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

다국어 초록 (Multilingual Abstract)

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.

참고문헌 (Reference)

1 Tatemichi S, "Uroselectivity in male dogs of silodosin(KMD-3213), a novel drug for the obstructive component of benign prostatic hyperplasia" 25 : 792-799, 2006

2 Abrams P, "The standardisation of terminology of lower urinary tract function : report from the Standardisation Sub-committee of the International Continence Society" 21 : 167-178, 2002

3 REXED B, "The cytoarchitectonic organization of the spinal cord in the cat" 96 : 414-495, 1952

4 Uta D, "TRPA1-expressing primary afferents synapse with a morphologically identified subclass of substantia gelatinosa neurons in the adult rat spinal cord" 31 : 1960-1973, 2010

5 Yoshiyama M, "Supraspinal and spinal alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and N-methyl-Daspartate glutamatergic control of the micturition reflex in the urethane-anesthetized rat" 132 : 1017-1026, 2005

6 Sugaya K, "Spinal mechanism of micturition reflex inhibition by naftopidil in rats" 116 : 106-111, 2014

7 Jung JH, "Silodosin for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia" 11 : CD012615-, 2017

8 Yoshizumi M, "Role of supraspinal and spinal alpha1-adrenergic receptor subtypes in micturition reflex in conscious rats" 299 : F785-91, 2010

9 Chen Z, "Role of alpha1-adrenergic receptors in detrusor overactivity induced by cold stress in conscious rats" 28 : 251-256, 2009

10 Yoshimura M, "Primary afferent-evoked synaptic responses and slow potential generation in rat substantia gelatinosa neurons in vitro" 62 : 96-108, 1989

11 Rohrmann S, "Prevalence and progression of lower urinary tract symptoms in an aging population" 95 : 158-163, 2016

12 Yang K, "Origins of spontaneous and noxious stimuli-evoked miniature EPSCs in substantia gelatinosa" 12 : 39-42, 2001

13 Matsumoto G, "Non-NMDA glutamatergic excitatory transmission in the descending limb of the spinobulbospinal micturition reflex pathway of the rat" 693 : 246-250, 1995

14 Todd AJ, "Neuronal circuitry for pain processing in the dorsal horn" 11 : 823-836, 2010

15 Takei R, "Naftopidil, a novel alpha1-adrenoceptor antagonist, displays selective inhibition of canine prostatic pressure and high affinity binding to cloned human alpha1-adrenoceptors" 79 : 447-454, 1999

16 Sakai T, "Naftopidil inhibits 5-hydroxytryptamine-induced bladder contraction in rats" 700 : 194-200, 2013

17 EAU Guideline Office, "Management of non-neurogenic male LUTS" 2018

18 Birder LA, "Increased c-fos expression in spinal neurons after irritation of the lower urinary tract in the rat" 12 : 4878-4889, 1992

19 Todd AJ, "Identifying functional populations among the interneurons in laminae I-III of the spinal dorsal horn" 13 : 2017

20 Uta D, "Effects of naftopidil on inhibitory transmission in substantia gelatinosa neurons of the rat spinal dorsal horn in vitro" 380 : 205-211, 2017

21 Sugaya K, "Effects of intrathecal injection of tamsulosin and naftopidil, alpha-1A and -1D adrenergic receptor antagonists, on bladder activity in rats" 2 (2): 74-76, 2002

22 Daisuke Uta, "Effects of High Concentrations of Naftopidil on Dorsal Root- Evoked Excitatory Synaptic Transmissions in Substantia Gelatinosa Neurons In Vitro" 대한배뇨장애요실금학회 22 (22): 252-259, 2018

23 Guo YX, "Distinct intrinsic and synaptic properties of pre-sympathetic and pre-parasympathetic output neurons in Barrington’s nucleus" 126 : 338-348, 2013

24 Nishino Y, "Comparison of two alpha1-adrenoceptor antagonists, naftopidil and tamsulosin hydrochloride, in the treatment of lower urinary tract symptoms with benign prostatic hyperplasia : a randomized crossover study" 97 : 747-751, 2006

25 Kwon SY, "Comparison of the effect of naftopidil 75 mg and tamsulosin 0.2 mg on the bladder storage symptom with benign prostatic hyperplasia:prospective, multi-institutional study" 111 : 145-150, 2018

26 Gotoh M, "Comparison of tamsulosin and naftopidil for efficacy and safety in the treatment of benign prostatic hyperplasia : a randomized controlled trial" 96 : 581-586, 2005

27 Matsukawa Y, "Comparison of silodosin and naftopidil for efficacy in the treatment of benign prostatic enlargement complicated by overactive bladder : a randomized, prospective study(SNIPER Study)" 197 : 452-458, 2017

28 Griwan MS, "Comparative evaluation of naftopidil and tamsulosin in the treatment of patients with lower urinary tract symptoms with benign prostatic hyperplasia" 6 : 181-186, 2014

29 Yoshimura M, "Blind patch-clamp recordings from substantia gelatinosa neurons in adult rat spinal cord slices : pharmacological properties of synaptic currents" 53 : 519-526, 1993

30 Yang K, "Baclofen inhibition of dorsal root-evoked inhibitory postsynaptic currents in substantia gelatinosa neurons of rat spinal cord slice" 900 : 320-323, 2001

31 Chen SL, "Acute anal stretch inhibits NMDA-dependent pelvic-urethra reflex potentiation via spinal GABAergic inhibition in anesthetized rats" 295 : F923-31, 2008

32 Yang K, "Action of capsaicin on dorsal root-evoked synaptic transmission to substantia gelatinosa neurons in adult rat spinal cord slices" 830 : 268-273, 1999