Hypoactivity of rat detrusor muscle in a model of cystitis: exacerbation by non-selective COX inhibitors and amelioration by a selective DP1 receptor antagonist

Abstract

Various studies have confirmed that prostaglandins (PG) alter the bladder motor activity and micturition reflex in both human and animals. However, no sufficient data is reported about the effect of cyclooxygenase (COX) inhibitors neither in normal bladder physiology nor in pathological conditions. This study aims to compare the potential effects of some COX inhibitors with varying COX-1/COX-2 selectivities (indomethacin, ketoprofen, and diclofenac) with that of the selective COX-2 inhibitor (DFU) on bladder function. The role played by some PGs and their receptors in controlling detrusor muscle function in normal condition and in cystitis is also studied. Organ bath experiments were performed using isolated rat detrusor muscle. Direct and neurogenic contractions were induced using ACh and electric stimulation (EFS), respectively. A model of hemorrhagic cystitis was induced by single injection of cyclophosphamide (300 mg/kg) in rats, and confirmed by histophathological examination. Results are expressed as mean ± SEM of 5–9 rats. Alprostadil and iloprost (1 nM- 10 µM) concentration-dependently potentiated ACh (100 μM)- and EFS (4 Hz)-induced contraction, with maximum potentiation of 40.01 ± 5.29 and 27.59 ± 6.64%, respectively, in case of ACh contractions. In contrast, ONO-AE1-259 (selective EP2 agonist, 1 nM–10 μM) inhibited muscle contraction. SC51322 (EP1-antagonist, 10 μM) and RO1138452 (IP antagonist, 10 μM) inhibited both direct and neurogenic responses. Hemorrhagic cystitis reduced both ACh and EFS responses as well as the potentiatory effect of iloprost and the inhibitory effect of RO1138452 on ACh contractions. ONO-AE3-237 (DP1 antagonist, 1 μM) significantly potentiated contractions in cystitis but showed no effect in normal bladder. A significant inhibition of contractile response was observed in presence of indomethacin, ketoprofen, and diclofenac at all tested concentrations (20, 50, and 100 μM). Highest effect was induced by diclofenac. The effect of these COX inhibitors on EFS contractions was intensified in case of cystitis, indomethacin being the most potent. Atropine (1 nM) significantly reduced indomethacin effect on ACh contraction only in normal rats. On the other hand, DFU (10−6 M) significantly potentiated the contractile effect of ACh in case of cystitis although it showed no effect in normal rats. EP1 receptors seem to play an important role in rat bladder contractility. DP1 receptors as COX-2, on the other hand, gain an important role only in case of cystitis. The use of non-selective COX inhibitors in cystitis may be associated with bladder hypoactivity; selective COX-2 inhibitors may be a safer option.

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Acknowledgements

We thank Prof. Mona Yehia, Ph.D., Professor and Head of the Department of Histochemistry and Cell Biology, Medical Health Institute, Alexandria University, Egypt, for her help in conducting histological studies. We also thank Dr. Takayuki Maruyama for providing the ONO compounds as a gift to Dr. Xavier Norel.

Funding

Part of this work was supported by Institue Francais en Egypte, French Agency for the Development of Higher Education and Research, and the Academy of Scientific Research and Technology in Egypt under the frame of “Imhotep Project N°: 31681XL” and “STDF/IFE Project N° 30630”.

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AS and TD conceived the idea. AS, XN, and TD designed research. WB conducted experiments. AS and WB analyzed and interpreted data. AS, WB, and TD revised data and wrote the manuscript. AS and XN were Egyptian and French PI of the project, respectively. All authors read and approved the manuscript.

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Correspondence to Amira M. Senbel.

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Bassiouni, W., Daabees, T., Norel, X. et al. Hypoactivity of rat detrusor muscle in a model of cystitis: exacerbation by non-selective COX inhibitors and amelioration by a selective DP1 receptor antagonist. Naunyn-Schmiedeberg's Arch Pharmacol 392, 437–450 (2019). https://doi.org/10.1007/s00210-018-01599-7

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Keywords

  • COX inhibitors
  • Cystitis
  • Detrusor muscle
  • Prostanoid