Fluoro-fatty acids and the impairment of cardiac function in the rat in vivo and in vitro

Summary

Dichapetalum toxicarium seeds contain long chain fluoro-fatty acids, particularly fluorooleic acid, which in doses as low as 10 mg/kg can cause death. We have used the rat heart both in vivo and in vitro to assess the cardiovascular effects of various doses of the fluoro-oleic acid extract of the seeds ofDichapetalum toxicarium. Intraperitoneal administration of 0.25 ml of seed extract solution/kg body weight (estimated to be equivalent to 10 mg fluoro-oleic acid/kg body weight) or 0.5 ml/kg body weight (equivalent to 20 mg fluoro-oleic acid/kg body weight) resulted in death in all animals (n−6 in each group). The mean time from administration to death was 36.4±4 h and 21.0±2 h, respectively. Death was attributable to severe bradycardia which developed progressively throughout the experiment. Thus, during the first 6 h, heart rate fell by 32.2% from 450±7 beats/min to 305±36 beats/min (p<0.01) in the 0.25 ml/kg group and by 66±10% to 150±20 beats/min (p<0.001) in the 0.5 ml/kg group. Administration of the extract solution alone or oleic acid alone (equivalent to 0.5 ml/kg seed extract) to control rats had no effect. Investigating the effects of the seed extract in vitro, hearts (n=6 in each group) were perfused with buffer containing 0.5 ml/l seed extract (equivalent to 20 mg fluoro-oleic acid/l) or with buffer containing extract solution alone. In control hearts, there were no changes in heart rate or LVEDP over 150 min of aerobic perfusion; there were small declines in coronary flow, LVDP and LVdP/dt_max. Perfusion with seed extract resulted in a progressive decline in heart rate which, over the first 60 min of perfusion, fell by 53±7% from its control value of 323±11 beats/min to 153±20 beats/min (p<0.001). Similarly, significant declines in coronaryflow (fell by 53±12% over 60 min), LVDP (fell by 61±12% over 60 min) and LVdP/dt_max (fell by 63±7% over 60 min) were observed. LVEDP began to increase after 30 min and by 60 min had increased to 2.8±0.4 kPa (control value=0 kPa). Perfusion with oleic acid (20 mg/l) alone had no adverse effect on cardiac contractile function. Metabolic studies showed that the administration of the seed extract resulted in a loss of myocardial high energy phosphates. Thus, ATP and creatine phosphate fell from their control values of 20.6±0.4 and 27.8±0.6 μmol/g dry weight to 3.9±0.4 and 2.4±0.4 μmol/g dry weight (p<0.001 in each instance), respectively. Lactic acid content increased from 1.4±0.2 to 21.7±1.4 μmol/g dry weight (p<0.001). In conclusion, our results indicate that the fluoro-oleic acid-containing extract ofDichapetalum toxicarium exerts its toxic effects by severely reducing cardiac function. In vivo this can lead to death of the animal.