The study has been designed to investigate downstream mechanisms in the
PTPase inhibition mediated attenuation of
diabetes mellitus and
hypercholesterolemia-induced vascular endothelial dysfunction.
Diabetes mellitus was induced in rats using
streptozotocin (55 mg/kg, i.v. once), while
hypercholesterolemia was produced by feeding high
cholesterol diet. After 4 weeks of
streptozotocin and
Cholesterol rich diet administration, vascular endothelium dysfunction was assessed, in terms of attenuation of
acetylcholine-induced, endothelium-dependent relaxation (Isolated Aortic Ring Preparation), a decrease in serum
nitrate/
nitrite level, as well as
mRNA expression of eNOS (rtPCR) and disruption of integrity of vascular endothelium (Electron microscopy). After 14 days of daily administration,
sodium orthovanadate (8 mg/kg, p.o., 16 mg/kg, p.o and 24 mg/kg, p.o) and
atorvastatin (30 mg/kg, p.o) (positive control) significantly improved
acetylcholine-induced endothelium-dependent relaxation, serum
nitrate/
nitrite level,
mRNA expression of eNOS and maintained integrity of vascular endothelium. However, this ameliorative effect of SOV was significantly blocked by
UCN-01, (PDK inhibitor) and
L-NAME (Inhibitor of eNOS). Therefore, it may be concluded that
sodium orthovanadate, a specific inhibitor of
PTPase, may stimulate PDK and eNOS and consequently improve vascular endothelium dysfunction. Thus, inhibition of
PTPase might be a useful approach in the
therapeutics of vascular endothelium dysfunction.