Search PubMed⌕ Search
Home/Archive/PubMed

PubMed · 15928509

Recent advances in basic science for overactive bladder.

Vivek Kumar·Rebecca L Cross·Russell Chess-Williams·Christopher R Chapple
View original source ↗Export metadata ↓

Abstract

PURPOSE OF REVIEW: Detrusor overactivity is a relatively common yet embarrassing symptom complex with significant impact on quality of life. The mainstay of current pharmacological treatment involves the use of muscarinic receptor antagonists, but their therapeutic effectiveness is limited by a combination of limited efficacy and troublesome side effects and has recently been challenged by Herbison et al. Recognition of the limitations of existing therapy has started the search for pharmacotherapeutic agents acting on alternative pathways underlying detrusor overactivity with the intention of improving storage symptoms of urgency, frequency and urge incontinence. RECENT FINDINGS: Recent research has suggested that several transmitters may modulate bladder storage. However, no agents currently available, acting via mechanisms other than muscarinic receptors have entered clinical practice so far. It is clear that far from being a passive container for urine, the urothelium is a crucial area within the bladder wall and its functions are complex and only now beginning to be appreciated. The release of several neurotransmitters from urothelium in response to distension and its action on receptors on sensory neurons is being increasingly recognized. The role for this afferent stimulation on the micturition reflex is gradually gaining importance in the pathophysiology of detrusor overactivity. SUMMARY: In this article, the recent developments in basic science related to the pathogenesis and pharmacological basis for future drug targets for effective management of overactive bladder are discussed.

Explore related subjects

Adenosine TriphosphateAnimalsCentral Nervous SystemHumansMuscle ContractionReceptors, MuscarinicUrinary BladderUrinary IncontinenceUrotheliumJournal ArticleReview

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Vivek Kumar, Rebecca L Cross, Russell Chess-Williams, Christopher R Chapple. 2005. Recent advances in basic science for overactive bladder.. https://doi.org/10.1097/01.mou.0000172393.52857.92

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2022

The human mitochondrial genome contains a second light strand promoter.

The human mitochondrial genome must be replicated and expressed in a timely manner to maintain energy metabolism and supply cells with adequate levels of adenosine triphosphate. Central to this process is the idea that replication primers and gene products both arise via transcription from a single light strand promoter (LSP) such that primer formation can influence gene expression, with no consensus as to how this is regulated. Here, we report the discovery of a second light strand promoter (LSP2) in humans, with features characteristic of a bona fide mitochondrial promoter. We propose that the position of LSP2 on the mitochondrial genome allows replication and gene expression to be orchestrated from two distinct sites, which expands our long-held understanding of mitochondrial gene expression in humans.

Adenosine Triphosphate↗
PubMed2021

GCN2 kinase activation by ATP-competitive kinase inhibitors.

Small-molecule kinase inhibitors represent a major group of cancer therapeutics, but tumor responses are often incomplete. To identify pathways that modulate kinase inhibitor response, we conducted a genome-wide knockout (KO) screen in glioblastoma cells treated with the pan-ErbB inhibitor neratinib. Loss of general control nonderepressible 2 (GCN2) kinase rendered cells resistant to neratinib, whereas depletion of the GADD34 phosphatase increased neratinib sensitivity. Loss of GCN2 conferred neratinib resistance by preventing binding and activation of GCN2 by neratinib. Several other Food and Drug Administration (FDA)-approved inhibitors, such erlotinib and sunitinib, also bound and activated GCN2. Our results highlight the utility of genome-wide functional screens to uncover novel mechanisms of drug action and document the role of the integrated stress response (ISR) in modulating the response to inhibitors of oncogenic kinases.

Adenosine Triphosphate↗
PubMed2007

Inhibition of insulin secretion by cerulenin might be due to impaired glucose metabolism.

BACKGROUND: Cerulenin, an inhibitor of protein acylation, has been used as a tool to study the potential role of protein acylation in a variety of activities in different cells, and in stimulus-secretion coupling in pancreatic islets and clonal beta-cells. METHODS: In the present study we investigated its effects on stimulated insulin secretion, glucose metabolism and utilization, oxygen consumption and ATP levels. RESULTS: In isolated rat pancreatic islets, cerulenin pre-treatment (100 microM) inhibited insulin secretion in response to glucose, and to the non-hydrolysable analogue of leucine, aminobicyclo-[2,2,1]heptane-2-carboxylic acid (BCH). These data are in accord with the hypothesis that protein acylation could be involved in the stimulation of insulin secretion. However, we also found that cerulenin profoundly decreased glucose oxidation, glucose utilization, oxygen consumption and ATP levels. Consequently, decreased metabolism provides an alternative mechanism to inhibition of protein acylation that could explain the inhibition of insulin secretion by cerulenin. CONCLUSIONS: Inhibition of insulin secretion by cerulenin can no longer be taken as evidence in favour of a role for protein acylation in the control of insulin release. As protein acylation is known to be involved in the normal functioning of proteins in stimulus-secretion coupling and exocytosis, more direct approaches to understand its role(s) are required.

Adenosine Triphosphate↗