Journal List > Korean J Urol > v.48(10) > 1004799

Kim, Hwang, and Kim: The Effect of Muscarinic Receptor Subtype Antagonists on Detrusor Overactivity Induced by Bladder Outlet Obstruction in Rats

Abstract

Purpose

We studied the role of the muscarinic receptor subtype on the urothelium and detrusor activity in rats with detrusor overactivity induced by bladder outlet obstruction (BOO).

Materials and Methods

Forty Sprague-Dawley rats were used for this study. They were divided into 15 controls and 25 experimental rats. Partial BOO was induced for 3 weeks and a sham operation was performed on the control group animals. A cystometrogram (CMG) was performed in 20 BOO and 10 control rats. During the CMG, M2 selective muscarinic receptor antagonist (methoctramine) and nonselective muscarinic receptor antagonist (tolterodine) drugs were administrated intravesically. The contraction intervals and pressure were evaluated. Bladder muscle strips were prepared from five BOO and five control rats. The contractile responses were evaluated at 2-, 4-, 8-, 16-, and 32Hz field stimulation in the control and BOO groups and after administration of the methoctramine and tolterodine.

Results

The results of the CMG showed that the rats in the BOO group had a decreased contraction interval and increased contraction pressure compared to the control group (p<0.05). The contraction intervals were increased after intravesical administration of methoctramine and tolterodine compared to the BOO group (p<0.05). However, the contraction pressures were similar among the methoctramine, tolterodine and BOO groups. For the muscle strip study, the BOO group demonstrated increased contractile responses compared to the control group (p<0.05). However, the contractile responses were decreased after administration of methoctramine (only in 32Hz) and tolterodine (p<0.05).

Conclusions

The results of this study showed that detrusor overactivity induced by BOO in rats is primarily mediated by M3 muscarinic receptors in the detrusor muscle, and by M2 and M3 muscarinic receptors in the urothelium.

Figures and Tables

Fig. 1
The changes of bladder weight in the controls and bladder outlet obstruction. The bladder weight of the BOO group was significantly higher than that of control group. The data were expressed as mean±SEM. *: p<0.05 as compared with control, BOO: bladder outlet obstruction.
kju-48-1044-g001
Fig. 2
The changes of the contraction interval in the control, BOO, methoctramine, and tolterodine group. The contraction interval in the BOO group decreased significantly compared with the control group. However, the contraction interval of methoctramine and tolterodine treated group increased compared with the BOO group. The data were expressed as mean±SEM. *: p<0.05 as compared with control group, : p<0.05 as compared with BOO group, : p<0.05 as compared with methoctramine group, BOO: bladder outlet obstruction.
kju-48-1044-g002
Fig. 3
The changes of contraction pressure in the control, BOO, methoctramine, and tolterodine group. The contraction pressure of the BOO group increased significantly compared with the control group. The contraction pressure of the methoctramine and tolterodine treated group was similar to the BOO group. The data were expressed as mean±SEM. *: p<0.05 as compared with control group, BOO: bladder outlet obstruction.
kju-48-1044-g003
Fig. 4
The contractile response of the bladder muscle strip to 2-, 4-, 8-, 16-, and 32Hz field stimulation in the control, obstruction, methoctramine, and tolterodine group. The data were expressed as mean±SEM. *: p<0.05 as compared with control group, : p< 0.05 as compared with BOO group, : p<0.05 as compared with methoctramine group, BOO: bladder outlet obstruction.
kju-48-1044-g004

References

1. de Groat WC, Yoshimura N. Pharmacology of the lower urinary tract. Annu Rev Pharmacol Toxicol. 2001. 41:691–721.
2. Schneider T, Fetscher C, Krege S, Michel MC. Signal transduction underlying carbachol-induced contraction of human urinary bladder. J Pharmacol Exp Ther. 2004. 309:1148–1153.
3. Kumar V, Cross RL, Chess-Williams R, Chapple CR. Recent advances in basic science for overactive bladder. Curr Opin Urol. 2005. 15:222–226.
4. Igawa Y. Discussion: functional role of M1, M2, and M3 muscarinic receptors in overactive bladder. Urology. 2000. 55(5A):Suppl. 47–49.
5. Chapple CR, Yamanishi T, Chess-Williams R. Muscarinic receptor subtypes and management of the overactive bladder. Urology. 2002. 60:Suppl 5A. 82–89.
6. Braverman AS, Tallarida RJ, Ruggieri MR Sr. Interaction between muscarinic receptor subtype signal transduction pathways mediating bladder contraction. Am J Physiol Regul Integr Comp Physiol. 2002. 283:R663–R668.
7. Lewis SA. Everything you wanted to know about the bladder epithelium but were afraid to ask. Am J Physiol Renal Physiol. 2000. 278:F867–F874.
8. de Groat WC. The urothelium in overactive bladder: passive bystander or active participant? Urology. 2004. 64(6):Suppl 1. 7–11.
9. Kim Y, Yoshimura N, Masuda H, de Miguel F, Chancellor MB. Antimuscarinic agents exhibit local inhibitory effects on muscarinic receptors in bladder-afferent pathways. Urology. 2005. 65:238–242.
10. Yoshida M, Inadome A, Maeda Y, Satoji Y, Masunaga K, Sugiyama Y, et al. Non-neuronal cholinergic system in human bladder urothelium. Urology. 2006. 67:425–430.
11. Wefer J, Truss MC, Jonas U. Tolterodine: an overview. World J Urol. 2001. 19:312–318.
12. Yono M, Yoshida M, Takahashi W, Inadome A, Ueda S. Comparison of the effects of novel antimuscarinic drugs on human detrusor smooth muscle. BJU Int. 2000. 86:719–725.
13. Yokoyama O, Yusup A, Miwa Y, Oyama N, Aoki Y, Akino H. Effects of tolterodine on an overactive bladder depend on suppression of C-fiber bladder afferent activity in rats. J Urol. 2005. 174:2032–2036.
14. Igawa Y, Zhang X, Nishizawa O, Umeda M, Iwata A, Taketo MM, et al. Cystometric findings in mice lacking muscarinic M2 or M3 receptors. J Urol. 2004. 172:2460–2464.
15. Krichevsky VP, Pagala MK, Vaydovsky I, Damer V, Wise GJ. Function of M3 muscarinic receptors in the rat urinary bladder following partial outlet obstruction. J Urol. 1999. 161:1644–1650.
16. Yamanishi T, Chapple CR, Yasuda K, Chess-Williams R. The role of M2 muscarinic receptorsubtypes in mediating contraction of the pig bladder base after cyclic adenosine monophosphate elevation and/or selective M3 inactivation. J Urol. 2002. 167:397–401.
17. Braverman AS, Ruggieri MR Sr. Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M3 toward M2. Am J Physiol Regul Integr Comp Physiol. 2003. 285:R701–R708.
18. Braverman AS, Luthin GR, Ruggieri MR. M2 muscarinic receptor contributes to contraction of the denervated rat urinary bladder. Am J Physiol. 1998. 275:1654–1660.
19. Pontari MA, Braverman AS, Ruggieri MR Sr. The M2 muscarinic receptor mediates in vitro bladder contractions from patients with neurogenic bladder dysfunction. Am J Physiol Regul Integr Comp Physiol. 2004. 286:R874–R880.
20. Giglio D, Delbro DS, Tobin G. On the functional role of muscarinic M2 receptors in cholinergic and purinergic responses in the rat urinary bladder. Eur J Pharmacol. 2001. 428:357–364.
TOOLS
Similar articles