Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal
Journal of Pharmacology and Experimental Therapeutics March 12, 2018, jpet.117.246371; DOI: https://doi.org/10.1124/jpet.117.246371
Currently, we have assessed the neuronal control of the urinary bladder in radiation cystitis and whether interstitial cells contribute to the condition. Fourteen days following bladder irradiation (20 Gy) rats were sedated and the urinary bladder was cut in two sagittal halves where electrical field stimulation (EFS; 5-20 Hz) was applied on the pelvic nerve afferents or stretch (80 mN) on one half of the urinary bladder, while contractions were registered on the contralateral half of the urinary bladder in the absence and presence of increasing doses of imatinib (1-10 mg/kg; inhibitor of c-kit+ interstitial cells), atropine (1 mg/kg; to block muscarinic M3 receptors) or PPADS (2 mg/kg; to block P2X1 purinoceptors). Urinary bladders were also excised for organ bath experiments, for western blot analysis, qPCR and immunohistochemistry. In vivo, EFS-evoked contractions were enhanced in the irradiated bladder and imatinib (1-10 mg/mg) was less potent in inhibiting EFS- and stretch-evoked contractions in the irradiated bladder than in controls. In vitro, atropine resistance was increased in the irradiated bladder and contractions generated by EFS (<20 Hz), ATP (0.1-1 mM) and methacholine (10-100 µM) were attenuated by imatinib (100 µM) both in irradiated bladders and controls. The urinary bladder expressions of P2X1, muscarinic M3 receptor, choline acetyltransferase, c-kit and the agonist of c-kit, stem cell factor, were not changed in response to irradiation. In conclusion, bladder irradiation affects several levels of neuronal control of the urinary bladder. Interstitial cells may contribute to some of the symptoms associated with radiation cystitis.
- animal models
- genitourinary system
- muscarinic receptors
- The American Society for Pharmacology and Experimental Therapeutics