1-S01-1
中枢神経系における排尿薬理機構の概説
Overview of current status of Central Neuro-Uro-Pharmacology
〇吉村直樹1
NaokiYoshimura1
1DEPT. OF PHARMACOL, UNIV. PITTSBURGH
1Dept. of Pharmacology & Chemical Biology and Dept. of Urology, Univ.of Pittsburgh, USA,, 2Dept. Urology, Univ. Pittsburgh Sch. Med.
The functions of the lower urinary tract (LUT), to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the urinary bladder, urethra, and external urethral sphincter. This activity is in turn coordinated by neural circuits in the central nervous system (CNS). Various neurotransmitters, including acetylcholine, norepinephrine, dopamine, serotonin, excitatory and inhibitory amino acids have been implicated in the CNS regulation of the LUT.Injuries or diseases of the CNS such as cerebral infarction, Parkinson disease, multiple sclerosis and spinal cord injury, as well as psychological stress or depression, can produce LUT dysfunctions leading to storage and voiding LUT symptoms such as urinary frequency, urgency, pain and incontinence or inefficient voiding and urinary retention. The recent research advancement in the field of CNS neuro-urology has led to the emergence of new concepts regarding neural control of the LUT and the etiology of LUT dysfunction.In this symposium, I will overview the recent advancement towards the identification of disease-related changes in receptor function and new delivery systems such as gene therapy techniques, which could lead to the future treatment of LUT dysfunction.
1-S01-2
脊髄損傷ラットにおけるPDE5阻害薬およびアドレナリンα1A/D受容体遮断薬の膀胱リモデリングに及ぼす効果
Effects of phosphodiesterase type 5 inhibitor and alpha-1A/D adrenoceptor antagonist on bladder remodeling in rats with spinal cord injury
〇嘉手川豪心1,2、菅谷公男1
KatsumiKadekawa1,2, KimioSugaya1
1株式会社サザンナイトラボラトリー、2沖縄協同病院泌尿器科
1Southern Knights' Laboratory Co.,Ltd, 2Okinawa Kyodo Hospital
Spinal cord injury (SCI) can lead to detrusor overactivity and detrusor-sphincter dyssynergia, which result in inefficient voiding and bladder wall tissue remodeling such as hypertrophy and fibrosis. However, no effective modality for controlling the bladder remodeling is available. Phosphodiesterase type 5 (PDE5) inhibitors and alpha1-adrenoceptor (α1-AR) antagonists are used for the treatment of male lower urinary tract symptoms with benign prostatic hyperplasia.
In animal study, PDE5 inhibitor or α1A/D-AR antagonist treatment suppressed the bladder fibrosis after SCI. PDE5 inhibitor might increases the blood flow and prevents bladder ischemia, resulting in the reducing the load in storage state and the suppressing of bladder fibrosis after SCI. Relaxing the bladder neck and proximal urethra after α1-AR antagonist treatment might decrease the resistance to urine flow from detrusor–sphincter dyssynergia and residual urine volume reduce the load of the bladder wall during both of voiding and storage states. Therefore, treatment with PDE5 inhibitors and α1A/D-AR antagonists could be effective for neurogenic lower urinary tract dysfunction including bladder remodeling after SCI.
1-S01-3
腹圧性尿失禁の中枢標的
Therapeutic targets for stress urinary incontinence in the central nervous system
〇宮里実1、芦刈明日香1
MinoruMiyazato1, AsukaAshikari1
1琉球大学大学院医学研究科腎泌尿器外科学
1Faculty of Medicine, University of the Ryukyus
Stress urinary incontinence (SUI) is a common and bothersome problem among middle-aged women. Various animal models of SUI have been developed to study the pathophysiological process involved in SUI, such as vaginal distention, pudendal nerve injury, or ovariectomy. We have also reported cerebral infarction rats induce not only bladder overactivity, but also SUI. Leak point pressure measurements are the most commonly used methods to evaluate the urethral dysfunction in SUI animal models. Originally, we have developed microtransducer-tipped catheter measurements of urethral activity during sneezing. Extensive our basic research has clarified potential strategies for pharmacotherapy of SUI in the central nervous system. Therapeutic targets include adrenergic and serotonergic (5-HT) receptors in the spinal cord projected from neurons in the locus coeruleus and raphe nucleus, respectively, which stimulate pudendal nerve innervating the external urethral sphincter. Activation of α1-adrenoceptors, 5-HT2C, or 5-HT7 receptors enhances the reflex at the spinal cord level whereas pre- or postsynaptic α2-adrenoceptors and/or 5-HT1A receptors inhibit the reflex. In addition, we have reported that stimulation of the spinal μ-opioid receptors may be a new candidate for the treatment of SUI. Thus, we review the recent advances in basic SUI research and potential targets for pharmacotherapy of SUI in the central nervous system.
1-S01-4
ストレス誘発性頻尿の脳内機序解明を目指して
Central regulation mechanisms for stress-induced frequent urination
〇清水孝洋1、清水翔吾1、東洋一郎1、吉村直樹2、齊藤源顕1
TakahiroShimizu1, ShogoShimizu1, YouichirouHigashi1, NaokiYoshimura2, MotoakiSaito1
1高知大・医・薬理、2ピッツバーグ大学医学部泌尿器科
1Dept. of Pharmacol., Kochi Med. Sch., Kochi Univ., 2Dept. of Urol., Univ. Pittsburgh Sch. Med.
Psychological stress exacerbates symptoms of bladder dysfunction including overactive bladder and bladder pain syndrome/interstitial cystitis not only in rodent models but also in human patients. Bombesin (BB)-related peptides and BB receptors in the brain have been implicated in the mediation/integration of stress responses. We have found that brain BB induces frequent urination through the BB receptors, serotoninergic nervous system and corticotropin-releasing factor (CRF) receptors. Interestingly, the BB-induced response is independent of the BB-induced activation of the sympatho-adrenomedullary outflow, one of the components of the primary systems for maintaining or reinstating homeostasis during stress exposure. These findings indicate that brain BB, 5-HT and CRF receptors could be new therapeutic targets for bladder dysfunction exacerbated by stress exposure. There are several concepts regarding central regulation mechanisms for the bladder function in the normal and pathological conditions. However, the exact brain pathophysiological mechanisms underlying stress-induced effects on the bladder are largely unknown. Therefore, our findings could pioneer a novel neuropharmacological field, central "Neuro-Uro-Pharmacology".