title: AT1-receptor antagonism improves endothelial function in coronary artery disease by a bradykinin/B2-receptor-dependent mechanism.
abstract: Impaired flow-dependent, endothelium-mediated vasodilation is an early finding in patients with coronary artery disease (CAD). Experimental and some clinical studies observed that angiotensin type-1 receptor antagonists (AT1A) enhance endothelium-dependent relaxation in CAD. The present study was designed to determine whether AT1A improves flow-dependent dilation (FDD) in patients with CAD and, if so, whether bradykinin and NO are involved. High-resolution ultrasound was used to measure radial artery diameter at rest and during reactive hyperemia, causing endothelium-mediated vasodilation. Twenty patients with CAD were randomly assigned to receive intrabrachial infusion of candesartan (800 microg/min) with and without icatibant, a bradykinin B2-receptor antagonist (90 microg/min; group A) or N-monomethyl-l-arginine (L-NMMA), an NO-synthase inhibitor (7 micromol/min; group B). The AT1A candesartan improved FDD by >40%, an effect that was inhibited by icatibant (group A: control, 7.3+/-0.9; candesartan, 10.3+/-1.1; candesartan+icatibant, 5.0+/-0.5%). Similarly, L-NMMA blunted the beneficial effect of candesartan (group B: control, 6.3+/-0.6; candesartan, 8.9+/-0.6; candesartan+L-NMMA: 4.7+/-0.5%; each P<0.01). The angiotensin type-1 receptor antagonist candesartan improves flow-dependent, endothelium-mediated vasodilation in patients with CAD. This effect is inhibited by either icatibant and or L-NMMA, suggesting that both bradykinin and NO contribute to the vascular effects of AT1-receptor antagonists in this patient population.
authors.affiliation: Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl Neuberg Str 1, 30625 Hannover, Germany. Hornig.Burkhard@mh-hannover.de
authors.forename: Burkhard
authors.initials: B
authors.lastname: Hornig
authors.forename: Christoph
authors.initials: C
authors.lastname: Kohler
authors.forename: Daniel
authors.initials: D
authors.lastname: Schlink
authors.forename: Helma
authors.initials: H
authors.lastname: Tatge
authors.forename: Helmut
authors.initials: H
authors.lastname: Drexler
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001783:Blood Flow Velocity / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007261:Infusions, Intra-Arterial; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D017534:Radial Artery / Q000187:drug effects / Q000503:physiopathology; D044140:Receptor, Angiotensin, Type 1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D000319:Adrenergic beta-Antagonists; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D065168:Bradykinin Receptor Antagonists; D004791:Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D013777:Tetrazoles; D009599:Nitroprusside; D019323:omega-N-Methylarginine; C065679:icatibant; D019001:Nitric Oxide Synthase; C081643:candesartan; D001920:Bradykinin