TRPA1-dependent regulation of bladder detrusor smooth muscle contractility in normal and type I diabetic rats

Abstract

TRPA1 is a Ca2+-permeable cation channel that is activated by painful low temperatures (˂17 °C), irritating chemicals, reactive metabolites and mediators of inflammation. In the bladder TRPA1 is predominantly expressed in sensory afferent nerve endings, where it mediates sensory transduction. The contractile effect of its activation on detrusor smooth muscle (DSM) is explained by the release from sensory afferents of inflammatory factors – tachykinins and prostaglandins, which cause smooth muscle cell contraction. Diabetes is a systemic disease, with common complications being diabetic cystopathies and urinary incontinence. However, data on how diabetes affects bladder contractility associated with TRPA1 activation are not available. In this study, by using a rat model with streptozotocin-induced type I diabetes, contractility measurements of DSM strips in response to TRPA1-activating and modulating pharmacological agents and assessment of TRPA1 mRNA expression in bladder-innervating dorsal root ganglia, we have shown that diabetes enhances the TRPA1-dependent mechanism involved in bladder DSM contractility. This is not due to changes in TRPA1 expression, but mainly due to the general inflammatory reaction caused by diabetes. The latter leads to an increase in cyclooxygenase-2-dependent prostaglandin synthesis through the mechanisms associated with substance P activity. This results in the enhanced functional coupling between the tachykinin and prostanoid systems, and the concomitant increase of their impact on DSM contractility in response to TRPA1 activation.

Alterations of voltage‐dependent K+ channels in the mesenteric artery during the early and chronic phases of diabetes

“…Type 1 diabetes is referred to as insulin‐dependent diabetes, and is characterized by the loss of insulin‐producing β‐cells in the islets of the pancreas. Several type 1 diabetic disease models including diabetes‐prone (DP) BB rats and streptozotocin (STZ)‐induced diabetic models have been used to study type 1 diabetes . Type 2 diabetes is characterized by insulin resistance, for which db/db mice, OLETF rats, and ZFDM rats serve as experimental animal models .…”

“…Type 1 diabetes is referred to as insulin-dependent diabetes, and is characterized by the loss of insulin-producing β-cells in the islets of the have been used to study type 1 diabetes. 21,22 Type 2 diabetes is characterized by insulin resistance, for which db/db mice, OLETF rats, and ZFDM rats serve as experimental animal models. [23][24][25][26][27][28][29] Among these, the OLETF rat is a useful animal model for type II diabetes.…”

Bladder Dysfunction in an Obese Zucker Rat: The Role of TRPA1 Channels, Oxidative Stress, and Hydrogen Sulfide

“…All these protein expression changes have been related to the bladder mucosa oversensitivity and OAB in rats with MS [12, 25]. TRPV1 and TRPA1 have been identified in urothelial cells and CSPA of the bladder and urethra, which upon activation elicit pain, protective reflexes, and local release from afferents of inflammatory mediators, such as tachykinins and prostaglandins, which cause smooth muscle contraction [6, 8]. Increased expression of these cation channels in the bladder wall is associated with the development of OAB, cystitis-associated hypersensitivity, and LUTS [1, 2, 5].…”

“…No significant changes, however, in the pre- or postjunctional TRPV1 expression in the OZR bladder were observed. As neuronal receptor activation is involved in the release from CSPA of sensory contractile neuropeptides, such as tachykinins [8], the increased expression of prejunctional TRPA1 observed in the OZR bladder may lead to an enhanced nerve-evoked contraction of DSM from the OZR. However, in the genetic obesity model, purinergic and cholinergic neurogenic DSM contractions were consistently diminished according to the lower nerve fiber density observed, thus suggesting that both proinflammation and neuropathy of the OZR bladder, produced by metabolic perturbations, play a pivotal role in causing obesity-associated bladder dysfunction [16].…”

“…These receptors are expressed in urothelial cells and primary afferents of the bladder and urethra, and the increased expression of TRPA1 in the bladder wall is associated with the establishment of OAB and lower urinary tract symptoms (LUTS) [1, 2]. In the type 1 diabetic rat model induced by STZ, an enhanced TRPA1-dependent mechanism is involved in changes of detrusor smooth muscle (DSM) contractility as a consequence of the produced inflammatory reaction which leads to an increase in cyclooxygenase-2-dependent prostaglandin synthesis [8]. In addition to these TRP channels, diabetic micturition disorder is also associated with increased hyperglycemia-induced oxidative stress of the bladder [9] and reduced plasmatic H 2 S concentration [10].…”