Doxorubicin Dose-Dependent Impact on Physiological Balance—A Holistic Approach in a Rat Model

SIMPLE SUMMARY: This study investigated how different doses of the chemotherapeutic drug doxorubicin affected physiological parameters and autonomic function in rats. A positive correlation was found between doxorubicin dose and blood pressure, heart rate, urinary norepinephrine, LF/HF ratio, and fibrotic heart area. We also found that higher doses of doxorubicin resulted in hypotension, bradycardia, and a decrease in the balance of autonomic activity (LF/HF), with 16 mg/kg being the threshold dose at which these changes became evident. These data suggest impaired control of cardiac function and highlight the importance of knowing the correct dosage of doxorubicin to minimize its adverse effects on the heart and improve treatment strategies for cancer patients. ABSTRACT: Doxorubicin (DOX) is commonly used in several chemotherapies to treat various cancers, but it is known to cause cardiotoxicity and cardiac symptoms. Autonomic dysfunction is thought to contribute to the cardiotoxic effects of DOX, but the specific dose required to disrupt homeostatic processes is still unclear and is influenced by numerous factors. This study aimed to investigate how the DOX dosage affects autonomic function and physiological parameters, to elucidate the neurocardiac mechanisms underlying the observed cardiovascular side effects. Wistar rats were treated with DOX for four weeks and divided into three dosing groups: DOX8 (2 mg/kg/week), DOX16 (4 mg/kg/week), and DOX20 (5 mg/kg/week). A control group received NaCl 0.9% saline (1 mL/kg/week). In an acute experiment, we recorded blood pressure (BP), electrocardiogram, heart rate (HR), and respiratory rate (RF). Baroreflex gain and chemoreflex sensitivity were calculated, and cardiac tissue was analyzed with picrosirius histochemistry to measure collagen content. Our results showed that the LF/HF ratio, indicative of autonomic activity, was altered along with hypotension and bradycardia at a cumulative DOX dose threshold of 16 mg/kg. We observed a positive correlation between DOX dose and BP, HR, urinary norepinephrine, LF/HF ratio, and fibrotic heart area. Lower LF/HF ratios were associated with high DOX doses, reflecting drug-induced impairment of autonomic control of HR. This study provides valuable insights into the dose-dependent effects of DOX on physiological parameters and the development of cardiovascular dysfunction. These findings are critical, which is important for optimizing the management and therapeutic strategies for patients undergoing DOX-based chemotherapy.