M. Lauth et al., ACE inhibitor and AT(1) antagonist blockade of deformation-induced gene expression in the rabbit jugular vein through B-2 receptor activation, ART THROM V, 21(1), 2001, pp. 61-66
Deformation-induced endothelin-1 synthesis in endothelial cells may contrib
ute to the intimal hyperplasia of venous bypass grafts. ACE inhibitors and
angiotensin II type 1 (AT(1)) receptor antagonists are capable of reducing
vein graft disease. Therefore, the effects of these drugs on endothelial pr
eproendothelin-1 (ppET-1) and smooth muscle endothelin B receptor (ETB-R) e
xpression were investigated in isolated perfused segments of the rabbit jug
ular vein. Pretreatment with ramiprilat (0.3 mu mol/L) or irbesartan (0.01
to 1 mu mol/L) had no effect on basal ppET-1 or ETB-R expression but marked
ly attenuated the deformation-induced expression of these gene products, an
d these effects were reversed by the B-2 receptor antagonist icatibant (Hoe
140) and by the NO synthase inhibitor N-G-nitro-L-arginine. Candesartan (1
mu mol/L) mimicked the inhibitory effect of irbesartan, Moreover, reporter
gene analysis with a rat ppET-1 promoter-luciferase construct transiently
transfected into porcine aortic cultured endothelial cells revealed that th
e inhibitory effect of both ramiprilat and irbesartan on deformation-induce
d ppET-1 expression is species independent and mediated at the level of tra
nscription. In addition, RT-PCR analysis detected only AT(1) receptor expre
ssion in the endothelium-intact rabbit jugular vein, and neither irbesartan
nor ramiprilat affected endothelial NO synthase expression. Thus, ACE inhi
bitors and AT(1) receptor antagonists are capable of suppressing deformatio
n-induced gene expression in the vessel wall in both an autocrine (ppET-1)
and a paracrine (ETB-R) manner via a common mechanism of action that consti
tutes a B-2 receptor-mediated increase in endothelial NO release.