The influence of oxazaphosphorines alkylating agents on autonomic nervous system activity in rat experimental...

The oxazaphosphorines alkylating agents (cyclophosphamide; CP and ifosfamide; IF) are often used in common clinical practice. However, treatment with CP/IF is burdened with the risk of many adverse drug reactions, especially including hemorrhagic cystitis (HC) that is associated with bladder overactivity symptoms (OAB). The HC pathophysiology is still not fully displayed; it seems that autonomic nervous system (ANS) functional abnormalities play important role in this disturbance. The aim of our study was to reveal the potential ANS differences in rat experimental HC model, evoked by CP and IF by an indirect ANS assessment--heart rate variability (HRV) study. We carried out our experimental research in three essential groups: control group (group 1), cyclophosphamide-induced HC (CP-HC; group 2) one and ifosfamide-induced HC (IF-HC; group 3) one. CP was i.p. administrated four times in dose of 75 mg/kg body weight while IF-treated rats received i.p. five drug doses; 50 mg/kg body weight. Control rats were administrated i.p. vehicle in appropriate volumes as CP/IF treated animals. HRV studies were performed the next day after the last oxazaphosphorines dose. Standard time- and spectral (frequency) domain parameters were estimated. We confirmed the HC development after both CP/IF in macroscopic assessment and bladder wet weight measurement; however, it was more aggravated in CP-HC group. Moreover, we demonstrated HRV disturbances, suggesting ANS impairment after both studied oxazaphosphorines, however, consistent with the findings mentioned above, the autonomic dysfunction was more emphasized after CP. CP treatment was also associated with changes of non-normalized HRV spectral components percentage distribution--a marked very low frequency--VLF [%] increase together with low frequency--LF [%] and high frequency--HF [%] decrease were observed. Taking into consideration the next findings, demonstrating the lack of both normalized power spectral components (nLF and nHF) values, the VLF percentage change seems to be of special meaning. IF produced smaller autonomic disturbances, and gentler bladders histological abnormalities comparing to CP. However, similar to CP, VLF [%] relative augmentation together with LF [%] and HF [%] drop accompanied the global ANS activity decrease. Additionally, in the case of IF treatment, a slight trend of nLF increase with nHF decrease was noted, suggesting the possible functional rearrangement between sympathetic (nLF) and parasympathetic (nHF) tension. It seems possible that the vagal withdrawal and--as a consequence--sympathetic overactivity, reflected by VLF [%] enlargement and HF and LF [%] diminishing (as well as LF and HF values decrease), may be an evidence of impaired anti-inflammatory cholinergic pathway, aggravating bladder inflammatory lesions. To sum up, our study showed ANS impairment in both CP- and IF-evoked experimental HC that was reflected in HRV recordings. HRV study, thus, may be considered to be a diagnostic tool for CP/IF treated patients, estimating autonomic abnormalities, associated with the HC development risk and its clinical course.