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Therapeutic receptor targets for lower urinary tract dysfunction.
Naunyn Schmiedebergs Arch Pharmacol. 2008 Jun; 377(4-6):437-48.NS

Abstract

The functions of the lower urinary tract, to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the bladder, urethra, and external urethral sphincter. During urine storage, the outlet is closed, and the bladder smooth muscle is quiescent. When bladder volume reaches the micturition threshold, activation of a micturition center in the dorsolateral pons (the pontine micturition center) induces a bladder contraction and a reciprocal relaxation of the urethra, leading to bladder emptying. During voiding, sacral parasympathetic (pelvic) nerves provide an excitatory input (cholinergic and purinergic) to the bladder and inhibitory input (nitrergic) to the urethra. These peripheral systems are integrated by excitatory and inhibitory regulation at the levels of the spinal cord and the brain. Injury or diseases of the nervous system, as well as drugs and disorders of the peripheral organs, can produce lower urinary tract dysfunction. In the overactive bladder (OAB) condition, therapeutic targets for facilitation of urine storage can be found at the levels of the urothelium, detrusor muscles, autonomic and afferent pathways, spinal cord, and brain. There is increasing evidence showing that the urothelium has specialized sensory and signaling properties including: (1) expression of nicotinic, muscarinic, tachykinin, adrenergic, bradykinin, and transient receptor potential (TRP) receptors, (2) close physical association with afferent nerves, and (3) ability to release chemical molecules such as adenosine triphosphate (ATP), acetylcholine, and nitric oxide. Increased expression and/or sensitivity of these urothelial-sensory molecules that lead to afferent sensitization have been documented as possible pathogenesis of OAB. Targeting afferent pathways and/or bladder smooth muscles by modulating activity of ligand receptors (e.g., neurokinin, ATP, or beta3-adrenergic receptors) and ion channels (e.g., TRPV1 or K) could be effective to suppress OAB. In the stress urinary incontinence condition, pharmacotherapies targeting the neurally mediated urethral continence reflex during stress conditions such as sneezing or coughing could be effective for increasing the outlet resistance. Therapeutic targets include adrenergic and serotonergic receptors in the spinal cord as well as adrenergic receptors at the urethral sphincter, which can enhance urethral reflex activity during stress conditions and increase baseline urethral pressure, respectively.

Authors+Show Affiliations

Department of Urology, University of Pittsburgh School of Medicine, Suite 700 Kaufmann Medical Building, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA. nyos@pitt.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

18034230

Citation

Yoshimura, Naoki, et al. "Therapeutic Receptor Targets for Lower Urinary Tract Dysfunction." Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 377, no. 4-6, 2008, pp. 437-48.
Yoshimura N, Kaiho Y, Miyazato M, et al. Therapeutic receptor targets for lower urinary tract dysfunction. Naunyn Schmiedebergs Arch Pharmacol. 2008;377(4-6):437-48.
Yoshimura, N., Kaiho, Y., Miyazato, M., Yunoki, T., Tai, C., Chancellor, M. B., & Tyagi, P. (2008). Therapeutic receptor targets for lower urinary tract dysfunction. Naunyn-Schmiedeberg's Archives of Pharmacology, 377(4-6), 437-48.
Yoshimura N, et al. Therapeutic Receptor Targets for Lower Urinary Tract Dysfunction. Naunyn Schmiedebergs Arch Pharmacol. 2008;377(4-6):437-48. PubMed PMID: 18034230.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Therapeutic receptor targets for lower urinary tract dysfunction. AU - Yoshimura,Naoki, AU - Kaiho,Yasuhiro, AU - Miyazato,Minoru, AU - Yunoki,Takakazu, AU - Tai,Changfeng, AU - Chancellor,Michael B, AU - Tyagi,Pradeep, Y1 - 2007/11/21/ PY - 2007/08/07/received PY - 2007/10/22/accepted PY - 2007/11/24/pubmed PY - 2008/12/17/medline PY - 2007/11/24/entrez SP - 437 EP - 48 JF - Naunyn-Schmiedeberg's archives of pharmacology JO - Naunyn Schmiedebergs Arch Pharmacol VL - 377 IS - 4-6 N2 - The functions of the lower urinary tract, to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the bladder, urethra, and external urethral sphincter. During urine storage, the outlet is closed, and the bladder smooth muscle is quiescent. When bladder volume reaches the micturition threshold, activation of a micturition center in the dorsolateral pons (the pontine micturition center) induces a bladder contraction and a reciprocal relaxation of the urethra, leading to bladder emptying. During voiding, sacral parasympathetic (pelvic) nerves provide an excitatory input (cholinergic and purinergic) to the bladder and inhibitory input (nitrergic) to the urethra. These peripheral systems are integrated by excitatory and inhibitory regulation at the levels of the spinal cord and the brain. Injury or diseases of the nervous system, as well as drugs and disorders of the peripheral organs, can produce lower urinary tract dysfunction. In the overactive bladder (OAB) condition, therapeutic targets for facilitation of urine storage can be found at the levels of the urothelium, detrusor muscles, autonomic and afferent pathways, spinal cord, and brain. There is increasing evidence showing that the urothelium has specialized sensory and signaling properties including: (1) expression of nicotinic, muscarinic, tachykinin, adrenergic, bradykinin, and transient receptor potential (TRP) receptors, (2) close physical association with afferent nerves, and (3) ability to release chemical molecules such as adenosine triphosphate (ATP), acetylcholine, and nitric oxide. Increased expression and/or sensitivity of these urothelial-sensory molecules that lead to afferent sensitization have been documented as possible pathogenesis of OAB. Targeting afferent pathways and/or bladder smooth muscles by modulating activity of ligand receptors (e.g., neurokinin, ATP, or beta3-adrenergic receptors) and ion channels (e.g., TRPV1 or K) could be effective to suppress OAB. In the stress urinary incontinence condition, pharmacotherapies targeting the neurally mediated urethral continence reflex during stress conditions such as sneezing or coughing could be effective for increasing the outlet resistance. Therapeutic targets include adrenergic and serotonergic receptors in the spinal cord as well as adrenergic receptors at the urethral sphincter, which can enhance urethral reflex activity during stress conditions and increase baseline urethral pressure, respectively. SN - 0028-1298 UR - https://www.unboundmedicine.com/medline/citation/18034230/Therapeutic_receptor_targets_for_lower_urinary_tract_dysfunction_ L2 - https://dx.doi.org/10.1007/s00210-007-0209-z DB - PRIME DP - Unbound Medicine ER -