Overview on the lower urinary tract

This chapter overviews our current knowledge on the subject of the urinary tract, whose fundamental role is to transport urine from the kidneys and then store it at low pressure in the lower urinary tract until it can be voided at a socially convenient time. Current understanding of lower urinary tract function and dysfunction is summarized, with reference to anatomy, innervation, and function. The importance of the neurological system in the normal function of the lower urinary tract is emphasized, with a brief overview of the consequence of neural injury at different levels within the central nervous system. The role of urodynamics in the evaluation of lower urinary tract symptoms is discussed with particular reference to the currently recommended terminology advocated by the International Continence Society and The International Urogynaecological Association.     

Neuroanatomy of the lower urinary tract

The lower urinary tract (LUT), which consists of the urinary bladder and its outlet, the urethra, is responsible for the storage and periodic elimination of bodily waste in the form of urine. The LUT is controlled by a complex set of peripheral autonomic and somatic nerves, which in turn are controlled through neural pathways in the spinal cord and brain. This influence of the central nervous system allows for the conscious control of the bladder, allowing the individual to choose an appropriate place to urinate. Defects in the CNS pathways that control the LUT can lead to incontinence, an embarrassing condition that affects over 200 million people worldwide. As a first step in understanding the neural control of the bladder, we will discuss the neuroanatomy of the LUT, focusing first on the peripheral neural pathways, including the sensory pathways that transmit information on bladder filling and the motoneurons that control LUT muscle contractility. We will also discuss the organization of the central pathways in the spinal cord and brainstem that are responsible for coordinating bladder activity, promoting continuous storage of urine except for a few short minutes per day when micturition takes place. To conclude, we will discuss current studies underway that aim to elucidate the higher areas of the brain that control the voluntary nature of micturition in higher organisms.     

Neurophysiology of the lower urinary tract

The lower urinary tract (LUT) has two functions: (1) the storage of waste products in the form of urine and (2) the elimination of those wastes through micturition. The LUT operates in a simple "on-off" fashion, either storing urine or releasing it during voiding. While this activity may seem simple, micturition is controlled by a complex set of peripheral neurons that are, in turn, coordinated by cell groups in the spinal cord, brainstem, and brain. When this careful coordination is interrupted, the control of the bladder is lost, resulting in incontinence or retention of urine. The purpose of this chapter is to review how the neural systems coordinating the activity of the lower urinary tract form neural circuits that are responsible for either maintaining continence (the storage reflex) or inducing micturition (the voiding reflex). We will also discuss the brain centers that enable higher organisms to voluntarily choose the time and place for voiding. Finally, we will discuss how defects in the pathways controlling micturition can lead to urinary incontinence and which treatments may normalize LUT function.     

Proteinase-activated receptors in the lower urinary tract

Proteinase-activated receptors (PARs) are G-protein-coupled receptors that convert specific extracellular proteolytic activity into intracellular signals, and have been suggested to play diverse roles in the body. In this review, evidence for the roles of PARs in bladder contractility and inflammation are presented. The role of PARs in prostate cancer is also reviewed. The existing literature in this area can be difficult to interpret due to the many nonspecific actions of the pharmacological tools employed. Although there are reports that PAR activators can cause contraction of bladder smooth muscle, further pharmacological and molecular studies are required to define roles for these receptors in bladder contractility. While structural studies suggest that roles for PARs in bladder inflammation are likely, few functional investigations have been performed. The significance of the expression of PARs on sensory nerves innervating the bladder and changes in receptor expression in inflammatory disease models are fascinating areas for future research. Finally, it seems probable that PARs, particularly PAR₁, may play important roles in the growth and metastasis of prostate cancers.     

Neuropeptides in lower urinary tract function

Numerous neuropeptide/receptor systems including vasoactive intestinal polypeptide, pituitary adenylate cyclase-activating polypeptide, calcitonin gene-related peptide, substance P, neurokinin A, bradykinin, and endothelin-1 are expressed in the lower urinary tract (LUT) in both neural and nonneural (e.g., urothelium) components. LUT neuropeptide immunoreactivity is present in afferent and autonomic efferent neurons innervating the bladder and urethra and in the urothelium of the urinary bladder. Neuropeptides have tissue-specific distributions and functions in the LUT and exhibit neuroplastic changes in expression and function with LUT dysfunction following neural injury, inflammation, and disease. LUT dysfunction with abnormal voiding, including urinary urgency, increased voiding frequency, nocturia, urinary incontinence, and pain, may reflect a change in the balance of neuropeptides in bladder reflex pathways. LUT neuropeptide/receptor systems may represent potential targets for therapeutic intervention.     

An update on the pharmacotherapy for lower urinary tract dysfunction

Introduction: The lower urinary tract (LUT) stores and evacuates urine. It is controlled by autonomic, somatic and sensory innervation. Pharmacotherapy has been developed to optimize neural control of the LUT in pathologic states.

Areas covered: The bladder can be overactive or underactive. For overactive bladder, medications targeting various receptors include i) antimuscarinics, ii) mixed-action drugs, iii) β-adrenergic receptor agonists and iv) other medications. There is no effective pharmacotherapy for underactive bladder, although medications have been used with limited success, including i) muscarinic receptor agonists, ii) anticholinesterase inhibitors and iii) α-adrenergic receptor antagonists. At the level of the outlet, there can be decreased resistance resulting in stress urinary incontinence (SUI) or increased resistance resulting in bladder outflow obstruction (BOO). The classes of medications for SUI include i) α-adrenergic receptor agonists, ii) β-adrenergic receptor agonists and iii) antidepressants. Medications used to treat BOO include i) α-adrenergic receptor antagonists, ii) 5-α reductase inhibitors, iii) benzodiazepines, iv) baclofen and v) PDE inhibitors.

Expert opinion: Pharmacotherapy for the LUT must be individualized based on degree of bother, medication side-effect profile, concomitant comorbidities, current medication regimen, and insurance coverage. This review describes current medical therapies for the LUT.     

Anatomy and histology of the lower urinary tract

The function of the lower urinary tract is basically storage of urine in the bladder and the at-will periodic evacuation of the stored urine. Urinary incontinence is one of the most common lower urinary tract disorders in adults, but especially in the elderly female. The urethra, its sphincters, and the pelvic floor are key structures in the achievement of continence, but their basic anatomy is little known and, to some extent, still incompletely understood. Because questions with respect to continence arise from human morbidity, but are often investigated in rodent animal models, we present findings in human and rodent anatomy and histology. Differences between males and females in the role that the pelvic floor plays in the maintenance of continence are described. Furthermore, we briefly describe the embryologic origin of ureters, bladder, and urethra, because the developmental origin of structures such as the vesicoureteral junction, the bladder trigone, and the penile urethra are often invoked to explain (clinical) observations. As the human pelvic floor has acquired features in evolution that are typical for a species with bipedal movement, we also compare the pelvic floor of humans with that of rodents to better understand the rodent (or any other quadruped, for that matter) as an experimental model species. The general conclusion is that the "Bauplan" is well conserved, even though its common features are sometimes difficult to discern.     

TRP channels in lower urinary tract dysfunction

Lower urinary tract dysfunction (LUTd) represents a major healthcare problem. Although it is mostly not lethal, associated social disturbance, medical costs, loss of productivity and especially diminished quality of life should not be underestimated. Although more than 15% of people suffer from a form of LUTd to some extent, pathophysiology often remains obscure. In the past 20 years, transient receptor potential (TRP) channels have become increasingly important in this field of research. These intriguing ion channels are believed to be the main molecular sensors that generate bladder sensation. Therefore, they are intensely pursued as new drug targets for both curative and symptomatic treatment of different forms of LUTd. TRPV1 was the first of its class to be investigated. Actually, even before this channel was cloned, it had already been targeted in the bladder, with clinical trials of intravesical capsaicin instillations. Several other polymodally gated TRP channels, particularly TRPM8, TRPA1 and TRPV4, also appear to play a prominent role in bladder (patho)physiology. With this review, we provide a brief overview of current knowledge on the role of these TRP channels in LUTd and their potential as molecular targets for treatment.

Linked Articles

This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-10     

Managing lower urinary tract symptoms in men

Over one-quarter of men aged 40 years or over in the UK have lower urinary tract symptoms. These symptoms, which may seriously disrupt day-to-day activity, include frequency, urgency, hesitancy, reduced flow, dribbling, nocturia, incontinence and incomplete emptying of the bladder. Here, we review non-surgical measures that may help men with such symptoms.     

Molecular biological researches of the lower urinary tract function

Adrenergic alpha1 and beta receptors are present in the target organs of sympathetic nerve and they participate in the signal transduction mechanism of the lower urinary tract. Adrenergic alpha1 receptors are present in urethral and prostatic smooth muscles, and contract these muscles. Among these receptor subtypes, the alpha1-A receptor has the most important role, and mRNA expression of the corresponding alpha1-a subtype is predominant. In the human urinary bladder detrusor smooth muscle, the expression of adrenergic beta3 receptor subtype mRNA is predominant, and relaxation of detrusor smooth muscle is mediated mainly via beta3 receptor. Afferent nerve with lower threshold can easily transmit bladder sensation and takes an important role in the pathophysiology of urge urinary incontinence. Successful molecular cloning of vanilloid receptors, which are present in these afferent nerves, revealed that vanilloid receptors are ion-channels, sensitive for heat and pH, and termed VR1 and VRL1. Among purinergic receptors, ion channel type P2X3 receptor is found in afferent nerve fibers and plays some roles in the signal transduction of bladder sensation. In the near future, agonist for the adrenergic beta3 receptor and selective antagonists for VR1, VRL1, or P2X3 will possibly become drugs for pollakisuria and urge urinary incontinence.     

妇科下尿路功能障碍141例尿动力学分析

目的探讨尿动力学在妇科下尿路功能障碍检查中的应用价值。方法对2009年1月至2010年9月我院141例下尿路功能障碍的妇科患者进行尿动力学检查,其中尿失禁106例,排尿困难14例,尿频21例。结果 106例尿失禁患者中,10例膀胱过度活动,42例未诱导出漏尿,22例膀胱流出道Linp-URR图示梗阻;14例排尿困难的患者中,1例膀胱过度活动,2例逼尿肌收缩乏力,5例检出漏尿,7例膀胱流出道Linp-URR图示无梗阻;21例尿频患者中,6例膀胱过度活动,4例顺应性欠佳,8例漏尿,无逼尿肌收缩乏力病例,5例膀胱流出道Linp-URR图示梗阻。尿失禁组患者的膀胱容量和最大尿流率明显高于排尿困难组和尿频组(P<0.05)。结论根据尿动力学检查结果有助于诊断并明确妇科下尿路功能障碍产生的原因。     

Therapeutic receptor targets for lower urinary tract dysfunction

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 beta(3)-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.     

Treatment of lower urinary tract infection in pregnancy

Urinary tract infection (UTI) is a common complication of pregnancy. Approximately 20--40% of women with asymptomatic bacteriuria will develop pyelonephritis during pregnancy. All pregnant women, therefore, should have their urine cultured at their first visit to the clinic. In a clinical study comparing single-dose treatment with 3 g fosfomycin trometamol versus a 3-day course of 400 mg ceftibuten orally, the inclusion criteria were acute symptomatic lower UTI (acute cystitis), significant bacteriuria (> or =10(3) CFU/ml), pyuria and confirmed pregnancy. Excluded were patients with asymptomatic bacteriuria or acute pyelonephritis. Predisposing factors comprised a history of recurrent UTI, diabetes mellitus, analgesic nephropathy, hyperuricaemia or Fanconi's syndrome. Escherichia coli was the most frequently isolated pathogen in both groups. Therapeutic success (clinical cure and bacteriological eradication of uropathogens) was achieved in 95.2% of the patients treated with fosfomycin-trometamol versus 90.0% of those treated with ceftibuten (P, non-significant). The treatment of acute cystitis in pregnant women using a single-dose of fosfomycin trometamol was equally effective as the 3-day course of oral ceftibuten. Both regimens were well tolerated with only minor adverse effects. Long-term chemoprophylaxis should be suggested in patients with recurrent UTI or following acute pyelonephritis during pregnancy.     

Pivmecillinam--therapy of choice for lower urinary tract infection

Pivmecillinam is the pro-drug of mecillinam, a beta-lactam antibiotic with a novel site of action and with specific and high activity against Gram-negative organisms such as Escherichia coli and other Enterobacteriaceae. Since its introduction, it has been widely used for the treatment of acute lower urinary tract infections (UTI), primarily in the Nordic countries. In contrast to the increasing resistance of urinary pathogens to other beta-lactams particularly ampicillin/amoxycillin and to other UTI antibiotics such as trimethoprim and trimethoprim/sulphamethoxazole (TMP/SMX), the level of resistance has remained on a low level. Less than 2% of E. coli community isolates are resistant to mecillinam. This paper reviews the clinical data on pivmecillinam with a special focus on the safety aspects. A large number of studies from the 70s to 80s have proven the clinical efficacy and safety of pivmecillinam for empirical treatment of acute cystitis. More recent studies confirm short-term treatment with pivmecillinam results in clinical and bacteriological cure rates similar to those obtained with other UTI agents. Both clinical studies in pregnant women with UTI and large epidemiological studies have confirmed the safety of pivmecillinam used in pregnancy. In the Nordic countries pivmecillinam has been the most widely used agent for treatment of UTI in pregnancy for many years. Ecological aspects of antibiotic treatment are important both with regard to adverse effects and development of resistance due to disturbance of the normal micro flora. Studies have shown that pivmecillinam has a very minor impact on the normal oropharyngeal, intestinal and skin microflora. The clinical implications of this are a low frequency of diarrhoea and Candida vaginitis as confirmed in the clinical studies. The high and increasing level of resistance among E. coli to currently recommended first-line agents for acute cystitis requires a re-evaluation of treatment guidelines. With the low resistance, its proven efficacy and favourable safety profile, pivmecillinam is a suitable first-line agent for empirical treatment of acute cystitis.     

Integrative control of the lower urinary tract: preclinical perspective

Storage and periodic expulsion of urine is regulated by a neural control system in the brain and spinal cord that coordinates the reciprocal activity of two functional units in the lower urinary tract (LUT): (a) a reservoir (the urinary bladder) and (b) an outlet (bladder neck, urethra and striated muscles of the urethral sphincter). Control of the bladder and urethral outlet is dependent on three sets of peripheral nerves: parasympathetic, sympathetic and somatic nerves that contain afferent as well as efferent pathways. Afferent neurons innervating the bladder have A-delta or C-fibre axons. Urine storage reflexes are organized in the spinal cord, whereas voiding reflexes are mediated by a spinobulbospinal pathway passing through a coordination centre (the pontine micturition centre) located in the brainstem. Storage and voiding reflexes are activated by mechanosensitive A-delta afferents that respond to bladder distension. Many neurotransmitters including acetylcholine, norepinephrine, dopamine, serotonin, excitatory and inhibitory amino acids, adenosine triphosphate, nitric oxide and neuropeptides are involved in the neural control of the LUT. Injuries or diseases of the nervous system as well as disorders of the peripheral organs can produce LUT dysfunctions including: (1) urinary frequency, urgency and incontinence or (2) inefficient voiding and urinary retention. Neurogenic detrusor overactivity is triggered by C-fibre bladder afferent axons, many of which terminate in the close proximity to the urothelium. The urothelial cells exhibit 'neuron-like' properties that allow them to respond to mechanical and chemical stimuli and to release transmitters that can modulate the activity of afferent nerves.     

整体护理干预对妇科术后患者尿路感染的影响的研究

目的深入分析和研究整体护理干预治疗方法对妇科术后患者尿路感染的影响效果,提高疾病的治疗水平。方法收集2012年5月至2012年6月在山东省即墨市人民医院进行妇科术后尿路感染的病患80例,按照护理方式的不同将病患分为对照组和观察组各40例,其中观察组按照常规方式进行护理,对照组除了按照常规方式进行护理以外,还另进行整体护理干预。在治疗之后对两组,在两组病患在疾病治疗的满意度上进行对比。结果采取不同的治疗后对两组在疾病治疗的满意度上进行分析,在非常满意、满意、一般、不满意的四个标准上,对照组对应数据为[n（%）],35（87.5）、4（10.0）、1（2.5）、0（0）。观察组对应数据为20（50.0）、10（25.0）、5（12.5）、5（12.5）。在四个指标上P〈0.05差异具有统计学意义。结论整体护理干预能够有效的减少尿路妇科术后患者尿路的感染,提高疾病治疗的满意度,值得广泛推广。     

Effects of natural tachykinins on ovine lower urinary tract smooth muscle

1 Numerous studies have demonstrated that the urinary bladder is particularly sensitive to tachykinins; rat, rabbit and guinea pig bladders, besides human detrusor, have been the most extensively studied, whereas very little is known about most large animal detrusors. The aim of this work was to study natural tachykinin activity on the lower urinary tract of ovine to make a comparison with data obtained in laboratory animals. 2 As in other animal species, tachykinins are also able to contract ovine bladder smooth muscle. 3 The results reported in this study indicate that in ovine bladder, neurokinin 2 (NK2) receptors are expressed most. In fact, on lamb and sheep bladder neurokinin A (NKA), a NK2‐ almost selective peptide, was shown to be > 100% more active than the natural tachykinins kassinin (KASS) and eledoisin (ELED). Eledoisin was shown to be 50% less active than KASS, which is typical behaviour for an almost exclusively NK2 receptor population. Moreover, NK1‐ preferential peptides, namely substance P (SP) and physalaemin (PHYS), showed a lack of activity even when applied at high concentrations. 4 The results reported in this study show that lamb and sheep detrusor represent a good alternative model for the characterization of NK2‐selective tachykinins.     

Effects of natural tachykinins on porcine lower urinary tract smooth muscle

1. The aim of our study was to ascertain the possible differences and/or similarities in natural tachykinin activity in vitro on lower urinary tract of large-sized animals as compared with data obtained in laboratory animals. 2. Besides tachykinins normally present in mammals, namely substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), we tested non-mammalian tachykinins, such as eledoisin (ELED), physalaemin (PHYS), kassinin (KASS) and PG-kassinin II (PG-KASS II). 3. NKA, KASS and ELED were found to be the most potent peptides in contracting detrusor strips from porcine bladder. In particular, NKA showed a pD2 of 7.14, whereas KASS and ELED showed pD2 values of 7.20 and 7.22, respectively. The activity of NKB and PG-KASS II corresponded to 72.4 and 55.0% respectively of that of NKA. SP and PHYS activity corresponded to only 2% of that of NKA. 4. NKA (pD2 7.92) was the most active peptide in contracting bladder neck tissues as well. ELED and KASS were found to have lower, similar pD2 values (7.62 and 7.70, respectively), whereas NKB and PG-KASS II were much less active (pD2 7.12 and 6.74, respectively). Moreover, SP and PHYS showed an activity range lower than 2% of that of NKA. 5. The reported results confirm that, on pig vesical neck and detrusor, NK1 receptors represent a minority as compared with NK2 and NK3 receptors. By contrast, the presence of NK2 receptors is demonstrated by a greater potency of NKA. The presence of NK3 receptors both on detrusor and neck is evidenced by NKB activity and by results achieved with PG-KASS II.