Diabetes attenuates urothelial modulation of detrusor contractility and spontaneous activity

Abstract

Abbreviations & AcronymsObjectives: To investigate the effect of diabetes on urothelial modulation of bladder contractility. Methods: Bladder strips (urothelium intact or denuded) were prepared from 8-week-old streptozotocin-induced diabetic (n = 19) and non-diabetic control rats (n = 10). The effect of modulators of MaxiK (iberiotoxin and tetraethylammonium) and Kv7 (XE991 and retigabine) potassium channel activity were investigated for their effects on both carbachol-induced force generation and spontaneous contractile activity. Results: In bladder strips from non-diabetic animals, the presence of the urothelium resulted in marked sensitivity to carbachol-induced force generation by modulators of MaxiK and Kv7 channel activity, whereas in the diabetic animal urothelial sensitivity to these agents was significantly diminished. Urothelial-intact bladder strips from non-diabetic animals were more sensitive to modulators of Kv7 activity in reducing the amplitude of spontaneous phasic contractions than urothelial-denuded bladder strips, whereas in diabetic animals the presence or absence of the urothelium did not alter the sensitivity to modulators of Kv7 activity. Spontaneous activity in the presence of tetraethylammonium was not affected by the urothelium in bladder strips from either diabetic or non-diabetic animals. Conclusions:The presence of the urothelium in bladders from non-diabetic animals modulates the activity of potassium blockers to affect bladder contractility, whereas in the diabetic bladder this effect is attenuated. These findings could help to explain the lack of success of pharmaceutical treatments targeting potassium channels to treat bladder pathology in patients with diseases imparing urothelial function.

Urothelial MaxiK-activity regulates mucosal and detrusor metabolism

“…Thus, if diabetes has differential effects on MaxiK activity in urothelium and detrusor, then diabetes-induced changes in the effect of IBTX on UBSM contractility maybe primarily mediated through the urothelium. Indeed, we and others [ 5 , 35 ] have published that the presence of the urothelium on UBSM strips from non-diabetic animals increases sensitivity of carbachol-induced contractility to IBTX, although this effect is attenuated with diabetes. The data presented here further establishes an important role for the urothelium in regulating bladder physiology, urothelial MaxiK activity not only regulates mucosal, but also detrusor activity.…”

“…However the surgery to insert the catheter was performed 4 days prior to the infusion of IBTX which would allow for healing of bladder tissue at the site of catheter entry. During the infusion of IBTX the bladder is not over-distended and several studies suggest that filling the bladder to capacity does not affect bladder permeability [ 5 – 7 ]. In addition, the surgery to insert the infusion catheter into the bladder lumen, or over-distention of the bladder during infusion, may result in the loss of barrier integrity.…”

“…Because of this concept, until recently most studies on the function of MaxiK in bladder physiology have focused on its role in detrusor and rarely differentiate between its presence or potential different role in other tissue compartments of the bladder. However, it is increasingly recognized that MaxiK-activity is present in the non-contractile tissues of the bladder (the mucosa: consisting of the urothelium, lamina propria and microvasculature) where its function is not well-defined [ 5 , 6 ]. Recent studies have suggested that MaxiK plays a role in regulating metabolism and intercellular signaling which may be more relevant to its function in the non-contractile tissues of the bladder [ 7 – 9 ].…”

Detrusor Smooth Muscle KV7 Channels: Emerging New Regulators of Urinary Bladder Function

“…The rat is the next most common animal species in which DSM K V 7 channels have been studied, but only three publications are currently available (Argentieri and Sheldon, 2006;Rode et al, 2010;Wang et al, 2014) and a single report on pig DSM (Svalo et al, 2013). In rat DSM, retigabine and ML213 effectively inhibited DSM spontaneous phasic, 20 mM KCl-induced phasic, or carbachol-potentiated phasic contractions (Argentieri and Sheldon, 2006;Rode et al, 2010;Wang et al, 2014). The elevation of extracellular K + , which results in a reduction of the driving force for K + , caused attenuation in retigabine-induced relaxation (Argentieri and Sheldon, 2006).…”

Pathophysiology of the underactive bladder

“…Dahlin et al [ 60 ] reported that thinly myelinated fibers were more susceptible to oxygen deprivation under ischemic conditions than thicker ones, whereas unmyelinated fibers were resistant to ischemic induction. Furthermore, attenuation of urothelial sensitivity to modulators of potassium channel activity has been observed in diabetic bladders [ 61 ], which may cause afferent sensory dysfunction [ 33 62 63 64 ], as well as contribute to contractile force and spontaneous activity of the detrusor smooth muscle [ 61 ]. Mohammed et al [ 65 66 ] reported that aged rats showed significant decreases in the expression of calcitonin gene-related peptide (CGRP) and substance P on the lumbosacral dorsal root ganglion neurons and in the density of pituitary adenylate cyclase-activating polypeptide innervation on the subepithelial plexus and the muscle layer of the bladder, whereas CGRP and substance P innervation on the muscle layer were slightly reduced.…”