likely to twist, especially in cystometries with freely moving animals. PE‐10 is usually used in mice studies,10, 18 in rats PE‐10,19 PE‐50,20–24 PE‐60,25 PE‐90,26, 27 and PE‐100,28 have been used, and for guinea pigs, PE‐100 or thicker tubing is employed 15, 29. For cystometry in anesthetized animals, the catheter can be inserted either via the urethra or via the bladder, and in this case, it can be externalized suprapubically.…”

Effect of Selective Prostaglandin E2 EP2 Receptor Agonist CP‐533,536 on Voiding Efficiency in Rats with Midodrine‐Induced Functional Urethral Obstruction

“…Nagabukuro et al reported that an intravenous infusion of phenylephrine induced a dose‐dependent decrease in VE in guinea pigs, suggesting that stimulation of α 1 ‐adrenoceptors causes voiding dysfunction via functional urethral constriction. Given our findings that intravenous administration of midodrine most likely elevated UPP in rats due to urethral constriction, we attempted to induce voiding dysfunction via midodrine administration to cause functional urethral constriction in conscious rats.…”

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

“…Previously, we examined the urodynamics and effects of α 1 -AR antagonist in a hormone-induced BPH rat model using PFS [23], and another group reported that pressure flow characteristics were used to evaluate the severity of bladder outlet obstruction (BOO) induced by the α 1 -AR agonist, phenylephrine, in guinea pigs [28]. These models focused mainly on obstructive symptoms.…”