The present studies were undertaken to investigate the potential effect of a
calcium channel blocker (CCB) to enhance the inhibitory effect of an
angiotensin (Ang) II type 1 (AT1) receptor blocker (ARB) on
vascular injury and the cellular mechanism of the effect of CCB on
vascular remodeling. In
polyethylene cuff-induced
vascular injury of the mouse femoral artery, proliferation of vascular smooth muscle cells (VSMCs) and neointimal formation associated with activation of
extracellular signal-regulated kinase (ERK), and
tyrosine-phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3, inflammatory response assessed by
monocyte chemoattractant protein-1 and
tumor necrosis factor-alpha expression, as well as oxidative stress such as expression of
NADH/
NADPH oxidase p22(
phox) subunit and
superoxide production, were less in AT1a receptor null mice. Administration of nonhypotensive doses of a CCB,
azelnidipine (0.5 or 1 mg/kg per day) attenuated these parameters in wild-type and AT1a receptor null mice. Coadministration of lower doses of an ARB,
olmesartan (0.5 mg/kg per day), and
azelnidipine (0.1 mg/kg per day), which did not affect
vascular remodeling, significantly inhibited these parameters in wild-type mice. Moreover, the effective dose of
azelnidipine (1 mg/kg per day) exaggerated the inhibitory action of
olmesartan at effective doses of 1 or 3 mg/kg per day on VSMC proliferation in the injured arteries. These results suggest that
azelnidipine could inhibit
vascular injury at least partly independent of the inhibition of AT1 receptor activation and that
azelnidipine could exaggerate the vascular protective effects of
olmesartan, suggesting clinical possibility that the combination of CCB and ARB could be more effective in the treatment of
vascular diseases.