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Abstract
Purpose
Adenosine triphosphate (ATP) from the urothelium acts as a sensory neurotransmitter and is augmented in many diseases, such as overactive bladder. We investigated the effects of intravesical instillation of oxybutynin on ATP-induced bladder overactivity to determine whether this effect is mediated by effects on urothelial muscarinic receptors.
Materials and Methods
Cystometry (at rate of 0.04 ml/min) was performed in female Sprague-Dawley rats (body weight 250 g) under urethane anesthesia (1.2 g/kg). After a 2-hour baseline period, protamine sulfate (10 mg/ml) was instilled for 1 hour, and then ATP (60 mM, pH 6.0) or a mixture of oxybutynin (10-6 M) and ATP (60 mM, pH 6.0) was instilled intravesically. We performed experiments with 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP) and methoctramine by the same methods. Cystometric parameters, such as the intercontraction interval (ICI), pressure threshold (PT), and maximal voiding pressure (MVP), were compared.
Results
With intravesical instillation of ATP after protamine sulfate treatment, the ICI was decreased compared with baseline (ICI: baseline, 487.1±64.8 s; protamine, 450.6±56.1 s; ATP, 229.7±35.3 s; p<0.05). Addition of oxybutynin, 4-DAMP, or methoctramine in the ATP solution did not significantly change the ICI compared with ATP solution alone (ICI: oxybutynin, 189.1±32.3 s; 4-DAMP, 161.1±22.8 s; methoctramine, 341.0±113.3 s; p>0.05). Intravesical instillation of ATP decreased MVP and PT significantly compared with baseline, but MVP and PT were not changed significantly with oxybutynin, 4-DAMP, or methoctramine compared with ATP.
Figures and Tables
Fig. 1
Typical cystometric findings. ICI decreased with intravesical ATP, but antimuscarinics did not affect the ATP-induced decrease in the ICI. (A) Oxybutynin, (B) 4-DAMP, (C) Methoctramine. ICI: intercontraction interval, ATP: adenosine triphosphate, 4-DAMP: 4-diphenylacetoxy-N-methylpiperidine methobromide.
Fig. 2
Changes in the ICI with intravesical instillation of saline, protamine, ATP, and mixtures of ATP and antimuscarinics. The ICI was significantly decreased with intravesical instillation of ATP. Addition of oxybutynin, 4-DAMP, or methoctramine to the ATP solution did not significantly change the ICI compared with ATP solution alone. ICI: intercontraction interval, ATP: adenosine triphosphate, 4-DAMP: 4-diphenylacetoxy-N-methylpiperidine methobromide. a: p<0.05 vs. saline.
References
1. Herbison P, Hay-Smith J, Ellis G, Moore K. Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. BMJ. 2003. 326:841–844.
2. Ford AP, Gever JR, Nunn PA, Zhong Y, Cefalu JS, Dillon MP, et al. Purinoceptors as therapeutic targets for lower urinary tract dysfunction. Br J Pharmacology. 2006. 147:Suppl 2. S132–S143.
3. Andersson KE, Chapple CR. Oxybutynin and the overactive bladder. World J Urol. 2001. 19:319–323.
4. Uchida S, Kurosawa S, Fujino Oki T, Kato Y, Nanri M, Yoshida K, et al. Binding activities by propiverine and its N-oxide metabolites of L-type calcium channel antagonist receptors in the rat bladder and brain. Life sci. 2007. 80:2454–2460.
5. Yoshimura N. Lower urinary tract symptoms (LUTS) and bladder afferent activity. Neurourol Urodyn. 2007. 26:Suppl 6. 908–913.
6. Yoo JS, Kim JC, Hwang TK. Predictors of antimuscarinic treatment response for female patients with overactive bladder. Korean J Urol. 2007. 48:66–71.
7. Chapple CR, Roehrborn CG. A shifted paradigm for the further understanding, evaluation, and treatment of lower urinary tract symptoms in men: focus on the bladder. Eur Urol. 2006. 49:651–658.
8. de Groat WC. The urothelium in overactive bladder: passive bystander or active participant? Urology. 2004. 64:6 Suppl 1. 7–11.
9. Yoshida M, Miyamae K, Iwashita H, Otani M, Inadome A. Management of detrusor dysfunction in the elderly: changes in acetylcholine and adenosine triphosphate release during aging. Urology. 2004. 63:3 Suppl 1. 17–23.
10. 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.
11. Andersson KE. Bladder activation: afferent mechanisms. Urology. 2002. 59:5 Suppl 1. 43–50.
12. Namasivayam S, Eardley I, Morrison JF. Purinergic sensory neurotransmission in the urinary bladder: an in vitro study in the rat. BJU Int. 1999. 84:854–860.
13. Khera M, Somogyi GT, Kiss S, Boone TB, Smith CP. Botulinum toxin A inhibits ATP release from bladder urothelium after chronic spinal cord injury. Neurochem Int. 2004. 45:987–993.
14. Andersson KE. Treatment-resistant detrusor overactivity-underlying pharmacology and potential mechanisms. Int J Clin Pract. 2006. 151:Suppl. 8–16.
15. Kachur JF, Peterson JS, Carter JP, Rzeszotarski WJ, Hanson RC, Noronha-Blob L. R and S enantiomers of oxybutynin: pharmacological effects in guinea pig bladder and intestine. J Pharmacol Exp Ther. 1988. 247:867–872.
16. De Wachter S, Wyndaele JJ. Intravesical oxybutynin: a local anesthetic effect on bladder C afferents. J Urol. 2003. 169:1892–1895.
17. Sugiyama Y, Yoshida M, Masunaga K, Satoji Y, Maeda Y, Nagata T, et al. Pharmacological effects of propiverine and its active metabolite, M-1, on isolated human urinary bladder smooth muscle, and on bladder contraction in rats. Int J Urol. 2008. 15:76–81.
18. Kim YT, Kim SJ, Lee JW, Kim DK, Kim HK, Son YW, et al. Effects of intravenous oxybutynin on bladder overactivity induced by intravesical instillation of adenosine triphosphate in rats. J Urol. 2008. 180:Suppl. 153.
19. Kim SJ, Mon HS, Choi HY, Kim YT. Characteristics of detrusor overactivity induced by intravesical instillation of adenosine 5'-triphosphate. Korean J Urol. 2008. 49:424–431.
20. Kullmann FA, Artim DE, Birder LA, de Groat WC. Activation of muscarinic receptors in rat bladder sensory pathways alters reflex bladder activity. J Neurosci. 2008. 28:1977–1987.
21. Kullmann FA, Artim D, Beckel J, Barrick S, de Groat WC, Birder LA. Heterogeneity of muscarinic receptor-mediated Ca2+ responses in cultured urothelial cells from rat. Am J Physiol Renal Physiol. 2008. 294:F971–F981.
22. Nishiguchi J, Hayashi Y, Chancellor MB, de Miguel F, de Groat WC, Kumon H, et al. Detrusor overactivity induced by intravesical application of adenosine 5'-triphosphate under different delivery conditions in rats. Urology. 2005. 66:1332–1337.
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