Effects of Potassium Channel Modulators on Myogenic Spontaneous Phasic Contractile Activity in Human Detrusor From Neurogenic Patients

Oger, Stéphanie; Behr‐Roussel, Delphine; Gorny, Diane; Bernabé, Jacques; Comperat, E.; Chartier-Kastler, E.; Denys, P.; Giuliano, F.

doi:10.1016/s1569-9056(08)60447-9

Cited by 4 publications

(7 citation statements)

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“…The smooth-muscle specific BK channel β1 subunits plays a key role in the control of DSM contractility (Petkov et al, 2001a). NS1619 has been reported to inhibit contraction amplitude and frequency of spontaneous phasic contractions in Guinea pig detrusor (Imai et al, 2001) and human detrusor (Oger et al, 2010). In line of extending some early findings; our analysis on all spontaneous contraction parameters in isolated rat DSM strips indicates that NS1619 significantly inhibited amplitude, muscle force integral, frequency, duration, and muscle tone of the spontaneous contractions.…”

Section: Discussionmentioning

confidence: 99%

Large conductance Ca2+-activated K+ channel activation with NS1619 decreases myogenic and neurogenic contractions of rat detrusor smooth muscle

Soder

Petkov

2011

European Journal of Pharmacology

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Large conductance voltage- and Ca2+-activated K+ channels are important in regulating detrusor smooth muscle (DSM) function. Here, we examined systematically how the BK channel pharmacological activation modulates DSM contractility. NS1619, a potent BK channel activator, was utilized as a pharmacological tool to investigate the effect of BK channel activation on rat DSM contractility. Isometric tension recordings of DSM strips isolated from rat urinary bladder were performed systematically under various experimental conditions. NS1619 (30 μM) substantially diminished DSM spontaneous contraction amplitude, muscle force integral, frequency, duration and muscle tone. This effect was blocked by iberiotoxin, a BK channel selective inhibitor. NS1619 inhibited the phasic and tonic contractions in DSM strips pre-contracted with either the cholinergic agonist, carbachol (0.1 μM), or the depolarizing agent, KCl (20 mM and 60 mM KCl). In the presence of elevated KCl, the inhibitory effect of NS1619 was significantly reduced, indicating that BK channel activation is the underlying mechanism of NS1619 action. BK channel activation with NS1619 dramatically decreased the amplitude of electrical field stimulation (EFS)-induced contractions under a range of stimulation frequencies (0.5–50 Hz). In the presence of specific neurotransmitter inhibitors, BK channel activation with NS1619 significantly decreased both cholinergic and purinergic components of EFS-induced contractions. We conclude that BK channel activation with NS1619 significantly inhibited spontaneous, pharmacologically induced and nerve-evoked DSM contractions. Targeting the BK channel with selective openers may offer a unique opportunity to control DSM contractile activity, including pathophysiological conditions such as overactive bladder and detrusor overactivity, regardless of the underlying cause.

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Section: Discussionmentioning

confidence: 99%

Large conductance Ca2+-activated K+ channel activation with NS1619 decreases myogenic and neurogenic contractions of rat detrusor smooth muscle

Soder

Petkov

2011

European Journal of Pharmacology

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“…Isolated bladder strips show phasic contractile activity, also referred to as spontaneous activity. Although there remains some controversy as to whether increased spontaneous phasic contractions are directly related to OAB, isolated bladder strips from patients with OAB and animal models of detrusor over‐activity show an increase in these spontaneous phasic contractions . We have shown that 8 weeks after induction of diabetes in rats using STZ, a time‐point when the bladder is considered to be in a compensated stage, there is an increase in bladder overactivity, and others have shown in the same animal model that isolated bladder strips show increased phasic activity .…”

Section: Introductionmentioning

confidence: 75%

“…As previously described, isolated bladder strips show spontaneous, phasic contractions . We investigated the effect of the urothelium on the amplitude of the spontaneous contractions, and because potassium channels have been reported to play a central role in regulation of spontaneous contractions, we focused on the role of potassium channels in spontaneous activity. First, we investigated the dose dependency of a Kv7 channel opener (retigabine) and blocker (XE 991) on the amplitude of spontaneous contractions in whole bladder strips with the urothelium.…”

Section: Resultsmentioning

confidence: 99%

“…We have shown that 8 weeks after induction of diabetes in rats using STZ, a time‐point when the bladder is considered to be in a compensated stage, there is an increase in bladder overactivity, and others have shown in the same animal model that isolated bladder strips show increased phasic activity . Several published reports show that potassium channels play a role in the development and regulation of these phasic contractions …”

Section: Introductionmentioning

confidence: 97%

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Diabetes attenuates urothelial modulation of detrusor contractility and spontaneous activity

Wang

Tar

et al. 2014

Int J of Urology

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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.

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“…The urinary bladder generates low-level spontaneous contractile activity that may maintain bladder wall tone but enable it to remain compliant during filling [1]; however, detrusor overactivity is accompanied by an increase in spontaneous contractions [2], a phenomenon also present in isolated detrusor preparations [3,4]. It is therefore of interest to develop paradigms that reduce spontaneous activity without causing structural and functional damage to the bladder wall or disrupting the physiological pathways that generate bladder wall tension to initiate voiding.…”

Section: Introductionmentioning

confidence: 99%

Mild external heating and reduction in spontaneous contractions of the bladder

et al. 2017

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Objectives To measure the effect of external heating on bladder wall contractile function, histological structure and expression of proteins related to tissue protection and apoptosis. Material and methods In vitro preparations of bladder wall and ex vivo perfused pig bladders were heated from 37°C to 42, 46 and 50°C for 15 minutes. Isolated preparations were heated by radiant energy and perfused bladders by altering perfusate temperature. Spontaneous contractions or pressure variations were recorded, as well as responses to the muscarinic agonist carbachol or motor nerve excitation in vitro during heating. Tissue histology in control and after heating was analysed using H&E staining and DAPI nuclear labelling. The effects of heating on protein expression levels of i) heat shock proteins HSP27-pSer82 and inducible-HSP70 and ii) caspase-3 and its downstream DNA-repair substrate, PARP were measured. Results Heating to 42°C reduced spontaneous contractions or pressure variations by about 70%, effects were fully reversible. There were no effects on carbachol or nerve-mediated responses. Tissue histology was unaffected by heating and expression of heat-shock proteins as well as caspase-3 and PARP were also unaltered. A TRPV1 antagonist had no effect on the reduction of spontaneous activity. Heating to 46°C had a similar effect on spontaneous activity and also reduced the carbachol contracture. Urothelial structure was damaged, caspase-3 levels were increased and inducible-HSP70 levels declined. At 50°C evoked contractions were abolished, the urothelium was absent and heat-shock proteins and PARP expression was reduced with raised caspase-3 expression. Conclusions Heating to 42°C caused a profound, reversible and reproducible attenuation of spontaneous activity with no tissue damage and no initiation of apoptosis pathways. Higher temperatures caused tissue damage and activation of apoptotic mechanisms. Mild heating offers a novel approach to reduce bladder spontaneous activity.

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Effects of Potassium Channel Modulators on Myogenic Spontaneous Phasic Contractile Activity in Human Detrusor From Neurogenic Patients

Cited by 4 publications

References 0 publications

Large conductance Ca2+-activated K+ channel activation with NS1619 decreases myogenic and neurogenic contractions of rat detrusor smooth muscle

Large conductance Ca2+-activated K+ channel activation with NS1619 decreases myogenic and neurogenic contractions of rat detrusor smooth muscle

Diabetes attenuates urothelial modulation of detrusor contractility and spontaneous activity

Mild external heating and reduction in spontaneous contractions of the bladder

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