A series of naturally occurring
bile alcohols,
bile acids and their conjugates has been investigated as part of our studies to develop unique
anticoagulants with a potent prophylactic effect against vascular endothelial cell injury induced by
lactic acidosis in vivo and in vitro. In an in vivo rat peripheral
arterial occlusion model induced by
lactic acid injection,
oral administration of a single dose of 3 mg/kg
scymnol significantly inhibited edematous swelling and development of lower limb lesions, including
gangrene, and reduced changes in clotting system functions and serum
lactate dehydrogenase activity. It had no effect on clotting system functions in
sham-operated rats. The structure-activity relationship suggests that the [24R-(+)-5beta-cholestane-3alpha,7alpha,24,26-pento l] or [3alpha,7alpha-dihydroxy-5beta-
cholanic acid] structure is important for a potent prophylactic effect following
oral administration.
Intravenous administration of a single dose of 0.3 mg/kg
sodium (25S)-scymnol
sulfate or
scymnol prevented lesion progression as effectively as
oral administration of
scymnol.
Sodium (25S)-scymnol
sulfate and
ursodeoxycholic acid showed clear protective effects against cultured vascular endothelial cell damage due to
lactic acidosis which were dose-dependent. The above results suggest that bile
steroids such as
scymnol,
sodium (25S)-scymnol
sulfate,
ursodeoxycholic acid, and
chenodeoxycholic acid may play a role in protecting endothelial cells against injury caused by
lactic acidosis. These compounds are candidates for novel anti-ischemic drugs that act by specifically protecting vascular endothelial cells.