endothelin-1 and ramiprilat

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(1)) 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 micromol/L) or irbesartan (0.01 to 1 micromol/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 B(2) receptor antagonist icatibant (Hoe 140) and by the NO synthase inhibitor N(G)-nitro-L-arginine. Candesartan (1 micromol/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(1) receptor expression in the endothelium-intact rabbit jugular vein, and neither irbesartan nor ramiprilat affected endothelial NO synthase expression. Thus, ACE inhibitors and AT(1) 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 B(2) receptor-mediated increase in endothelial NO release.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Cells, Cultured; Endothelin-1; Gene Expression Regulation; Glyceraldehyde-3-Phosphate Dehydrogenases; In Vitro Techniques; Irbesartan; Male; Peptide Fragments; Perfusion; Pressure; Rabbits; Ramipril; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptor, Bradykinin B2; Receptor, Endothelin B; Receptors, Angiotensin; Receptors, Bradykinin; Receptors, Endothelin; RNA, Messenger; Swine; Tetrazoles; Transfection; Vasoconstriction