To test the hypothesis that naftopidil prolongs intercontraction intervals in rats undergoing chronic stress as observed in previous animal models, voiding behavior and bladder function were measured and analyzed. Female Sprague-Dawley rats weighing 200-230 g were exposed to repeated variate stress (RVS) for 1 week, chronic variable mild stress for 2 weeks, or simple mild stress for 1 week. Voiding behavior was assessed in metabolic cages. Voiding frequency and urine output were measured, and changes of these values were compared for the different types of stress. Micturition reflex was analyzed using unconscious cystometry. Naftopidil was administered orally at 30 mg/kg/day for 2 weeks. Unexpectedly, no stress-exposed rats exhibited increased micturition frequency compared to the normal nonstressed control. However, intercontraction intervals were shortened with each type of stress in the unconscious condition, especially by RVS (P<0.01). Naftopidil prolonged the shortened intervals. Although voiding behavior appears approximately normal in rats chronically exposed to emotional stress, internal bladder function can be affected. With anesthesia, micturition intervals were moderately shortened by emotional stress and clearly improved by naftopidil. Therefore, naftopidil appears to act at the spinal level at least.

Purpose: The aim of this study was to characterize the responsiveness of miniature excitatory postsynaptic currents (mEPSCs) to alpha 1-adrenoceptor blockers in substantia gelatinosa (SG) neurons from the spinal cord to develop an explanation for the efficacy of alpha 1-adrenoceptor blockers in micturition dysfunction. Methods: Male adult Sprague-Dawley rats were used. Blind whole-cell patch-clamp recordings were performed using SG neurons in spinal cord slices. Naftopidil (100 mu M), tamsulosin (100 mu M), or silodosin (30 mu M), alpha 1-adrenoceptor blockers, was perfused. The frequency of mEPSCs was recorded in an SG neuron to which the 3 blockers were applied sequentially with wash-out periods. Individual frequencies in a pair before naftopidil and tamsulosin perfusion were plotted as baseline, and the correlation between them was confirmed by Spearman correlation coefficient; linear regression was then performed. The same procedure was performed before naftopidil and silodosin perfusion. Frequencies of pairs after naftopidil and tamsulosin perfusion and after naftopidil and silodosin perfusion were similarly analyzed. The ratios of the frequencies after treatment to before were then calculated. Results: After the treatments, Spearman rho and the slope were decreased to 0.682 from 0.899 at baseline and 0.469 from 1.004 at baseline, respectively, in the tamsulosin group relative to the naftopidil group. In the silodosin group, Spearman rho and the slope were also decreased to 0.659 from 0.889 at baseline and 0.305 from 0.989 at baseline, respectively, relative to the naftopidil group. Naftopidil significantly increased the ratio of the frequency of mEPSCs compared to tamsulosin and silodosin (P = 0.015 and P = 0.004, respectively). Conclusions: There was a difference in responsiveness in the frequency of mEPSCs to alpha 1-adrenoceptor blockers, with the response to naftopidil being the greatest among the alpha 1-adrenoceptor blockers. These data are helpful to understand the action mechanisms of alpha 1-adrenoceptor blockers for male lower urinary tract symptoms in clinical usage.

The aim of this study was to assess the potential involvement of a specific subtype of 5-hydroxytryptamine (5-HT), 5HT₂ receptors in neurally-induced contractions of the human detrusor. Contractile responses to electrical field stimulation (EFS) were examined in human isolated urinary bladder muscle strips. The potentiation of EFS-induced detrusor contraction was examined by adding cumulative concentrations of a 5-HT and 5-HT₂ receptor agonist, α-methyl-serotonin (α-Me-5-HT) (1nM-100μM) in the presence or absence of a 5-HT₂ antagonist, ketanserin (5-HT_2A>5-HT_2C) or naftopidil (5-HT_2B>5-HT_2A) (0.3-3μM). 5-HT and α-Me-5-HT potentiated EFS-induced contraction with a maximal effect (E_max) of 37.6% and 38.6%, respectively, and with pEC₅₀ (negative logarithm of the concentration required for a half-maximal response to an agonist) values of 8.3 and 6.8, respectively. Neither ketanserin nor naftopidil at any concentration produced a rightward displacement of the α-Me-5-HT concentration response curve. Instead, the E_max of α-Me-5-HT increased in the presence of ketanserin at 0.3-1μM and in the presence of naftopidil at 1μM to 51% and 56%, respectively, while the E_max in the presence of vehicle alone was 36%. The highest concentration (3μM) of either drug, however, fully reversed the enhancement. The potentiating effect of α-Me-5-HT on neurally-induced contraction of human urinary bladder muscle strips was not found to be mediated via any 5-HT₂ receptor subtypes. The underlying mechanism for the enhancement of the α-Me-5-HT potentiating effect on detrusor contractility by ketanserin and naftopidil remains unknown; however, our results suggest that these drugs may be useful for treating contractile dysfunction of the detrusor, as manifested in conditions such as underactive bladder.

Purpose: Naftopidil ((+/-)-1-[4-(2-methoxyphenyl) piperazinyl]-3-(1-naphthyloxy) propan-2-ol) is prescribed in several Asian countries for lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Previous animal experiments showed that intrathecal injection of naftopidil abolished rhythmic bladder contraction in vivo. Naftopidil facilitated spontaneous inhibitory postsynaptic currents in substantia gelatinosa (SG) neurons in spinal cord slices. These results suggest that naftopidil may suppress the micturition reflex at the spinal cord level. However, the effect of naftopidil on evoked excitatory postsynaptic currents (EPSCs) in SG neurons remains to be elucidated. Methods: Male Sprague-Dawley rats at 6 to 8 weeks old were used. Whole-cell patch-clamp recordings were made using SG neurons in spinal cord slices isolated from adult rats. Evoked EPSCs were analyzed in A delta or C fibers. Naftopidil or prazosin, an alpha 1-adrenoceptor blocker, was perfused at 100 mu M or 10 mu M, respectively. Results: Bath-applied 100 mu M naftopidil significantly decreased the peak amplitudes of A delta and C fiber-evoked EPSCs to 72.0% +/- 7.1% (n = 15) and 70.0%+/- 5.5% (n = 20), respectively, in a reversible and reproducible manner. Bath application of 10 mu M prazosin did not inhibit A delta or C fiber-evoked EPSCs. Conclusions: The present study suggests that a high concentration of naftopidil reduces the amplitude of evoked EPSCs via a mechanism that apparently does not involve alpha 1-adrenoceptors. Inhibition of evoked EPSCs may also contribute to suppression of the micturition reflex, together with nociceptive stimulation.