ACE inhibitor and AT1 antagonist blockade of deformation-induced gene expression in the rabbit jugular vein through B2 receptor activation.
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.
Lauth
M
M
Department of Cardiovascular Physiology, University of Göttingen, Göttingen, Germany.
Cattaruzza
M
M
Hecker
M
M
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000494:pharmacology*; D066298:In Vitro Techniques; D000077405:Irbesartan; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D010477:Perfusion; D011312:Pressure; D012333:RNA, Messenger / Q000096:biosynthesis; D011817:Rabbits; D017257:Ramipril / Q000031:analogs & derivatives* / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D043782:Receptor, Bradykinin B2; D044023:Receptor, Endothelin B; D011945:Receptors, Angiotensin / Q000378:metabolism*; D018002:Receptors, Bradykinin / Q000378:metabolism*; D017466:Receptors, Endothelin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology; D014162:Transfection; D014661:Vasoconstriction / Q000187:drug effects / Q000235:genetics*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D019332:Endothelin-1; D010446:Peptide Fragments; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D043782:Receptor, Bradykinin B2; D044023:Receptor, Endothelin B; D011945:Receptors, Angiotensin; D018002:Receptors, Bradykinin; D017466:Receptors, Endothelin; D013777:Tetrazoles; C068142:glyceraldehyde 3-phosphate dehydrogenase (304-313); C052549:ramiprilat; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D000077405:Irbesartan; D017257:Ramipril