Bladder instability: a re-appraisal of classical experimental approaches and development of new therapeutic strategies.
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.
Department of Experimental and Applied Pharmacology, School of Pharmacy, University of Pavia, Viale Taramelli, 14, I-27100 Pavia, Italy.
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Boselli
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Govoni
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Condino
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D'Agostino
D000109:Acetylcholine / Q000502:physiology; D006801:Humans; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000502:physiology / Q000503:physiopathology; D018048:Receptors, Purinergic P2 / Q000502:physiology; D058469:Receptors, Purinergic P2X; D009435:Synaptic Transmission; D001743:Urinary Bladder / Q000503:physiopathology*; D001745:Urinary Bladder Diseases / Q000503:physiopathology* / Q000628:therapy
D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D000109:Acetylcholine