Abstract
The mechanism by which the coumarin anticoagulants block the action of vitamin K has not been clearly established. Although it is often assumed (1) that they function as direct antagonists of the vitamin at its metabolically active site, there is little experimental evidence to support this view. Bell and Matschiner (2) have suggested that coumarins act by increasing the liver concentration of the 2,3-epoxide of vitamin K which then antagonizes the action of vitamin K. A third theory has been proposed by Lowenthal, who has suggested (3) that warfarin functions as an anticoagulant by blocking some specific cellular transport route for vitamin K. The theory is based on the nature of the antagonism observed between vitamin K and the vitamin K antagonist, 2-chloro-3-phytyl-1,4-naphthoquinone (chloro-K) (4), in vitamin K-deficient, and warfarin-treated rats. Lowenthal's observations were based on the response of plasma factor VII (proconvertin) to the various treatments utilized. The activity of this clotting factor increases faster than that of prothrombin, and may respond to levels of the vitamin which show little effect on prothrombin concentrations. We have therefore studied the effect of chloro-K on prothrombin production, and have extended these observations to the warfarin-resistant rat. These animals, which have hereditary resistance to warfarin (5), provide an additional system for investigating the mechanism of action of warfarin, and these studies provide additional information regarding this strain of rats.
Methods. Normal Holtzman strain rats, and rats homozygous for the warfarin-resistant trait (6, 7) were used. The rats (165–170 g) were housed in coprophagy preventing cages (8) and fed a diet low in vitamin K (9) for 6 to 7 days (normal) or 2 to 3 days (warfarin resistant). After this time, their plasma prothrombin concentrations were usually less than 15 units/ml plasma (normal values are 210–240 units).
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