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Overactive Bladder Pathophysiology


Lorenzetti, F.*; Dambros, M.**
* MSc in Urology – Federal University of São Paulo
*Assistant Physician – Geriatric Urology Group – Federal University of São Paulo
**Head of the Geriatric Urology Group – Federal University of São Paulo


General Remarks

The Overactive Bladder Syndrome (OB) is defined by the International Continence Society as a syndrome characterized by micturition urgency, with or without incontinence, usually associated with frequency and nocturia (ICS, 2002). With this concept, the diagnosis of OB is based on symptoms only, it is not necessary to have an urodynamic demonstration of detrusor overactivity (DO) (Abrams et al., 2002). The prevalence is between 12 – 17 % in adult Europeans, causing an important deterioration in quality of life. The prevalence of OB increases with age, and there is a leap increase from 4.8% in women below 25 years of age to 30.9% in those above 65 years.


The mechanisms associated with the OB genesis go fundamentally through alterations in the Central Nervous System integration and impairments in the ultrastructure of detrusor muscle intercellular relations.
An adult patient can have a multifactorial cause for OB, and in many instances it may be very difficult to distinguish whether there is a predominance of a neurogenic (disorders in the afferent/efferent mechanisms of the detrusor innervation) or myogenic component (intrinsic alterations of the contractility mechanisms). On the other hand, in 90% of the cases, the cause remains obscure, therefore being called idiopathic OB.
There is an association between OB and the individual’s dietary habit, resulting from the ingestion of products that cause an increase in bladder excitability, as caffeine, in its different presentations as in tea, infusions, energetic drinks and cola sodas.
A higher water intake (volumetric overactive bladder), voluntarily (diet) or provoked (psychosis such as polydipsia) can cause polyuria and nocturia.
OB can be a consequence of an obstructive process, usually below the bladder, such as benign prostate hyperplasia (BPH), urethra stenosis or bladder neck stenosis. It is worth stressing that the obstructive pattern (not related to the complications of surgical repair for stress urinary incontinence) may be present in females.
The overactive bladder of neurologic origin is a consequence of nervous system disorders that affect the centers and pathways which interfere in micturition coordination. Among the most prevalent disorders we have: multiple sclerosis, hemiplegia, Parkinson’s disease, myelomeningocele and medullary lesions.
The lesions that affect the spinal chord (myelomeningocele, multiple sclerosis, traumas or cord infarctions) and cause clinical signs and symptoms of dysfunction or upper motor neuron syndrome, have significant morbidity with a negative impact on the patient’s quality of life.
There is a loss of supra-spinal control, inducing involuntary and reflex bladder contractions, which are frequently associated with incontinence. Moreover, in many a case there can be miscoordination between the detrusor and the bladder sphincter apparatus (detrusor external sphincter dyssynergia) which increase intra-bladder pressure during micturition, vesicoureteral reflux and subsequent renal lesion and insufficiency.
This clinical setting explains the high prevalence of chronic renal failure, leading the patient to need dialysis or renal transplant in patients with spinal cord lesions; and significant mortality among these individuals because of complications associated with this very process.
There are three main objectives in approaching these patients: keep the bladder under low pressures during urine storage, low pressures during micturition and proper bladder emptying with no post-micturition urinary residue.
Overactive bladders can be caused by irritative inflammation as a consequence of some urologic process (urologic infection, prostatitis, lithiasis, carcinoma in situ, bladder diseases) or diseases that cause regional involvement of the urinary, gynecological and gastro-intestinal tracts (diverticulitis, Crohn’s disease, rectum carcinoma, hemorrhoids). Moreover, it may be caused by medication therapy, often times geared towards other diseases the patient may have. Diuretics are mentioned because of an increase in diuresis and alpha-blockers, since they act relaxing the bladder neck and causing micturition reflex at the time the urine penetrates the proximal urethra. Besides these ones, the parasympathomimetic drugs used to improve intestinal peristalsis can also cause OB.
Didactically, the overactive bladder pathophysiology is divided among cellular, myogenic and neurogenic causes.

1. Cellular Causes

M1 – M3 muscarinic receptors are pharmacologically well seen in the detrusor, and they are directly responsible for detrusor contraction and for the mechanism of extracellular calcium release and input by the L-type channels and rho kinase activation.
While the opening of Ca+ channels causes a marked increase in intracellular calcium, the rho-kinase activation increases contractile filaments sensitivity.
The activated M3 receptors result in an increase in intracellular Ca2+, causing the mobilization of calcium intracellular reserves and this ion’s influx from the extracellular space. Acting on the intracellular storage, two different molecular mechanisms were identified; - IP3 (inositol triphosphate) and ryanodine receptors which are sensitive to calcium and – calcium induces the release of calcium (Somlyo, Somlyio, 1994). The activation of the cholinergic pathway causes the activation of protein G release, which stimulates IP3 production and Ca2+ release from the endoplasmic reticulum (Eglen et al., 1994).
M2 receptors are present in greater number in the detrusor and seem to facilitate the contraction mediated by M3 receptors (Schneider, 2004).
By means of pharmacologic studies, it has been shown that the M2 receptors are not directly related to the contractile response; however, the activation of M2 receptors may cause contraction in some bladder disease stages (Pontari, Steves, 2004).
Understanding M2 receptor dominance is associated with causing an indirect contraction because of blocking the action of β adrenergic receptors, which stimulate muscle relaxation (Hedge et al, 1997; Yamanishi, 2000).
Bladder distention caused by the increase in urine volume, causes afferent inputs to the central nervous system. The molecular sensorial identity of a bladder distention is yet to be unveiled, but recent data suggests that the urothelium plays a role in this process (Birder, De Groat, 2007).
We must notice that the urothelium represents not only a functional barrier and sensitivity for bladder distention, but it also activates the release of contractile agents, including acetylcholine and ATP, and of an urothelium-derived relaxing factor (Apostolidis et al., 2006; Chopra et al., 2005; Hawthorn et al., 2000; Wuest et al., 2005).
Gillespie et al 2003, showed the presence of muscarinic receptors in the urothelial and suburothelial regions, and they are activated during bladder distention. Fovaeus 1999 and Hawthorn 2000, wrote that these receptors would be involved in preventing detrusor contraction in the bladder filling phase.

2. Myogenic Causes

The overactive bladder can have been caused by detrusor myogenic abnormalities, resulting in an overactive detrusor.
Recently, experimental studies have shown the positive association between OB triggering and the generation of free radicals (Ohnishi et al., 1998; Masick et al., 2001). Results from an experimental study involving smooth muscle fragments submitted to a period of repetitive electrical stimulation showed a high level of lipid peroxidation products, and a reduction in bladder smooth muscle contractility, which is proportional to the exudative stress (Ohnishi et al., 1998).
Bisogni et al 2007 showed the existence of muscle contraction deterioration, and the appearance of oxygen-reactive species, in the bladder of animals submitted to chronic urethral obstruction, thus suggesting that free radicals generation is an important factor in the reduction of detrusor contractility seen in patients with Benign Prostatic Hyperplasia.
Aging studies with experimental animals and human beings have shown the infiltration of muscle cells in the bladder wall by elastin and collagen, bladder wall denervation and alterations in the junctional exchanges among the muscle cells of the bladder wall.
Urodynamic studies indicate that approximately 50% of the elderly patients with OB empty less than one third of bladder content during a detrusor involuntary contraction (Resnick e Yalla, 1987). An incomplete bladder emptying may contribute to an increase in urinary frequency having a reduction of bladder functional capacity.
In patients with obstructive symptoms it is common to see BPH and urethral stenosis.
The surgeries that cause an improvement in obstructive symptoms in men with BPH, in some cases are not capable of improving storage symptoms (Peters et al,1997; Taylor et al, 2007), thus suggesting that the obstruction induces bladder alterations which continue even after the obstruction is removed. Obstructed bladders are partially denervated and have an increase in extracellular matrix deposition, mainly due to the action of a beta growth factor.
Moreover, bladder hypertrophy carries alterations in gene expression associated with the filaments (Lefebvre et al., 2006). Consequently, contractility and relaxation can be altered in the smooth muscle cells (Chacko et al., 2004;Zhang et al., 2004).
All these factors must contribute to the contractility alterations seen in vivo in obstructed bladders.
Post-junctional alterations also can explain the reduced contractile response during the electrical stimulus. This is due to the lack of response for the muscarinic receptor agonists, in the presence or absence of nerve terminals.

3. Neurogenic Causes

Nervous system lesions or diseases can lead to the rupture in the micturition voluntary control, causing the reactivation of the micturition reflex, thus causing OB. Because of the complexity of the lower urinary tract control by the central nervous system, urgency incontinence may happen as a result of different neurologic disorders.
Other neurogenic dysfunction situations can be associated with excitability alterations by demyelination of C-sensitive afferent urothelial receptors to capsain. The afferent C fibers can mediate the feeling of incomplete bladder filling and that of urgency.
The stimulation of receptors associated with afferent C-fibers can trigger a bladder contraction, thus causing symptoms of urgency with low bladder volumes, characterizing the overactive bladder syndrome.

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