Dual Contribution of Cyclooxygenase and Lipoxygenase Pathways in Bladder Contractility

Dual Contribution of Cyclooxygenase and Lipoxygenase Pathways in Bladder Contractility ALTHOUGH stromal-urothelial interactions are known to occur during bladder development, little is known about the influence of bladder mucosa on detrusor contractions, and the relative importance of this communication for spontaneous activity of the dome and trigone regions. Elegant studies have described that in the dome the intact urothelium and suburothelium reduce the inhibitory effect of cromakalim (an adenosine triphosphate sensitive potassium channel opener) on spontaneous contractions. However, in the trigone these structures appear to have little influence and an intact urothelium has a predominant influence in the dome region.1 Novel image techniques mapping Ca2⫹ mobilization point to the urothelial origin of intrinsic activity and, thereby, enhance intrinsic detrusor contractions.2 The nature of the putative mediator(s) responsible for the mucosa-muscle communication is still unclear. However, due to the expression and activity of peptidases in the bladder mucosa, metabolic alterations subsequent to mucosal damage have great impact on bladder smooth muscle contractility3 as well as responses to peptides such as neurokinin A4 and substance P.5 The finding that mucosa and detrusor muscle are capable of releasing eicosanoids such as leukotrienes and prostaglandins indicates that these proinflammatory substances may have a key role in the communication between these 2 layers.6 Indeed in the chronically ischemic/hypoxic bladder there is a shift in the importance of these 2 layers as indicated by a loss of urothelial mediated tone and a predominance of leukotrienes mediating smooth muscle instability.7 These findings further address the importance of prostaglandins as

modulators of smooth muscle contractility in the healthy bladder, whereas under ischemic conditions leukotrienes have a predominant role in control of bladder tone and increased smooth muscle contraction in bladder overactivity.8 Translational research also indicates that human detrusor muscle responds to leukotrienes that are capable of potentiating the contractile responses to histamine.9 In this issue of The Journal Tarcan et al (page 2780) report that in the absence of mucosa contractile responses to muscarinic agonists and electrical field stimulation were significantly enhanced. Interestingly lipoxygenase and cyclooxygenase inhibitors reverted the effects of denuded mucosa, and the combination of the 2 inhibitors brought the contractions to normal. In addition, in the denuded bladder relaxation in response to adrenergic agonists was significantly reduced. The role of prostaglandins and leukotrienes as key molecules in our understanding of urothelialmuscle communication will shed some light on new pharmaceutical targets in bladder inflammation, detrusor instability and overactive bladder. Indeed some preclinical studies are already proposing that intravesical instillation with cyclooxygenase-2 inhibitors can be considered a possible treatment for overactive bladder.10 Ricardo Saban Department of Physiology College of Medicine Oklahoma University Health Sciences Center Oklahoma City, Oklahoma

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