title: AT1 receptor blockade prevents the decrease in conduit artery flow-mediated dilatation during NOS inhibition in humans.
abstract: Whether AT(1) (angiotenin II type 1) receptor blockade can prevent the decrease in conduit artery FMD (flow-mediated dilatation) during NOS (nitric oxide synthase) inhibition by alternative endothelial pathways has not been explored previously in humans. In 12 healthy subjects, we measured radial artery diameter (echotracking) and flow (Doppler) during FMD induced by sustained reactive hyperaemia during a control period and following NOS inhibition [1.5 mg.min(-1).l(-1) L-NMMA (N(G)-monomethyl-L-arginine)], after a single oral administration of telmisartan (80 mg) or placebo, using a randomized double-blind cross-over design. In six volunteers, we also assessed the roles of prostacyclin and EDHF (endothelium-derived hyperpolarizing factor) during radial FMD after AT(1) receptor blockade by oral administration of aspirin (500 mg) alone, aspirin+L-NMMA or aspirin+L-NMMA+fluconazole (a cytochrome epoxygenases inhibitor; 0.37 mg.min(-1).l(-1)). Telmisartan did not affect radial artery FMD in the control period (10.9+/-0.6% with placebo compared with 9.9+/-0.7% with telmisartan), but prevented its decrease after L-NMMA (9.3+/-0.8% with placebo compared with 12.6+/-1.2% with telmisartan; P<0.05) with no modification in baseline parameters, hyperaemia and radial artery endothelium-independent dilatation to sodium nitroprusside. Moreover, in telmisartan-treated subjects, radial artery FMD, compared with control (9.0+/-1.0%), was not modified by aspirin alone (9.4+/-0.7%) or associated with L-NMMA (9.5+/-0.5%), but was reduced by the combination of aspirin, L-NMMA and fluconazole (7.5+/-0.6%; P<0.05). These results demonstrate that AT(1) receptor blockade prevents the decrease in conduit artery FMD during NOS inhibition in humans, suggesting the development of a compensatory endothelial mechanism. This mechanism appears to be independent of prostacyclin and could possibly be related to an EDHF release.
authors.affiliation: Department of Pharmacology, Institut National de la Santé et de la Recherche Medicale (INSERM) U644, Institut Federatif de Recherche Multidisciplinaire sur les Peptides 23, Rouen University Hospital, Rouen Cedex, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Bellien
authors.forename: Michele
authors.initials: M
authors.lastname: Iacob
authors.forename: Helene
authors.initials: H
authors.lastname: Eltchaninoff
authors.forename: Ryad
authors.initials: R
authors.lastname: Bourkaib
authors.forename: Christian
authors.initials: C
authors.lastname: Thuillez
authors.forename: Robinson
authors.initials: R
authors.lastname: Joannides
mesh_terms: D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D019540:Area Under Curve; D001241:Aspirin / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D015725:Fluconazole / Q000494:pharmacology; D006801:Humans; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D017534:Radial Artery; D012039:Regional Blood Flow / Q000187:drug effects; D000077333:Telmisartan; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001562:Benzimidazoles; D001565:Benzoates; D014665:Vasodilator Agents; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D015725:Fluconazole; D019001:Nitric Oxide Synthase; D001241:Aspirin; D000077333:Telmisartan