The influence of fasting and stress on the response of rats to warfarin

A study was undertaken to investigate the influence of fasting (24 hours), epinephrine (four 0.25 mg/kg s.c. doses at hourly intervals), adrenocorticotropin (two 40 I.U. s.c. doses at 2-hour intervals) and immobilization stress (4 hours) on the response of rats to some coumarin or indanedione anticoagulants. The anticoagulants were always administered first and were followed immediately or within the next hour by the appropriate challenge. Fasting produced a significant enhancement of the antiprothrombin response to warfarin (0.5 mg/kg i.v. or 0.75-3.0 mg/kg s.c.), bishydroxycoumarin (7.5 mg/kg i.p. or 10 mg/kg s.c.) and phenindione (40 mg/kg p.o). Epinephrine and immobilization stress, but not adrenocorticotropin, similarly prolonged the prothrombin time after warfarin (0.75-3.0 mg/kg s.c.). When used in the absence of anticoagulants, all challenges had no effect on the prothrombin time. In addition, fasting did not affect the response of anticoagulated animals to vitamin K. Plasma free fatty acids were significantly increased by the various challenges. The binding constant of warfarin to undiluted plasma proteins were decreased from the control value by a factor of 1.7 and 2.0 as a result of immobilization stress and fasting, respectively. Fasting per se increased the amount of bound endogenous free fatty acids per mole of protein; the latter parameter was further increased in the presence of warfarin. The present data show that fasting and stress enhance the anticoagulant response to warfarin and suggest that this might be due to an interference of endogenous free fatty acids with binding of warfarin to plasma proteins.