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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:61.)
© 2001 American Heart Association, Inc.

Vascular Biology

ACE Inhibitor and AT₁ Antagonist Blockade of Deformation-Induced Gene Expression in the Rabbit Jugular Vein Through B₂ Receptor Activation

Manfred Lauth; Marco Cattaruzza; Markus Hecker

From the Department of Cardiovascular Physiology, University of Göttingen, Göttingen, Germany.

Correspondence to Dr Markus Hecker, Department of Cardiovascular Physiology, University of Göttingen, Humboldtallee 23, 37073 Göttingen, Germany. E-mail hecker{at}veg-physiol.med.uni-goettingen.de

Abstract—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 (AT₁) 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_B-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_B-R expression but markedly attenuated the deformation-induced expression of these gene products, and these effects were reversed by the B₂ receptor antagonist icatibant (Hoe 140) and by the NO synthase inhibitor N^G-nitro-L-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 AT₁ receptor expression in the endothelium-intact rabbit jugular vein, and neither irbesartan nor ramiprilat affected endothelial NO synthase expression. Thus, ACE inhibitors and AT₁ receptor antagonists are capable of suppressing deformation-induced gene expression in the vessel wall in both an autocrine (ppET-1) and a paracrine (ET_B-R) manner via a common mechanism of action that constitutes a B₂ receptor–mediated increase in endothelial NO release.

Key Words: blood pressure • endothelin-1 • gene expression • graft failure • nitric oxide

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