Abstract
Given that vascular calcification is inversely correlated with the clinical intake of menaquinone, a rat model of warfarin-induced calcification may be useful for testing menaquinone and vitamin K-1 potential effects on vascular function. The aim of the present study was to investigate effects of vitamin K-1 and menaquinone-7 treatments on blood pressure and vascular function in warfarin-induced vascular calcification model during five-week intervention in normotensive Wistar-Kyoto rats. Blood pressure was measured weekly, and at the end of the intervention in vitro vascular reactivity measurements were done. Alizarin Red S and von Kossa stainings were used to record possible calcification of aortic sections. Routine clinical chemistry was done from serum and urine samples. Vascular calcification was seen only in a few warfarin-treated animals in histological staining. Warfarin-treatment did not change significantly blood pressure of the rats. Warfarin-treatment increased slightly the endothelium-dependent relaxation of aorta after the L-type calcium channels were blocked. Also the vascular relaxation improved after NOS inhibition in the aorta of the healthy controls and menaquinone-7 treated animals, indicating that the relaxation in those groups was not totally dependent on NO. Clinical chemistry from serum showed some differences in urea, creatinine as well as lipid and glucose metabolism between the healthy controls and warfarin-treated rats.
Highlights
Vascular calcification, the extracellular deposition of calcium in the vascular wall, occurs in relation to a number of vascular disorders, including vascular smooth muscle apoptosis and endothelial dysfunction
The healthy control group (H-C) was heavier than the other groups (p < 0.01) and kidney, heart and left ventricle were smaller compared to the warfarin-treated groups (Table 2) (p < 0.01 for kidney)
There were no differences in feed consumption between the groups, the higher body weight of the healthy group cannot be explained by that (Table 2)
Summary
The extracellular deposition of calcium in the vascular wall, occurs in relation to a number of vascular disorders, including vascular smooth muscle apoptosis and endothelial dysfunction. Several weeks of warfarin treatment has been shown to induce artery wall (elastic lamellae) and heart valves calcification [5]-[12] in experimental models. This phenomenon is not related to anticoagulation or decreased activity of factors II, VII, IX, X, or protein C and S. Other vitamin K-dependent proteins include osteocalcin, nephrocalcin, plaque Gla protein, growth arrest specific gene 6 (Gas 6) and proline rich Gla proteins [13]. Reduced carboxylation of these proteins is likely to be an unavoidable side-effect of warfarin therapy. Warfarin seems to inhibit the activation of MGP and causes vascular calcification in animal models [15] [16]
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