Multiple etiology factors has been implicated in its pathogenesis of UAB including aging, bladder outlet obstruction, diabetes mellitus contributing in myogenic UAB, Parkinson’s disease resulting in neurogenic UAB, spinal cord injury, multiple sclerosis, infectious neurological problems (e.g., AIDS, herpes zoster infection), and pelvic surgery and radical prostatectomy that can lead to iatrogenic UAB (Miyazato et al. 2013). Iatrogenic UAB could also be caused by side effects of drugs including neuroleptics, calcium channel antagonists, and α-receptor agonists. Although the prevalence of UAB is higher in the aged population, UAB is not part of the normal aging process.

Underactive bladder includes both functional and anatomical causes (Fig. 4.2). The following are the factors that alone or in combination contribute to UAB:

It may be helpful to consider the two tradition hypotheses on underactive bladder pathophysiology: myogenic and neurogenic. The classic myogenic hypothesis focuses on the ability of the detrusor to adequately contract. More recently, the neurogenic hypothesis focuses on defect in bladder afferent innervation, micturition control at spinal and supraspinal center, or both that may also lead to UAB (Tyagi et al. 2014).

Since direct human experimentation on UAB subjects is not possible for ethical reasons, hypotheses stated for UAB will require alternatives to test the derived predictions. Animal models can be used to generate novel directions of research and corroborate findings obtained in case studies or other methods. Animals who share similar integrative physiology of the lower urinary tract and the neural control of micturition as humans provide a suitable tool to dissect the underlying mechanisms in clinical features of UAB. Animal models can be used to reproduce some or all of the facets of UAB seen clinically as a consequence of myogenic or neurogenic dysfunction to help identify suitable interventions (Table 1). Animal models provide suitable platforms of intact biological systems for assessing results from simpler in vitro research. The clinical context of animal studies can help build a confidence in a new treatment approach before clinical testing.

Development of an animal model for UAB is hindered by the lack of a surrogate that predicts treatment outcome. A number of animal models have been proposed to study UAB and they are discussed next.

UAB is often seen in aged patients (Zimmern et al. 2014); therefore, aged animals would be an appropriate model to study UAB. Aged mouse (Lai et al. 2007; Smith et al. 2012) or rat models reproduce some of the UAB features, with age-dependent loss of bladder volume sensitivity manifesting as increased intercontractile interval (Fig. 4.3). Cystometry of young and old mice shows that detrusor contractility is preserved, but the response to rise in bladder volume is diminished in 26-month-old animals. Similar findings were observed in aged rats with increased volume and pressure thresholds for voiding (Chai et al. 2000). Age-dependent loss of bladder volume sensitivity in aged rats may be explained by the decreased response to intravesical capsaicin which is suggestive of reduced C-fiber afferent activity in aged rat (Chai et al. 2000). Intravesical capsaicin is expected to increase detrusor contractility because of neurokinins released from afferent nerves following activation of transient receptor potential (TRP) channels. Aged rats also exhibit a reduction in the maximal bladder pressure generated during pelvic nerve stimulation (Hotta et al. 1995; Hotta and Uchida 2010). Staining for calcitonin gene-related peptide, substance P in lumbosacral dorsal root ganglion neurons (Mohammed and Santer 2002), and density of pituitary adenylate cyclase-activating peptide innervation of the bladder base are also decreased in aged rats (Mohammed et al. 2002).

Significant decreases in the amplitude of neurogenic contractions were associated with fibrosis but without accompanying a decrease in nerve density in the bladder neck. These findings from aged rats implicate impairment of both afferent and efferent transmission results in incomplete voiding. There may also be an upregulation of purinergic receptors in the urothelium and bladder nerve bundles compared to control rats. This may correspond to the increased non-adrenergic and non-cholinergic innervation seen in aging humans. Upregulation of β-adrenoceptors (Iaina et al. 1988) has also reported in aged rat bladder (Lluel et al. 2003b).

Aged male rats exhibited urethral dysfunction and impairment of the urethrovesical coordination (Lluel et al. 2000, 2003a, b). Decrease in resting urethral pressure at voiding threshold and a significant delay in urethral relaxation that leads to increased post-void residual urine volume was observed in aged male rats. The responses to carbachol in the bladder body and to phenylephrine and carbachol in the urethra have also been observed in the aged male rat bladder.

Decreased detrusor contractility in UAB can result from a lack of contractile stimulus (acetylcholine and ATP) (Yoshida et al. 2004) and/or a lack of tissue responsiveness due to irreversible changes in the bladder wall. Similar decrease in muscle function has been described as sarcopenia (loss of muscle tissue, increased collagen deposition) (Brierly et al. 2003a, b). Several factors may contribute to altered excitation and contraction coupling mechanisms in UAB including changes in the properties and density of calcium (Gomez-Pinilla et al. 2011) and potassium channels, gap junctions, and receptors in detrusor smooth muscles.

Effects similar to BOO in humans have been well documented in a variety of animal species including pig, rat, guinea pig, and rabbit. Most typical BOO model is one created by inducing partial obstruction of the urethra using some form of ligature that either obstruct the urethra immediately or does so gradually as the animal grows (Murakami et al. 2008). Partial BOO can be created in female rats by ligating the proximal urethra over a 1 mm catheter. The obstructed animals are followed and evaluated from 2 weeks up to 6 months. Prolonged BOO caused a decrease in electrical field stimulation, acetylcholine release, and the number of nerves in the rat urinary bladder. The amount of acetylcholine can be measured in the dialysate fraction obtained from a microdialysis probe inserted into the muscle strips during electrical field stimulation. The reduced density of acetylcholinesterase-positive nerves in obstructed bladders may play an important role in insufficient efferent activation that can lead to UAB.

Epidemiological studies have suggested bladder ischemia and metabolic syndrome as potential etiological factors of UAB. Evidence suggests that there is likely to be both vascular and neurogenic components and that chronic bladder ischemia (Fu and Longhurst 1998) secondary to atherosclerosis may induce UAB. Cystometry of myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits shows significantly shorter micturition intervals, smaller voided volume with non-voiding contractions, and lower micturition pressure (Yoshida et al. 2010), as compared to control animals. The carbachol and electrical field stimulation-induced contractions of these rabbit’s detrusor strips were also significantly decreased. Also, a rat model of bladder ischemia induced by balloon endothelial injury of the common iliac arteries shows the progressive vascular damage resulting in bladder dysfunction that develops from OAB to UAB conditions (Nomiya et al. 2014). These animal models may serve well to screen for drugs that seek to improve detrusor contractility.

Animal models of neurogenic UAB can be broadly divided into peripheral and central models based on the predominant site of the deficit. Peripheral models are those resulting from direct damage to the bladder and its peripheral innervation or blood supply, whereas central models are developed following injuries to the spinal cord or brainstem.