We investigated the effects of
TH-142177 (N-n-butyl-N-[2'-(1-H-
tetrazole-5-yl)
biphenyl-4-yl]-methyl-(N-carboxy methyl-benzylamino)-
acetamide), a novel selective antagonist of
angiotensin II type 1-receptor (AT1-R) on
angiotensin II (AII)-induced proliferation and migration of vascular smooth muscle cells (VSMC), and on neointimal formation in the rat carotid artery after balloon injury, and on the intracellular signaling by the stimulation of AT1-R. High affinity AII receptor sites were detected in rat VSMC by the use of [125I]Sar1,Ile8-AII.
TH-142177 and
losartan competed with [125I]Sar1,Ile8-AII for the binding sites in VSMC in a monophasic manner, although PD123177, a selective antagonist of
angiotensin II type 2-receptor (AT2-R), had little inhibitory effect, demonstrating the predominant existence of AT1-R in rat VSMC.
TH-142177 prevented AII-induced
DNA synthesis and migration, with a significant inhibition of 74 and 55%, respectively, at the concentration of 100 nM. AII-induced activation of p21ras,
mitogen-activated protein kinase (p42MAPK and p44MAPK), and
protein kinase C was significantly (50-78%) inhibited by
TH-142177 (100 nM), suggesting that the activation of these
enzymes is mediated through the stimulation of AT1-R. Balloon-injured left carotid arteries in rats showed extensive neointimal thickening, and
TH-142177 (3 mg/kg) brought out a marked decrease in the neointimal thickening after balloon injury. In conclusion,
TH-142177 inhibited AII-induced proliferation and migration of rat VSMC and neointimal formation in the carotid artery after balloon injury, and these effects may be related, in part, to the suppression of ras, p42MAPK and p44MAPK, and
protein kinase C activities through the blockade of AT1-R. Thus,
TH-142177 may have therapeutic potential for the treatment of
vascular diseases such as
atherosclerosis and restenosis.