Beschreibung:
<jats:p>
<jats:italic>Abstract</jats:italic>
—Deformation-induced endothelin-1 synthesis in endothelial cells may contribute to the intimal hyperplasia of venous bypass grafts. ACE inhibitors and angiotensin II type 1 (AT
<jats:sub>1</jats:sub>
) receptor antagonists are capable of reducing vein graft disease. Therefore, the effects of these drugs on endothelial preproendothelin-1 (ppET-1) and smooth muscle endothelin B receptor (ET
<jats:sub>B</jats:sub>
-R) expression were investigated in isolated perfused segments of the rabbit jugular vein. Pretreatment with ramiprilat (0.3 μmol/L) or irbesartan (0.01 to 1 μmol/L) had no effect on basal ppET-1 or ET
<jats:sub>B</jats:sub>
-R expression but markedly attenuated the deformation-induced expression of these gene products, and these effects were reversed by the B
<jats:sub>2</jats:sub>
receptor antagonist icatibant (Hoe 140) and by the NO synthase inhibitor
<jats:italic>N</jats:italic>
<jats:sup>G</jats:sup>
-nitro-
<jats:sc>l</jats:sc>
-arginine. Candesartan (1 μmol/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 the inhibitory effect of both ramiprilat and irbesartan on deformation-induced ppET-1 expression is species independent and mediated at the level of transcription. In addition, RT-PCR analysis detected only AT
<jats:sub>1</jats:sub>
receptor expression in the endothelium-intact rabbit jugular vein, and neither irbesartan nor ramiprilat affected endothelial NO synthase expression. Thus, ACE inhibitors and AT
<jats:sub>1</jats:sub>
receptor antagonists are capable of suppressing deformation-induced gene expression in the vessel wall in both an autocrine (ppET-1) and a paracrine (ET
<jats:sub>B</jats:sub>
-R) manner via a common mechanism of action that constitutes a B
<jats:sub>2</jats:sub>
receptor–mediated increase in endothelial NO release.
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