Indirect autonomic nervous system activity assessment with heart rate variability in rats with cyclophosphamide-induced hemorrhagic cystitis treated with melatonin or agomelatine

AIM OF THE STUDY: Melatonin (MLT) is reported to exert uroprotective effect due to its antioxidant/anti-inflammatory properties. It is unknown whether that effect also results from melatonin receptor activation, or it is attributed to the modulation of the autonomic nervous system (ANS) activity. Our purpose was to evaluate the effect of MLT and agomelatine (AMT) – melatonin receptor agonist on ANS activity, indirectly assessed by heart rate variability (HRV), in rats with cyclophosphamide-induced hemorrhagic cystitis (CP-HC). MATERIAL AND METHODS: CP-HC was induced in all rats by four doses of cyclophosphamide given intraperitoneally (i.p.) at the dose of 75 mg/kg/dose. Rats were divided on three experimental groups and during induction of cystitis were treated i.p. with: (1) saline (control group); (2A/2B) MTL given at the dose of 40 or 100 mg/kg/dose; (3A/3B) AMT given at the dose of 40 or 100 mg/kg/dose. HRV recordings were performed in anesthetized rats at the eight day of the study. RESULTS: Both 2A and 2B animals were characterized by an increase in all non-normalized components in HRV spectrum. Furthermore, normalized LF (nLF) increase along with normalized HF (nHF) decrease were demonstrated in 2B rats. AMT treatment resulted only in an increase in total power (TP) and very low frequency (VLF) in 3A animals. CONCLUSIONS: CP-HC rats treated with MLT were characterized by global ANS activity elevation, with a marked sympathetic tone predominance in subgroup 2B. Since the AMT treatment had no effect on autonomic function, it seems that melatonin modulates autonomic activity via non-receptor mechanisms

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

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

The influence of montelukast on the autonomic nervous system activity in rats with cyclophosphamide-induced hemorrhagic cystitis

The complex pathogenesis of cyclophosphamide-induced hemorrhagic cystitis involves arachidonic acid-derived inflammatory mediators, among them leukotrienes. Montelukast, a leukotriene receptor antagonist, is reported to exert an alleviatory effect in the course of cystitis associated with overactive bladder symptoms. The aim of this study was to verify whether the effect of montelukast is also associated with its influence on autonomic activity. The experiment included 20 rats with cyclophosphamide-induced hemorrhagic cystitis (75 mg/kg, four doses every second day), among them, 10 treated with oral montelukast (10 mg/kg for 8 days) and 10 controls. Time and frequency domain analyses of heart rate variability (HRV) were conducted in all the rats as an indirect measure of their autonomic activity. The montelukast-treated animals showed an increase in root mean square of successive differences (rMSSD), as well as an increase in HRV spectrum total power (TP) and power of very low (VLF) spectral component. This suggests that due to its anti-inflammatory and its anti-leukotriene effect, montelukast improves overall autonomic activity, with no preferential influence on either the sympathetic or parasympathetic part. Furthermore, the increase in VLF corresponds to attenuation of inflammatory response. In conclusion, this study showed that aside from its antagonistic effect on leukotriene receptors, montelukast can also modulate autonomic activity