The inhibitory effects of ghrelin on micturition reflex in urethane-anesthetized rats

Honda M1, Tsounapi P1, Kimura Y1, Kawamoto B1, Shimizu S2, Hikita K1, Shimizu T2, Saito M2, Takenaka A1

Research Type

Pure and Applied Science / Translational

Abstract Category

Neurourology

Abstract 421
Open Discussion ePosters
Scientific Open Discussion Session 21
Thursday 30th August 2018
13:50 - 13:55 (ePoster Station 11)
Exhibition Hall
Animal Study Basic Science Physiology
1. Department of Urology, Tottori University Faculty of Medicine, 2. Department of Pharmacology, Kochi Medical School
Presenter
M

Masashi Honda

Links

Poster

Abstract

Hypothesis / aims of study
Ghrelin, a 28 amino acid growth hormone, is widely distributed throughout the peripheral and central nervous systems [1]. Ghrelin’s many physiological functions include growth promotion, suppression of inflammation, and enhancement of food intake [2]. Increasingly, evidence suggests an antinociceptive role of ghrelin in murine pain models [3]. However, whether ghrelin also plays a role in controlling the micturition reflex is unclear. Therefore, The aim of this study was to investigate the effects of intravenous administration of ghrelin on the micturition reflex in rats.
Study design, materials and methods
Adult female Sprague-Dawley rats weighing 228 to 252 g were used. Rats were anesthetized with isoflurane followed by urethane (1.2 g/kg subcutaneously). Thereafter the abdomen was opened through a midline incision and a PE-50 polyethylene catheter connected to a pressure transducer and amplifier was implanted into the bladder through the bladder dome. This catheter was used to fill the bladder by continuous infusion of saline and record intravesical pressure during cystometry. After intravesical catheter insertion, saline was continuously infused for 2 hours at a rate of 0.04 ml per minute to record cystometrograms during a control period. Stable micturition cycles were established, and ghrelin (300, 600, and 900 μg/kg, n=6 per dose) was then administered intravenously and changes in bladder activity were monitored. In another group of animals, ghrelin (900 μg/kg, n=6) was administered intravenously when the first bladder contraction was observed after intravenous administration of naloxone, an opioid receptor antagonist (3 mg/kg, n=6) to determine whether the effect of ghrelin was mediated by the opioid systems. Intravenous injections were made through a cannula (PE-10) inserted into the right jugular vein. Cystometric parameters were recorded and compared before and after drug administration. All data values are expressed as the mean ± standard deviation. A one-way ANOVA followed by Dunnett’s multiple comparison test was used for the statistical analysis between the vehicle and drug-treated groups. Wilcoxon’s signed rank test was used to compare cystometric variables before and after treatment. For all statistical tests, p <0.05 was considered significant.
Results
Intravenous administration of ghrelin at 300, 600, and 900 μg/kg increased intercontraction intervals in a dose-dependent fashion to 119.1 ± 3.8%, 147.5 ± 8.3%, and 154.4 ± 11.5% of the control value, respectively (p <0.01). These inhibitory effects were seen immediately after administration and returned to the pre-control level within 80 minutes. Intravenous administration of ghrelin at 300, 600, and 900 μg/kg also increased threshold pressure in a dose-dependent fashion to 9.58 ± 1.03 cmH2O, 12.7 ± 1.51 cmH2O, and 15.6 ± 3.11 cmH2O, respectively, from the control value of 4.49 ± 1.32 cmH2O (p <0.01). There were no significant changes in maximum pressure, basal pressure or post void residual at any doses tested. When naloxone was administered one voiding cycle before ghrelin administration, the increases in intercontraction intervals and threshold pressure induced by ghrelin administration alone were not seen.
Interpretation of results
In the present study, ghrelin administered intravenously increased intercontraction intervals and threshold pressure in urethane-anesthetized rats. These findings indicate that ghrelin has an inhibitory action on the micturition reflex in urethane-anesthetized rats. The main function of ghrelin seems to be mediated by modulation of afferent activity because ghrelin induced increases in intercontraction intervals and threshold pressure without affecting maximum pressure or basal pressure. In addition, because the ghrelin-induced increases in intercontraction intervals and threshold pressure were prevented when naloxone was administered prior to ghrelin application, indicating that the effects of ghrelin were mediated by activation of the opioid system.
Concluding message
These results in this study indicate that ghrelin plays an important role in the control of the micturition reflex and that ghrelin can inhibit the micturition reflex through activation the opioid system. Thus, ghrelin could be effective for the treatment of bladder dysfunction such as overactive bladder.
References
  1. Colldén G, Tschöp MH, Müller TD et al. Therapeutic potential of targeting the ghrelin pathway. Int J Mol Sci 2017; 18(4): E798.
  2. Narula T, deBoisblanc BP. Ghrelin in critical illness. Am J Respir Cell Mol Biol 2015; 53(4): 437-442.
  3. Bianchi E, Boekelheide K, Sigman M et al. Ghrelin ameliorates adhesions in a postsurgical mouse model. J Surg Res 2016; 201(1): 226-234.
Disclosures
Funding None Clinical Trial No Subjects Animal Species Rat Ethics Committee Institutional Animal Care and Use Committee of Tottori University
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