Effect of Alpha 1-Adrnoceptor Antagonists on Postsynaptic Sensitivity in Substantia Gelatinosa Neurons From Lumbosacral Spinal Cord in Rats Using Slice Patch-Clamp Technique for mEPSC

Daisuke Uta,Tsuyoshi Hattori,Megumu Yoshimura 대한배뇨장애요실금학회 2020 International Neurourology Journal Vol.24 No.2

Purpose: Alpha1-adrenoceptors participate in improving storage symptoms of male lower urinary tract symptoms (LUTS). However, the mechanism of action of these compounds remains unclear. To clarify the mechanism of the α1-adrenoceptor antagonists, the amplitude of miniature excitatory postsynaptic currents (mEPSCs) was analyzed in the lumbosacral spinal cord in rats. Methods: Male adult Sprague-Dawley rats were used. Blind whole-cell patch-clamp recordings were performed on substantia gelatinosa (SG) neurons in spinal cord slice preparations. The amplitude of mEPSCs was recorded in individual SG neurons to which α1-adrenoceptors (100μM naftopidil, 100μM tamsulosin, and 30μM silodosin) were applied sequentially with intervening washout periods. Individual amplitudes were analyzed. Results: Pearson correlation coefficients (r) for the amplitudes of mEPSCs between the baseline and postadministration of α1- adrenoceptor antagonists indicated changes of the amplitude ranked in the order of naftopidil (r =0.393), tamsulosin (r=0.738), and silodosin (r=0.944). Together, the α1-adrenoceptor antagonists yielded significant increases in the amplitude of mEPSCs in SG neurons (n=108, P=0.012). However, the effects of each α1-adrenoceptor antagonist on the amplitude were as follows (relative to the baseline; n=36 each): naftopidil, P=0.129; tamsulosin, P=0.201; and silodosin, P=0.005. The rate of response to naftopidil for the outward current was relatively high among the α1-adrenoceptor blockers. An inward current was observed only with the naftopidil application. Conclusions: Alpha1-adrenoceptor antagonists changed the amplitudes of mEPSCs in a subset of SG neurons in slices prepared from the L6–S1 levels of rat spine. Although the α1-adrenoceptor antagonists generated inward or outward currents in the SG neurons, different rates of response were observed with each antagonist. These results are important for understanding the mechanisms of action (at the spinal level) of α1-adrenoceptor antagonists for the storage symptoms of male LUTS.

백내장 수술 중 발생하는 홍채이완증후군의 유병률 및 위험인자

박호균,최상경,Ho Gyun Park,MD,Sangkyung Choi,MD 대한안과학회 2014 대한안과학회지 Vol.55 No.1

Purpose: To determine the incidence and risk factors of intraoperative floppy iris syndrome (IFIS) in patients undergoing cataract surgery. Methods: The present study included 981 eyes of 655 patients who underwent cataract surgery and development and grade of IFIS were recorded. Correlation analysis was performed to determine the relationship between the IFIS and risk factors such as α1-adrenergic antagonist (tamsulosin, terazosin, alfuzosin), benzodiazepine, 5-α-reductase inhibitor, age, gender, hypertension, diabetes and glaucoma. Results: IFIS developed in 178 eyes (18.1%) out of 981 eyes. There was a correlation between the development of the IFIS and α1-adrenergic antagonist and benzodiazepine and male gender; however, there was no correlation with 5-α -reductase inhibitor, age, gender, hypertension, diabetes and glaucoma. IFIS grade tended to be higher as the cumulative dosage of the α1-adrenergic antagonist increased. Odds ratio of the patients using tamsulosin was the highest among the other risk factors, which was 3.8 times higher than the patients using terazosin, 9.0 times higher than the patients using alfuzosin and 11.1 times higher than the patients using benzodiazepine. Among patients who underwent cataract surgery on both eyes and who were confirmed with IFIS in 1 or both eyes, no significant grade differences between the 2 eyes were noted. Conclusions: Alpha 1-adrenergic antagonist and benzodiazepine were risk factors for the development of the IFIS, and as the cumulative dosage of the α1-adrenergic antagonist increased, the probability of developing a higher grade of IFIS increased. Therefore, predicting and preparing for potential IFIS in patients who have the above-mentioned risk factors are necessary before planning cataract surgery. Additionally, the IFIS aspect of the first eye could be utilized as a predictive value for developing IFIS profile of the fellow eye. J Korean Ophthalmol Soc 2014;55(1):73-78

Analysis of Prescriptions of Alpha-Blockers and Phosphodiesterase 5 Inhibitors from the Urology Department and Other Departments

강동혁,이주용,정재훈,조희주,조정만,문홍상,김용태,유탁근,최홍용,박해영,이승욱 대한배뇨장애요실금학회 2011 International Neurourology Journal Vol.15 No.4

Purpose: We analyzed the prescriptions of alpha-blockers and phosphodiesterase 5 inhibitors (PDE5Is) in the urology department as well as in other departments of the general hospital. Methods: We investigated the frequency of prescription of alpha-blockers and PDE5Is from 3 general hospitals from January 1, 2007 to December 31, 2009. For alpha-blockers, data were collected from patients to whom alpha-blockers were prescribed from among patients recorded as having benign prostatic hyperplasia according to the 5th Korean Standard Classification of Diseases. For PDE5Is, data were collected from patients to whom PDE5Is were prescribed by the urology department and by other departments. Alpha-blockers were classified into tamsulosin, alfuzosin, doxazosin, and terazosin, whereas PDE5Is were classified into sildenafil, tadalafil, vardenafil, udenafil, and mirodenafil. Results: Alpha-blockers were prescribed to 11,436 patients in total over 3 years, and the total frequency of prescriptions was 68,565. Among other departments, the nephrology department had the highest frequency of prescription of 3,225 (4.7%), followed by the cardiology (3,101, 4.5%), neurology (2,576, 3.8%), endocrinology (2,400, 3.5%), pulmonology (1,102, 1.6%), and family medicine (915, 1.3%) departments in order. PDE5Is were prescribed to 2,854 patients in total over 3 years, and the total frequency of prescriptions was 10,558. The prescription frequency from the urology department was 4,900 (46.4%). Among other departments, the endocrinology department showed the highest prescription frequency of 3,488 (33.0%), followed by the neurology (542, 5.1%), cardiology (467, 4.4%), and family medicine (407, 3.9%) departments in order. Conclusions: A high percentage of prescriptions of alpha-blockers and PDE5Is were from other departments. For more specialized medical care by urologists is required in the treatment of lower urinary tract symptoms and erectile dysfunction.

Differential Effects of Alpha 1-Adrenoceptor Antagonists on the Postsynaptic Sensitivity: Using Slice Patch-Clamp Technique for Inhibitory Postsynaptic Current in Substantia Gelatinosa Neurons From Lumbosacral Spinal Cord in Rats

Uta Daisuke,Hattori Tsuyoshi,Yoshimura Megumu 대한배뇨장애요실금학회 2020 International Neurourology Journal Vol.24 No.2

Purpose: Alpha1-adrenoceptors participate in improving storage symptoms of male lower urinary tract symptoms. However, the mechanism of action of these compounds remains unclear. The goal of the present study was to clarify the effect of α1- adrenoceptor antagonists on γ-aminobutyric acid (GABA)/glycine-mediated outward currents of the inhibitory postsynaptic current (IPSC) in substantia gelatinosa (SG) neurons from the lumbosacral spinal cord in rats. Methods: Male adult Sprague-Dawley rats were used. Blind whole-cell patch-clamp recordings were performed in SG neurons from isolated spinal cord slice preparations. IPSCs were recorded in individual SG neurons to which naftopidil (100μM), tamsulosin (100μM), silodosin (30μM), or prazosin (10μM) were applied sequentially with intervening washout periods. Strychnine (2μM), bicuculline (10μM), or tetrodotoxin (TTX)(1μM) were added before naftopidil. Individual outward currents were analyzed. Results: The bath application of naftopidil, yielded outward IPSCs in 13 of 52 SG neurons. The naftopidil response was unchanged in the presence of TTX. Regression analysis of the outward currents between the 1st and 2nd applications of naftopidil revealed a Pearson correlation coefficient of 0.996 with a line slope of 0.983. The naftopidil-induced outward current was attenuated in the presence of strychnine and/or bicuculline. The GABA/glycine-mediated outward currents induced by tamsulosin, silodosin, and prazosin were smaller than those obtained with naftopidil. Conclusions: Naftopidil-induced GABA/glycine-mediated outward currents in a subset of SG neurons prepared from the L6– S1 level of rat spinal cord. The results indicated that α1-adrenoceptor antagonists, particularly naftopidil, induce neural suppression (in part) by mediating hyperpolarization. The response is associated with glycinergic and/or GABAergic neural transmission. Naftopidil may suppress the micturition reflex and improve urinary storage symptoms as a subsidiary effect resulting from hyperpolarization in SG neurons of the spinal cord.

Characterization on Responsiveness of Excitatory Synaptic Transmissions to α1-Adrenoceptor Blockers in Substantia Gelatinosa Neurons Isolated From Lumbo-Sacral Level in Rat Spinal Cords

Daisuke Uta,Tsuyoshi Hattori,Megumu Yoshimura 대한배뇨장애요실금학회 2019 International Neurourology Journal Vol.23 No.1

Purpose: The aim of this study was to characterize the responsiveness of miniature excitatory postsynaptic currents (mEPSCs) to α1-adrenoceptor blockers in substantia gelatinosa (SG) neurons from the spinal cord to develop an explanation for the efficacy of α1-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 (100μM), tamsulosin (100μM), or silodosin (30μM), α1-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 ρ 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 ρ 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 α1-adrenoceptor blockers, with the response to naftopidil being the greatest among the α1-adrenoceptor blockers. These data are helpful to understand the action mechanisms of α1-adrenoceptor blockers for male lower urinary tract symptoms in clinical usage.

Effects of High Concentrations of Naftopidil on Dorsal Root- Evoked Excitatory Synaptic Transmissions in Substantia Gelatinosa Neurons In Vitro

Daisuke Uta,Tsuyoshi Hattori,Megumu Yoshimura 대한배뇨장애요실금학회 2018 International Neurourology Journal Vol.22 No.4

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 Aδ or C fibers. Naftopidil or prazosin, an α1-adrenoceptor blocker, was perfused at 100 μM or 10 μM, respectively. Results: Bath-applied 100 μM naftopidil significantly decreased the peak amplitudes of Aδ 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 10μM prazosin did not inhibit Aδ 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 α1-adrenoceptors. Inhibition of evoked EPSCs may also contribute to suppression of the micturition reflex, together with nociceptive stimulation.

a-Blocker Monotherapy and a-Blocker Plus 5-Alpha-Reductase Inhibitor Combination Treatment in Benign Prostatic Hyperplasia; 10 Years’ Long-Term Results

신택준,김천일,박철희,김병훈,권영기 대한비뇨의학회 2012 Investigative and Clinical Urology Vol.53 No.4

Purpose: We compared the effects of alpha-adrenergic receptor blocker (a-blocker) monotherapy with those of combination therapy with a-blocker and 5-alpha-reductase inhibitor (5-ARI) on benign prostatic hyperplasia (BPH) progression for over 10 years. Materials and Methods: A total of 620 patients with BPH who received a-blocker monotherapy (a-blocker group, n=368) or combination therapy (combination group, n=252) as their initial treatment were enrolled from January 1989 to June 2000. The incidences of acute urinary retention (AUR) and BPH-related surgery were compared between the two groups. Incidences stratified by follow-up period, prostate-specific antigen (PSA), and prostate volume (PV) were compared between the two groups. Results: The incidence of AUR was 13.6% (50/368) in the a-blocker group and 2.8% (7/252) in the combination group (p<0.001). A total of 8.4% (31/368) and 3.2% (8/252) of patients underwent BPH-related surgery in the a-blocker and combination groups, respectively (p=0.008). According to the follow-up period, the incidence of AUR was significantly decreased in combination group. However, the incidence of BPH-related surgery was significantly reduced after 7 years of combination therapy. Cutoff levels of PSA and PV for reducing the incidences of AUR and BPH-related surgery were 2.0 ng/ml and 35 g, respectively (p<0.001). Conclusions: Long-term combination therapy with a-blocker and 5-ARI can suppress the progression of BPH more efficiently than a-blocker monotherapy. For patients with BPH with PSA >2.0 ng/ml or PV >35 ml, combination therapy promises a better effect for reducing the risk of BPH progression. Purpose: We compared the effects of alpha-adrenergic receptor blocker (a-blocker) monotherapy with those of combination therapy with a-blocker and 5-alpha-reductase inhibitor (5-ARI) on benign prostatic hyperplasia (BPH) progression for over 10 years. Materials and Methods: A total of 620 patients with BPH who received a-blocker monotherapy (a-blocker group, n=368) or combination therapy (combination group, n=252) as their initial treatment were enrolled from January 1989 to June 2000. The incidences of acute urinary retention (AUR) and BPH-related surgery were compared between the two groups. Incidences stratified by follow-up period, prostate-specific antigen (PSA), and prostate volume (PV) were compared between the two groups. Results: The incidence of AUR was 13.6% (50/368) in the a-blocker group and 2.8% (7/252) in the combination group (p<0.001). A total of 8.4% (31/368) and 3.2% (8/252) of patients underwent BPH-related surgery in the a-blocker and combination groups, respectively (p=0.008). According to the follow-up period, the incidence of AUR was significantly decreased in combination group. However, the incidence of BPH-related surgery was significantly reduced after 7 years of combination therapy. Cutoff levels of PSA and PV for reducing the incidences of AUR and BPH-related surgery were 2.0 ng/ml and 35 g, respectively (p<0.001). Conclusions: Long-term combination therapy with a-blocker and 5-ARI can suppress the progression of BPH more efficiently than a-blocker monotherapy. For patients with BPH with PSA >2.0 ng/ml or PV >35 ml, combination therapy promises a better effect for reducing the risk of BPH progression.

Long-term Combination Therapy With α-Blockers and 5α-Reductase Inhibitors in Benign Prostatic Hyperplasia: Patient Adherence and Causes of Withdrawal From Medication

Hueih Ling Ong,Chun-Hou Liao,Hann-Chorng Kuo 대한배뇨장애요실금학회 2016 International Neurourology Journal Vol.20 No.4

Purpose: To investigate long-term therapeutic effects and patient adherence to a combination therapy of a 5α-reductase inhibitor and an α-blocker and to identify causes of withdrawal from medication in patients with clinical benign prostatic hyperplasia (BPH). Methods: BPH patients with lower urinary tract symptoms (LUTS) receiving combination therapy with follow-ups for 1–12 years were retrospectively analyzed. Therapeutic effects were assessed at baseline and annually by measuring International Prostatic Symptoms Score, quality of life index, total prostate volume (TPV), maximal flow rate, voided volume, postvoid residual volume and prostate-specific antigen level. Causes of discontinued combination therapy were also investigated. Results: A total of 625 patients, aged 40–97 years (mean, 73 years) were retrospectively analyzed. All measured parameters showed significant improvements after combination therapy. Three hundred sixty-nine patients (59%) discontinued combination therapy with a mean treatment duration of 2.2 years. The most common reasons for discontinued treatment were changing medication to monotherapy with α-blockers or antimuscarinics (124 patients, 19.8%), receiving surgical intervention (39 patients, 6.2%), and LUTS improvement (53 patients, 8.5%). Only 64 patients (10.2%) were loss to follow-up and 6 (1.0%) discontinued combined treatment due to adverse effects. Smaller TPV after short-term combination treatment caused withdrawal from combination therapy. Conclusions: BPH patients receiving long-term combination therapy showed significant improvement in all measured parameters. Changing medication, improved LUTS and choosing surgery are common reasons for discontinuing combination herapy. A smaller TPV after short-term combination treatment was among the factors that caused withdrawal from combination therapy.

Impact of Intravesical Protrusion of the Prostate in the Treatment of Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia of Moderate Size by Alpha Receptor Antagonist

서유미,김형지 대한배뇨장애요실금학회 2012 International Neurourology Journal Vol.16 No.4

Purpose: To evaluate whether intravesical protrusion of the prostate (IPP) is related to the treatment effect of alpha-1 receptor antagonist in patients with lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) with a prostate size of less than 40 g. Methods: A total of 77 BPH patients over 50 years of age treated with alfuzosin (alpha blocker) were enrolled prospectively. The study included only patients with BPH of 40 g or less. The patients were classified into two groups depending on the presence of IPP at baseline: the IPP group (41 patients) and the non-IPP group (36 patients). Prostate volume, prostate-specific antigen (PSA), International Prostate Symptom Score and quality of life (IPSS/QoL), maximum flow rate (Qmax), and postvoid residual (PVR)volume were compared between the groups. The clinical significance of IPP was evaluated after the patients had been taking alfuzosin for 8 weeks. Results: PSA and IPSS (total and voiding subscore) showed significant correlations with IPP (P<0.05). Comparison of parameters before and after 8 weeks showed that alfuzosin improved the total IPSS and all subscores(P<0.001), QoL (P<0.001), Qmax (P<0.001), and PVR (P=0.030) in the non-IPP group. Conclusions: Alfuzosin may be less effective in improving symptom scores, PVR, and Qmax in the treatment of LUTS/BPH in the presence of IPP.

Expression of bladder α1-adrenoceptor subtype after relief of partial bladder outlet obstruction in a rat model

이지용,박종목,나용길,송기학,임재성,양승우,김건화,신주현 대한비뇨의학회 2020 Investigative and Clinical Urology Vol.61 No.3

Purpose: Many patients with benign prostatic hyperplasia require treatment for persistent storage symptoms, even when the obstruction is successfully relieved by surgery. Previous studies identified a characteristic increase in α1D-adrenoceptor levels in the bladder in a bladder outlet obstruction (BOO) model. Here, we investigated the expression of α1-adrenoceptor subtypes in the bladder after relief of partial BOO (pBOO) in a rat model. Materials and Methods: A total of 60 female Sprague–Dawley rats were randomly divided into three groups (sham-operated, pBOO, and pBOO relief groups), and the expression of α1-adrenoceptor subtypes in the urothelium and detrusor muscle tissues was examined by western blot. Results: The expression of the α1D-adrenoceptor was significantly higher in the urothelium and detrusor muscle tissue of the pBOO and pBOO relief groups than in the corresponding tissue of the sham-operated group. Additionally, the α1A-adrenoceptor was predominant in the sham-operated group but significantly decreased in the urothelium in the pBOO group. No significant differences were found in α1A-adrenoceptor levels in detrusor muscle or whole bladder. Conclusions: Our results showed that α1D-adrenoceptor levels were consistently increased with pBOO, even after relief, suggesting that the α1D-adrenoceptor might be a cause of persistent storage symptoms after relief of pBOO.