Hypothesis / aims of study
The aims of this study, in an experimental animal model of bladder outlet obstruction (BOO), is to determine the mechanisms of action of the alpha 1-blocker, naftopidil by investigating a possible association between bladder functions and intravesically released prostaglandin E2 (PGE2) or adenosine 5’-triphosphate (ATP), and a possible association between the effects of naftopidil and resiniferatoxin (RTX)-sensitive C fibers or transient receptor potential cation channel V1 (TRPV1), which is the site of action of RTX.
Study design, materials and methods
Thirty-five rats were randomly divided into the sham or BOO groups, and rats in each group were given vehicle or RTX (0.3 mg/kg) subcutaneously 3 days before cystometry to determine the effect of desensitization of TRPV1 on changes in the level of intravesical ATP or PGE2 induced by BOO. Incomplete urethral ligation was applied to the BOO group, and the other group underwent sham surgery under anesthesia with halothane. Filling cystometry was performed in the conscious condition 5 weeks after the operation. Cystometry was repeated at least three times and determine the BC. Levels of ATP and PGE2 were measured in the instilled perfusate that was collected at 30% and 80% bladder capacity (BC). After then, naftopidil, 1 mg/kg, was administered intravenously in BOO rats at the start of the second session of cystometry. The BC was determined with the same method as mentioned above. Levels of ATP and PGE2 were measured again. The bladders were then removed and weighed. Differences were analyzed by the Mann-Whitney U test or Wilcoxon signed-rank test. P< 0.05 was considered to indicate a significant difference.
Interpretation of results
Intravesically administered PGE2 or α,β-methylene ATP is known to induce detrusor overactivity. BOO enlarged BC, induced the enhancement of NVCs and increased intravesically released amount of PGE2 and ATP, however, RTX also enlarged BC and enhanced NVCs without increase in intravesical levels of PGE2 and ATP. Therefore, NVCs in BOO rats were considered to be associated with the increase in BC, i.e., the bladder wall distension.
Naftopidil increased BC without the RTX treatment but not increase BC with the treatment. This suggests that one site of action of naftopidil may be TRPV1-sensitive afferent nerves. Naftopidil may enlarge BC via the suppression of TRPV1-sensitive afferents.
Even in BOO rats with the RTX treatment, i.e., under the condition of TRPV1 desensitization, naftopidil inhibited NVCs. Therefore, naftopidil inhibited NVCs via an action other than TRPV1 suppression. Naftopidil inhibited NVCs as well as decreased the intravesical level of PGE2 but not ATP in BOO rats with the RTX treatment. This finding may indicate that naftopidil inhibits PGE2 release in the bladder and then inhibits NVCs. The mechanism for naftopidil to inhibit PGE2 release deserves further investigation.