Bladder instability: a re‐appraisal of classical experimental approaches and development of new therapeutic strategies

Abstract

1 Despite the growing social interest in human urinary tract disorders, the aetiology of detrusor instability remains poorly understood. Myogenic and neural impairment of detrusor activity caused by CNS or autonomic injuries can results in dysfunctions of normal voiding of the bladder such as urinary incontinence. 2 The contractility of human detrusor smooth muscle is critically dependent on acetylcholine-induced muscarinic receptor activation. Biochemical and functional in vivo and in vitro studies suggest the presence of an heterogeneous population of muscarinic receptor subtypes (M1-M4) localized at muscular and neutral sites. There is increasing evidence on the prejunctional auto- and hetero-regulation of acetylcholine release from parasympathetic nerve endings in modulating detrusor muscle contraction during micturition. 3 Activation of P2X purinoreceptors closely associated with the parasympathetic varicosities seems to be implicated to varying extent in the contractility in normal or instable human detrusor. Interestingly, P2X(1) subtype expression on smooth muscle increases considerably in the symptomatically obstructed bladder. A striking absence of P2X(3) and P2X(5) subtypes was observed in the cholinergic innervation of detrusor from patients with urgent incontinence. Thus, it is likely that alteration of the neural acetylcholine control can play a critical role in pathological states. 4 If the failures in storage and voiding can be recognized urodynamically, considerable difficulties remain in investigating the underlying functional changes especially because the study of the pathophysiology requires techniques that can be justified in animals but not in humans. 5 Recently, to solve this problem an alternative technique using human smooth muscle cells in culture has been developed. Human cell lines may be relevant in investigating the molecular pathways in physiological and pathological conditions. 6 The potential development of novel molecular therapeutic strategies such as gene therapy and tissue engineering is also discussed.

Neural Control of the Lower Urinary Tract

“…Increased detrusor myogenic activity which is an important contributor to BOO induced DO can be induced by many mechanisms including: denervation supersensitivity of cholinergic (muscarinic) receptors (583), increases in purinergic receptor mediated contractile responses as well as expression of purinergic receptors such as P2X1 (75, 485), changes in the cell-to-cell communication in detrusor muscles due to upregulation of gap-junction proteins such as connexin 43 (112, 253) and increased in the number of interstitial cells (328, 349). …”

Pathophysiology and Therapeutic Potential of Purinergic Signaling

“…ATP release from bladder epithelial cells from patients with interstitial cystitis is significantly greater than that from healthy cells (Sun and Chai, 2002), and there is a change in expression of both P2X and P2Y receptors in urothelial cells (Birder et al, 2004;Tempest et al, 2004). P2X 1 receptor subtype expression markedly increased in obstructed bladder (Boselli et al, 2001) and in the absence of P2X 3 receptors in mouse knockouts, the bladder is hyperactive (Cockayne et al, 2000;Vlaskovska et al, 2001). Botulinum toxin A, which has antinociceptive effects in treating interstitial cystitis, inhibits distension-mediated urothelial release of ATP in conditions of bladder inflammation (Smith et al, 2004).…”

The Forefront for Novel Therapeutic Agents Based on the Pathophysiology of Lower Urinary Tract Dysfunction: Pathophysiology and Pharmacotherapy of Overactive Bladder

“…Partial BOO increases intravesical pressure and induces bladder hypertrophy and partial denervation of the bladder smooth muscle, leading to various functional changes in smooth muscles. These changes include denervation supersensitivity of cholinergic (muscarinic) receptors (6), increases in purinergic receptor-mediated contractile responses as well as expression of purinergic receptors such as P2X 1 (7,8), and changes in the cell-to-cell communication in detrusor muscles due to up-regulation of gap-junction proteins such as connexin 43 (9,10). Thus, increases in receptor-mediated muscle contractility and interaction between smooth muscles cells can result in coordinated myogenic contraction of the entire bladder and detrusor overactivity.…”