Potential for control of detrusor smooth muscle spontaneous rhythmic contraction by cyclooxygenase products released by interstitial cells of Cajal

Abstract

Interstitial cells of Cajal (ICCs) have been identified as pacemaker cells in the upper urinary tract and urethra, but the role of ICCs in the bladder remains to be determined. We tested the hypotheses that ICCs express cyclooxygenase (COX), and that COX products (prostaglandins), are the cause of spontaneous rhythmic contraction (SRC) of isolated strips of rabbit bladder free of urothelium. SRC was abolished by 10 μM indomethacin and ibuprofen (non-selective COX inhibitors). SRC was concentration-dependently inhibited by selective COX-1 (SC-560 and FR-122047) and COX-2 inhibitors (NS-398 and LM-1685), and by SC-51089, a selective antagonist for the PGE-2 receptor (EP) and ICI-192,605 and SQ-29,548, selective antagonists for thromboxane receptors (TP). The partial agonist/antagonist of the PGF-2α receptor (FP), AL-8810, inhibited SRC by ∼50%. Maximum inhibition was ∼90% by SC-51089, ∼80–85% by the COX inhibitors and ∼70% by TP receptor antagonists. In the presence of ibuprofen to abolish SRC, PGE-2, sulprostone, misoprostol, PGF-2α and U-46619 (thromboxane mimetic) caused rhythmic contractions that mimicked SRC. Fluorescence immunohistochemistry coupled with confocal laser scanning microscopy revealed that c-Kit and vimentin co-localized to interstitial cells surrounding detrusor smooth muscle bundles, indicating the presence of extensive ICCs in rabbit bladder. Co-localization of COX-1 and vimentin, and COX-2 and vimentin by ICCs supports the hypothesis that ICCs were the predominant cell type in rabbit bladder expressing both COX isoforms. These data together suggest that ICCs appear to be an important source of prostaglandins that likely play a role in regulation of SRC. Additional studies on prostaglandin-dependent SRC may generate opportunities for the application of novel treatments for disorders leading to overactive bladder.

Prostaglandin E2 excitatory effects on rat urinary bladder: a comparison between the β-adrenoceptor modulation of non-voiding activity in vivo and micro-contractile activity in vitro

“…The present study has shown that PGE 2 augments spontaneous basal MCs observed in isolated rat urinary bladder strips as observed in many other species such as guinea pig (De Jong et al 2007), rabbit (Collins et al 2009) and mouse (Kobayter et al 2012). …”

Evidence that actomyosin cross bridges contribute to “passive” tension in detrusor smooth muscle

“…9E). We recently showed that spontaneous rhythmic contraction in DSM can be abolished by cyclooxygenase inhibitors, suggesting that prostaglandins are basally released by detrusor (6). Thus, prostaglandin receptor activation may rather selectively activate cell signaling systems involved in regulating APS.…”

Expression and distribution of key enzymes of the cyclic GMP signaling in the human clitoris: relation to phosphodiesterase type 5 (PDE5)

“…28 It has been suggested that ICs may have a pivotal role as so-called pacemakers and mediators of neurotransmission in the bladder, urethra and penile erectile tissue. [14][15][16][17]29 The role of ICs in the clitoris remains to be established. Some hypotheses have been proposed: adult mesenchymal cells, which might participate in (a) intercellular signaling or (b) chemo-mechanical transducing or act as (c) players in pace-making through direct cell-to-cell communication.…”