New insights into the pharmacology of the bladder

Abstract

Purpose of review Pharmacotherapy of a number of bladder disorders has traditionally focused on targeting the ‘sensory’ component or bladder nerves and the smooth muscle. This review aims to provide an insight into recent (experimental and clinical) developments in mechanisms of existing therapies as well as novel targets. Recent findings Traditionally, sensory signaling in the urinary bladder has been attributed to activation of bladder afferents, but new findings have pointed to the urothelium and interstitial cells as key participants in the transduction of sensory events. Recent advances provide strong support for the development of subtype selective receptor agonists/antagonists, the modulation of signal transduction cascades and new and expanded uses for various neurotoxins. Summary The development of therapeutic options for the treatment of a number of bladder disorders is complicated, and most treatments are associated with an increased incidence of side effects or lack of specificity. Recent studies suggest that selective targeting of receptors/ion channels or a disease-specific (i.e. phosphorylated) form of the receptor may represent a viable therapeutic target. Though the mechanisms regulating ion channel expression under pathological conditions are not fully known, an increased understanding of these pathways has important implications for drug development.

The physiological function of lower urinary tract smooth muscle

“…The body of the bladder -the dome -consists of smooth muscle bounded on the inner face by a urothelium/suburothelium and on the outer face by serosa (Figure 2). Although beyond the scope of this review, the urothelium/suburothelium does more than separate the detrusor muscle from the urine in the bladder lumen, it is the site of afferent sensation and also can exert a direct influence on detrusor function itself (see below) -(reviewed in Birder and de Groat, 2007;Hanna-Mitchell and Birder, 2008). Detrusor muscle cells are spindle-shaped single nucleated cells organized into bundles separated by connective tissue.…”

Three Gaseous Neurotransmitters, Nitric oxide, Carbon Monoxide, and Hydrogen Sulfide, Are Involved in the Neurogenic Relaxation Responses of the Porcine Internal Anal Sphincter

“…14 Similarly, in the urinary bladder, muscarinic receptors are responsible for direct smooth muscle contraction, 15 but they may also stimulate release of NO from urothelial cells. [16][17][18] In the present study experiments were performed on muscle strips with the mucosa removed to allow neurotransmission to be examined without the complication of epithelial influences and no relaxation responses were observed. The non-nitrergic relaxation induced by EFS in the presence of L-NNA was also investigated.…”

Onabotulinum toxin A for the treatment of neurogenic detrusor overactivity due to spinal cord injury or multiple sclerosis

“…Only the light chain, containing a zinc-dependent endopeptidase catalytic domain, will be internalized into the neuron cytosol after receptormediated endocytosis. It is this catalytic domain that specifically cleaves the synaptosomal associated protein 25 (SNAP-25), one of the vesicle-soluble N-ethylmaleimide-sensitive fusion attachment receptor (SNARE) proteins, causing inhibition of neuronal acetylcholine secretion and finally resulting in a loss or reduction of neuronal activity in the bladder [50,51]. Indeed, SNARE proteins, such as SNAP-25 on the plasma membrane and synaptobrevin in the synaptic vesicles, are responsible for the fusion of synaptic vesicles with the presynaptic membrane and thus neurotransmitter release (Figure 1) [49].…”