Assessment of emetine cardiotoxicity in a subacute toxicity experiment in rats

We explored the usefulness of cardiovascular function studies for the detection and characterization of emetine cardiotoxicity in a subacute toxicity experiment. Rats received 1 mg/kg, s.c., emetine five times weekly for up to 7 weeks. In unanesthetized animals, statistically significant changes of the electrocardiogram (EKG) appeared in the following sequence: prolongation of QRS interval (5th day), flattening of T wave (beginning of 4th week), and prolongation of PR interval (end of 4th week). Terminal cardiovascular studies were conducted under urethane anesthesia. EKG changes were comparable to those recorded in conscious rats, but no decrease in T wave voltage occurred. Blood pressure and heart rate remained unchanged. Cardiac output was decreased after 5 and 7 weeks of treatment, when heart weights were also significantly reduced. The response of cardiac output and mean arterial blood pressure to intravenously injected norepinephrine and epinephrine remained unchanged. Catecholamine-induced arrhythmias occurred less frequently in emetine-treated animals than in controls. No significant structural lesions of the heart muscle were detected by light microscopy. The cardiotoxic effects observed in rats were similar to those reported in humans receiving the usual therapeutic dose of approximately 1 mg/kg/day. We conclude that cardiovascular function studies can make an important contribution to the predictive value of animal toxicity experiments.