Loss of ryanodine receptor calcium‐release channel expression associated with overactive urinary bladder smooth muscle contractions in a detrusor instability model

Abstract

RESULTSIn DI bladder muscle, spontaneous contractile activity persisted in the presence of blockers for known neurotransmitter receptors in the bladder wall. The RyR blocker ryanodine significantly increased the spontaneous contractile frequency in normal bladder strips, but failed to affect spontaneous contractions in DI muscle. Caffeine inhibited spontaneous contractile activity in both the DI and normal strips. After administering the L -type Ca 2 + channel antagonist nimodipine, the myogenic contractile activity was abolished in normal strips; in contrast, in DI strips, the amplitude of contractions was reduced but the frequency of contractions was unchanged. Western blot analysis showed that RyR expression was lower in DI muscle than in normal bladder muscle. CONCLUSIONThese results provide the first characterization of a loss of regulation of spontaneous contractile activity by RyRs in DI muscle associated with a significant decrease in RyR expression. RyRs in normal detrusor muscle act as negative-feedback regulators of spontaneous contractile activity, presumably by releasing Ca 2 + that activates Ca 2 + -dependent K + channels to decrease contractility. This mechanism might be weakened in DI muscle, resulting in spontaneous contractile overactivity.

Original Research: Combined model of bladder detrusor smooth muscle and interstitial cells

“…12 The inhibition of VOCC (Figure 4(d)) completely suppressed the spontaneous Ca 2þ transients (Figure 4(b)), which matched the experimental data.…”

“…activation of Ca 2þ release). 12,18 By modifying the parameters of sarcoplasmic reticulum Ca 2þ -release (Table 1), the model was able to reproduce both types of behavior: an increased frequency of spontaneous Ca 2þ transients (Figure 3 It also activates the Ca 2þ -dependent K þ -conductance probably due to a (local) increase in Ca 2þ concentration. 19 These effects were completely reproduced by the model: inhibition of phasic Ca 2þ -release led to a substantial suppression of Ca 2þ -transients (Figure 4(a)), whereas Ca 2þ -dependent K þ -conductance was significantly increased (higher amplitude and longer duration, Figure 4(c)).…”

“…In general, the model completely reproduced the experimental data reported earlier in the OAB setting. 12 …”

β-Adrenergic relaxation of mouse urinary bladder smooth muscle in the absence of large-conductance Ca2+-activated K+ channel

“…3 above). 5) Expression of RyR, which provides negative feedback regulation of the BK channel to control normal UBSM contractility, is decreased in rat UBSM with experimental PBOO (11). Furthermore, experiments on RyR type 2 (RyR2) heterozygous KO mice (RyR2 ϩ/Ϫ ) suggest that RyR2 deficiency changes UBSM membrane potential and excitation-contraction coupling via BK channel modulation (10).…”

Urothelial/Lamina Propria Spontaneous Activity and the Role of M3 Muscarinic Receptors in Mediating Rate Responses to Stretch and Carbachol

“…In this condition spontaneous bladder contractions occur during the filling stage of the micturition cycle, but the mechanisms involved are unknown. Local mechanisms appear to be involved since spontaneous contractile activity of isolated tissues has been observed (Jiang et al, 2005). In recent years the urothelium and the underlying lamina propria (here abbreviated to U&LP) have been recognized as important regulators of bladder activity, releasing factors that modulate detrusor contraction (Hawthorn et al, 2000, Templeman et al, 2002 and sensory nerve activity (Cockayne et al, 2000).…”