Abstract
Vascular smooth muscle cell (SMC) proliferation is a key process in the pathogenesis
of atherosclerosis. Numerous factors are involved in the regulation of SMC growth.
Nitric oxide (NO) induces the inhibition of SMC proliferation whereas oxidized low-density
lipoproteins (LDL) have a mitogenic effect. Calcium dobesilate (Doxium) is an angioprotective
agent for treating vascular diseases. It has been shown to increase NO production
and to have antioxidant properties but its mechanism of action is not yet fully understood.
This study investigated the effect of calcium dobesilate on proliferation of rat aortic
SMC in culture. Proliferation was evaluated by cell number and DNA synthesis. Orally
administered calcium dobesilate (30, 100, or 200 mg/kg/day for 7 days) induced a dose-dependent
decrease of proliferation of SMC in primary culture compared with controls.In vitro treatment with calcium dobesilate (0.05–5 mM) inhibited both DNA synthesis and proliferation
in a time- and concentration-dependent manner. In bothex vivo andin vitro models, the inhibition was reversible upon removal of the drug. Calcium dobesilate
also stimulated NO production and NO synthase activity. Inhibitors of NO synthesis
attenuated the inhibitory effect of calcium dobesilate (300 μM) on DNA synthesis.
In addition, calcium dobesilate (2.5–40 μM) induced a dose-dependent protection of
cooper-induced LDL oxidation. These results showed that calcium dobesilate inhibits
SMC proliferation, partly by a NO-dependent mechanism, and suggest that it could be
effective in the treatment of pathological disorders associated with vascular SMC
proliferation.
