The urothelium, which lines the inner surface of the renal pelvis, the ureters, and the urinary bladder, not only forms a high-resistance barrier to ion, solute and water flux, and pathogens, but ...also functions as an integral part of a sensory web which receives, amplifies, and transmits information about its external milieu. Urothelial cells have the ability to sense changes in their extracellular environment, and respond to chemical, mechanical and thermal stimuli by releasing various factors such as ATP, nitric oxide, and acetylcholine. They express a variety of receptors and ion channels, including P2X3 purinergic receptors, nicotinic and muscarinic receptors, and TRP channels, which all have been implicated in urothelial-neuronal interactions, and involved in signals that via components in the underlying lamina propria, such as interstitial cells, can be amplified and conveyed to nerves, detrusor muscle cells, and ultimately the central nervous system. The specialized anatomy of the urothelium and underlying structures, and the possible communication mechanisms from urothelial cells to various cell types within the bladder wall are described. Changes in the urothelium/lamina propria ("mucosa") produced by different bladder disorders are discussed, as well as the mucosa as a target for therapeutic interventions.
Oxidative stress is considered to reflect an imbalance between the systemic manifestation of reactive oxygen and nitrogen species (RONS) and a biological system's ability to readily detoxify the ...reactive intermediates or to repair the resulting damage. RONS are not only harmful agents that cause oxidative damage in pathologies; they also have important roles as regulatory agents in a range of biological phenomena. They are normally generated as by‐products of oxygen metabolism; however, environmental stressors (i.e., ultraviolet radiation, ionizing radiations, pollutants, heavy metal, and xenobiotics) contribute to greatly increase RONS production. Several antioxidants have been exploited in recent years for their actual or supposed beneficial effect against oxidative stress, but to date, none has been approved for any indication because they have not met the criteria of efficacy for drug approval. The present review discusses the concept of oxidative stress, how to measure it, how to prevent it, and its occurrence in different organ systems with special reference to the lower urinary tract.
In the last decades, a number of new antimuscarinic drugs have been introduced for treatment of the overactive bladder (OAB), defined symptomatically (OAB syndrome) or urodynamically (detrusor ...overactivity). Recently, three new drug principles have been approved for clinical use, the β3‐adrenoceptor agonist, mirabegron, the phosphodiesterase‐5 inhibitor, tadalafil and the blocker of afferent and efferent nerves, botulinum toxin. However, new alternatives are continuously being explored. OAB is a filling disorder, and ATP is involved in the generation of afferent impulses. One way of blocking the ATP afferent pathway is through the use of P2X3 receptor antagonists. In animal models, this strategy appears to work very well, but whether it translates effectively to man remains to be established. Evidence suggests that components of the endocannabinoid system are involved in regulation of bladder function. Clinical studies of cannabinoid extracts on LUTS are scarce and essentially restricted to patients with MS, and the results have so far not been convincing. Amplification of endocannabinoid activity by inhibiting their degradation via fatty acid amide hydrolase inhibitors may be an attractive approach, but no clinical experiences in OAB have been reported. Studies of the lower urinary tract have indicated that several transient receptor potential (TRP) channels, including TRPV1, TRPV2, TRPV4, TRPM8 and TRPA1, are expressed in the bladder and may act as sensors of stretch and/or chemical irritation. Animal studies have shown that inhibition of these pathways can be effective for the reduction in bladder activity. However, the roles of these channels for normal function and in pathological states have not been established, and so far adverse effects (hyperthermia) have hampered development of antagonists.
Chronic bladder ischemia is potentially a common cause of lower urinary tract symptoms in the elderly. Epidemiological studies have shown a close association between lower urinary tract symptoms and ...vascular risk factors for atherosclerosis, and investigations using transrectal color Doppler ultrasonography have shown a negative correlation between decreased lower urinary tract perfusion and International Prostate Symptom Score in elderly patients with lower urinary tract symptoms. Bladder blood flow is also known to decrease in men with bladder outlet obstruction as a result of benign prostatic hyperplasia. Studies in animal models suggest that chronic bladder ischemia and repeated ischemia/reperfusion during a micturition cycle might produce oxidative stress, leading to denervation of the bladder and the expression of tissue‐damaging molecules in the bladder wall, which could be responsible for the development of bladder hyperactivity progressing to bladder underactivity. The effects of drugs with different mechanisms of action; for example, α1‐adrenoceptor antagonists, phosphodiesterase type 5 inhibitors, free radical scavengers and β3‐adrenoceptor agonist, have been studied in animal models of chronic bladder ischemia. The drugs, representing different treatment principles for increasing blood flow and decreasing oxidative stress, showed protective effects not only on urodynamic parameters, but also on negative effects on muscle contractility and on detrimental structural bladder wall changes. Improvement of lower urinary tract perfusion and control of oxidative stress can be considered new therapeutic strategies for treatment of bladder dysfunction induced by chronic ischemia.
From time to time we publish a full review of drugs that are available for the treatment of common conditions. In this issue, the review is written by two of the leading authorities in the world, ...Paul Abrams and Karl‐Erik Andersson, on the topic of overactive bladder and antimuscarinic agents. This in‐depth review covers the entire range of questions that might be asked about this common area of interest.
Overactive bladder (OAB) is a syndrome characterized by urinary urgency, with or without urgency urinary incontinence, usually with frequency and nocturia. OAB symptoms are often associated with detrusor overactivity (DO). Like OAB symptoms, the prevalence of DO increases with age and can have a neurogenic and/or myogenic aetiology. Bladder outlet obstruction can be a contributing factor in DO, possibly through cholinergic denervation of the detrusor and supersensitivity of muscarinic receptors to acetylcholine, although the prevalence of OAB is similar in men and women across age groups. Acetylcholine is the primary contractile neurotransmitter in the human detrusor, and antimuscarinics exert their effects on OAB/DO by inhibiting the binding of acetylcholine at muscarinic receptors M2 and M3 on detrusor smooth muscle cells and other structures within the bladder wall. Worldwide, there are six antimuscarinic drugs currently marketed for the treatment of OAB: oxybutynin, tolterodine, propiverine, trospium, darifenacin, and solifenacin. Each has demonstrated efficacy for the treatment of OAB symptoms, but their pharmacokinetic and adverse event profiles differ somewhat due to structural differences (tertiary vs quaternary amines), muscarinic receptor subtype selectivities, and organ selectivities. Antimuscarinics are generally well tolerated, even in special populations (e.g. men with bladder outlet obstruction, elderly patients, children). The most frequently reported adverse events in clinical studies of antimuscarinics are dry mouth, constipation, headache, and blurred vision; few patients withdraw from clinical trials because of adverse events.
Development of an antimuscarinic with functional selectivity for the bladder would reduce the occurrence of antimuscarinic adverse events. The therapeutic potential of several other agents, such as α3‐adrenoceptor agonists, purinergic receptor antagonists, phosphodiesterase inhibitors, neurokinin‐1 receptor antagonists, opioids, and Rho‐kinase inhibitors, is also under investigation for the treatment of OAB.
Opinions differ on what drugs have both a rationale and a development potential for the treatment of bladder storage dysfunction.
In the present review, the focus is given to small molecule blockers ...of TRP channels (TRPV1, TRPV4, TRPA1, and TRPM8), P2 × 3receptor antagonists, drugs against oxidative stress, antifibrosis agents, cyclic nucleotide - dependent pathways, and MaxiK±channel - gene therapy.
TRPV1 channel blockers produce hypothermia which seems to be a problem even with the most efficacious second-generation TRPV1 antagonists. This has so far precluded their application to urine storage disorders. Other TRP channel blockers with promising rationale have yet to be tested on the human lower urinary tract. The P2 × 3receptor antagonist, eliapixant, was tested in a randomized controlled clinical trial, was well tolerated but did not meet clinical efficacy endpoints. Antifibrosis agent still await application to the human lower urinary tract. New drug principles for oxidative stress, purine nucleoside phosphorylase inhibition, and NOX inhibition are still at an experimental stage, and so are soluble guanylate cyclase stimulators. Gene therapy with MaxiK±channels is still an interesting approach but no new trials seem to be in pipeline.
Abstract Context Antimuscarinics are the drugs of choice for the treatment of detrusor overactivity (DO) and overactive bladder (OAB) syndrome. However, the mechanisms for their beneficial effects ...have not yet been definitely established. Objective Literature available on the pathophysiologic aspects of storage symptoms and of antimuscarinic actions on the bladder was reviewed. Evidence acquisition Medline was searched for the period ending October 2010 and included studies on human and animal tissues and animal models. Clinical studies exploring mechanisms involved in the effects of antimuscarinics were included. Searches were limited to the English language. Evidence synthesis Evidence for release of acetylcholine (ACh) from non-neuronal as well as neuronal sources during bladder filling has been demonstrated in isolated animal bladders as well as the human bladder. Urothelially derived ACh, probably via release of adenosine triphosphate, may stimulate afferent activity (“afferent noise”) from the bladder contributing to OAB and DO. Afferent noise may also be generated by local ACh release within the detrusor muscle. This afferent activity can be inhibited by antimuscarinics at the low concentrations obtained with doses recommended for clinical use in OAB/DO. Within this therapeutic window, antimuscarinics may decrease OAB symptoms and DO without affecting the voiding contraction. Changes in muscarinic receptor functions have been demonstrated with aging and in different disorders associated with OAB/DO. Conclusions ACh, derived from non-neuronal as well as neuronal sources and during bladder filling, directly or indirectly stimulates afferent activity from the bladder, contributing to OAB and DO. By inhibiting this effect, antimuscarinics may decrease OAB symptoms and DO without affecting the voiding contraction. Even if changes in muscarinic receptor functions may occur with aging and in different disorders associated with OAB/DO, such changes have not been shown convincingly to modify the beneficial effect of antimuscarinics in OAB/DO.
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