Short-term and long-term models of doxorubicin-induced cardiomyopathy in rats: A comparison of functional and histopathological changes.

OBJECTIVES: Doxorubicin (DXR), an anthracyclic antineoplastic agent, is one of the most commonly drug utilized to induce dilated cardiomyopathy (DCM) and heart failure (HF), but the well optimized protocol for cardiomyopathy induction leading to development of cardiac systolic dysfunction is unclear. This study aims to critically compare short-term and long-term DXR injection protocols for the induction of DCM in rats. METHODS: Animals were allocated into 3 experimental groups: a ST (short-term DXR injection) group, in which animals received 6 intraperitoneal (i.p.) injections of DXR (2.5mg/kg per dose) over a period of 2 weeks (cumulative dose of 15mg/kg); a LT (long-term DXR injection) group in which animals received weekly i.p. injections of DXR (2mg/kg per dose) over a period of 9 weeks (cumulative dose of 18mg/kg); and a control group in which animals received an appropriate volume of 0.9% saline i.p. All animals were submitted to echocardiography analysis at baseline and after completion treatment. Afterwards, the hearts were collected for conventional light microscopy and collagen quantification. RESULTS: Morphological myocardial analysis of both DXR-treated groups showed an identical pattern of swollen and vacuolated cardiomyocytes and disorganization of myofibrils. There was pronounced interstitial fibrosis in both groups of DXR-treated hearts as compared to controls, as assessed by the interstitial collagen volume fraction. There was no difference in interstitial fibrosis between the ST and LT groups. The echocardiography analysis of the LT group showed structural and functional findings compatible with DCM, including increased left ventricular systolic (5.02±0.96mm) and diastolic (7.68±0.96mm) dimensions and reduction of ejection fraction (69.40±8.51%) as compared to the ST group (4.10±0.89mm, 7.32±0.84, and 79.68±7.23%, respectively) and control group (4.07±0.72mm, 7.17±0.68mm and 80.08±4.71%, respectively), ANOVA p<0.01. CONCLUSIONS: These results indicate that LT injection of DXR is more effective than ST injection in inducing left ventricular dysfunction and structural cardiac changes resembling those found in dilated cardiomyopathy.

Chronic cholinergic stimulation promotes changes in cardiovascular autonomic control in spontaneously hypertensive rats.

Hypertension is often accompanied by autonomic dysfunction, which is detrimental to cardiac regulation. On the other hand, cholinergic stimulation through inhibition of acetylcholinesterase appears to have beneficial effects on cardiac autonomic control. Thus, our objective was to investigate the effects of chronic cholinergic stimulation on hemodynamic and cardiovascular autonomic control parameters in spontaneously hypertensive rats (SHR). For this, 26-week-old SHR (N = 32) and Wistar Kyoto rats (WK; N = 32) were divided into two groups: one treated with vehicle (H2O; N = 16) and the other treated with pyridostigmine bromide (PYR; N = 16) in drinking water (25 mg/kg/day) for 2 weeks. All groups were subjected to recording of arterial pressure (AP) and heart rate (HR), quantification of ejection fraction (EF), evaluation of cardiac tonic autonomic balance by means of double autonomic blockade with methylatropine and propranolol, analysis of systolic AP (SAP) and HR variability (HRV), and evaluation of baroreflex sensitivity (BRS). AP, HR, and EF were reduced in the SHR-PYR group compared with the SHR-H2O group. Evaluation of autonomic parameters revealed an increase in vagal tone participation in cardiac tonic autonomic balance and reduced SAP variability; however, no changes were observed in HRV or BRS. These results suggest that chronic cholinergic stimulation with pyridostigmine bromide promotes reduction in the hemodynamic parameters AP, HR, and EF. Additionally, tonic autonomic balance was improved and a reduction in LF oscillations of SAP variability was observed that could not be attributed to BRS, as the latter did not change. Further studies should be conducted to identify the mechanisms involved in the observed responses.