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

Collins C, Klausner AP, Herrick B, Koo HP, Miner AS, Henderson SC, Ratz PH - J. Cell. Mol. Med. (2009)

Bottom Line: Maximum inhibition was approximately 90% by SC-51089, approximately 80-85% by the COX inhibitors and approximately 70% by TP receptor antagonists.In the presence of ibuprofen to abolish SRC, PGE-2, sulprostone, misoprostol, PGF-2alpha and U-46619 (thromboxane mimetic) caused rhythmic contractions that mimicked SRC.Additional studies on prostaglandin-dependent SRC may generate opportunities for the application of novel treatments for disorders leading to overactive bladder.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Urology Division, Virginia Commonwealth University School of Medicine, VA 23298-0614, USA.

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 microM 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-2alpha receptor (FP), AL-8810, inhibited SRC by approximately 50%. Maximum inhibition was approximately 90% by SC-51089, approximately 80-85% by the COX inhibitors and approximately 70% by TP receptor antagonists. In the presence of ibuprofen to abolish SRC, PGE-2, sulprostone, misoprostol, PGF-2alpha 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.

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The average amplitudes (A and C) and frequencies (B and D) of rhythmic contractions produced by PGE-2 and the PGE-2-mimetics, sulprostone (SUL) and misoprostol (MIS; A and B) and PGF-2α and the thromboxane mimetic, U-46619 (C and D). For a comparison, the average plus S.E. and average minus S.E. values of control SRC are shown by dashed lines. Data are means ± S.E., n= 4–8.
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fig05: The average amplitudes (A and C) and frequencies (B and D) of rhythmic contractions produced by PGE-2 and the PGE-2-mimetics, sulprostone (SUL) and misoprostol (MIS; A and B) and PGF-2α and the thromboxane mimetic, U-46619 (C and D). For a comparison, the average plus S.E. and average minus S.E. values of control SRC are shown by dashed lines. Data are means ± S.E., n= 4–8.

Mentions: If prostaglandins produced within the bladder wall were responsible for induction of SRC, then addition of exogenous prostaglandins should produce a contraction. To test this hypothesis, tissues were treated with 10 μM ibuprofen to abolish endogenous prostaglandin production and SRC, and challenged with PGE-2 and the EP 1/3 agonists, sulprostone and misoprostol. Each agonist was added individually to produce a cumulative CRC (see Fig. 4A). Ibuprofen, like indomethacin, abolished SRC, and all three agents caused modest contractions (see Fig. 4 for the effect of PGE-2). Notably, the form of contraction was rhythmic, despite the fact that tissues were exposed to constant (not varying) concentrations of PGE-2. Moreover, at a certain prostaglandin concentration, the rhythmic contraction was similar in amplitude and frequency to that induced spontaneously (i.e. similar to SRC; see Fig. 5). At concentrations greater than 10−6 M, contractions displayed a slower wave, higher amplitude rhythm (see Fig. 4A). PGE-2 induced the most potent contractile response compared to sulprostone and misoprostol (Fig. 5), and 10−8 M PGE-2 caused contraction that displayed an average tension value and a rhythmic frequency ∼2-fold greater than that induced spontaneously (Fig. 5A and B, compare the open symbols at 10−8 M to the two horizontal dashed lines that represent the average plus S.E. and average minus S.E. values of the control SRC). The maximum strength of contraction was ∼0.15–0.2-fold that induced by KCl (i.e. modest in strength), and the maximum frequency achieved was ∼25 cycles per min (Fig. 5). PGF-2α and the thromboxane mimetic, U-46619, likewise caused modest concentration-dependent rhythmic contractions, although the maximum frequency was less than that produced by the EP receptor agonists (Fig. 5C and D).


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

Collins C, Klausner AP, Herrick B, Koo HP, Miner AS, Henderson SC, Ratz PH - J. Cell. Mol. Med. (2009)

The average amplitudes (A and C) and frequencies (B and D) of rhythmic contractions produced by PGE-2 and the PGE-2-mimetics, sulprostone (SUL) and misoprostol (MIS; A and B) and PGF-2α and the thromboxane mimetic, U-46619 (C and D). For a comparison, the average plus S.E. and average minus S.E. values of control SRC are shown by dashed lines. Data are means ± S.E., n= 4–8.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4516481&req=5

fig05: The average amplitudes (A and C) and frequencies (B and D) of rhythmic contractions produced by PGE-2 and the PGE-2-mimetics, sulprostone (SUL) and misoprostol (MIS; A and B) and PGF-2α and the thromboxane mimetic, U-46619 (C and D). For a comparison, the average plus S.E. and average minus S.E. values of control SRC are shown by dashed lines. Data are means ± S.E., n= 4–8.
Mentions: If prostaglandins produced within the bladder wall were responsible for induction of SRC, then addition of exogenous prostaglandins should produce a contraction. To test this hypothesis, tissues were treated with 10 μM ibuprofen to abolish endogenous prostaglandin production and SRC, and challenged with PGE-2 and the EP 1/3 agonists, sulprostone and misoprostol. Each agonist was added individually to produce a cumulative CRC (see Fig. 4A). Ibuprofen, like indomethacin, abolished SRC, and all three agents caused modest contractions (see Fig. 4 for the effect of PGE-2). Notably, the form of contraction was rhythmic, despite the fact that tissues were exposed to constant (not varying) concentrations of PGE-2. Moreover, at a certain prostaglandin concentration, the rhythmic contraction was similar in amplitude and frequency to that induced spontaneously (i.e. similar to SRC; see Fig. 5). At concentrations greater than 10−6 M, contractions displayed a slower wave, higher amplitude rhythm (see Fig. 4A). PGE-2 induced the most potent contractile response compared to sulprostone and misoprostol (Fig. 5), and 10−8 M PGE-2 caused contraction that displayed an average tension value and a rhythmic frequency ∼2-fold greater than that induced spontaneously (Fig. 5A and B, compare the open symbols at 10−8 M to the two horizontal dashed lines that represent the average plus S.E. and average minus S.E. values of the control SRC). The maximum strength of contraction was ∼0.15–0.2-fold that induced by KCl (i.e. modest in strength), and the maximum frequency achieved was ∼25 cycles per min (Fig. 5). PGF-2α and the thromboxane mimetic, U-46619, likewise caused modest concentration-dependent rhythmic contractions, although the maximum frequency was less than that produced by the EP receptor agonists (Fig. 5C and D).

Bottom Line: Maximum inhibition was approximately 90% by SC-51089, approximately 80-85% by the COX inhibitors and approximately 70% by TP receptor antagonists.In the presence of ibuprofen to abolish SRC, PGE-2, sulprostone, misoprostol, PGF-2alpha and U-46619 (thromboxane mimetic) caused rhythmic contractions that mimicked SRC.Additional studies on prostaglandin-dependent SRC may generate opportunities for the application of novel treatments for disorders leading to overactive bladder.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Urology Division, Virginia Commonwealth University School of Medicine, VA 23298-0614, USA.

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 microM 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-2alpha receptor (FP), AL-8810, inhibited SRC by approximately 50%. Maximum inhibition was approximately 90% by SC-51089, approximately 80-85% by the COX inhibitors and approximately 70% by TP receptor antagonists. In the presence of ibuprofen to abolish SRC, PGE-2, sulprostone, misoprostol, PGF-2alpha 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.

Show MeSH
Related in: MedlinePlus