title: Heterogenous nature of flow-mediated dilatation in human conduit arteries in vivo: relevance to endothelial dysfunction in hypercholesterolemia.
abstract: Flow-mediated dilatation (FMD) of conduit arteries is dependent on an intact endothelium, although the mechanisms are not fully understood. Using high-resolution ultrasound, we examined the role of endothelial mediators in radial artery dilatation in response to transient (short period of reactive hyperemia) and sustained (prolonged period of reactive hyperemia, hand warming, or an incremental infusion of acetylcholine into the distal radial artery) hyperemia. After short episodes of reactive hyperemia, FMD was abolished by local infusion of the nitric oxide synthesis inhibitor N:(G)monomethyl-L-arginine (5.3+/-1.2% versus 0.7+/-0.7%, P:<0.001). In contrast, basal vessel diameter and dilatation after prolonged episodes of reactive hyperemia, hand warming, and distal infusion of acetylcholine were not attenuated by nitric oxide synthesis inhibition. Inhibition of cyclooxygenase or local autonomic nervous system blockade also had no effect on FMD. Patients with hypercholesterolemia exhibited reduced FMD in response to transient hyperemia, but the response to sustained hyperemia was normal. These data suggest heterogeneity of endothelial responses to blood flow that are dependent on the characteristics of the flow stimulus. Dilatation after brief episodes of hyperemia is mediated by release of nitric oxide, whereas dilatation during sustained hyperemia is unaffected by NO synthesis inhibition. Hypercholesterolemia seems to differentially affect these pathways with impairment of the nitric oxide-dependent pathway and preservation of non nitric oxide-mediated dilatation to sustained flow stimuli.
authors.affiliation: Vascular Physiology Unit, Institute of Child Health and the Centre for Clinical Pharmacology, University College London, London, UK. MichaelJMullen@cs.com
authors.forename: M J
authors.initials: MJ
authors.lastname: Mullen
authors.forename: R K
authors.initials: RK
authors.lastname: Kharbanda
authors.forename: J
authors.initials: J
authors.lastname: Cross
authors.forename: A E
authors.initials: AE
authors.lastname: Donald
authors.forename: M
authors.initials: M
authors.lastname: Taylor
authors.forename: P
authors.initials: P
authors.lastname: Vallance
authors.forename: J E
authors.initials: JE
authors.lastname: Deanfield
authors.forename: R J
authors.initials: RJ
authors.lastname: MacAllister
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001241:Aspirin / Q000494:pharmacology; D001337:Autonomic Agents / Q000494:pharmacology; D001783:Blood Flow Velocity / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004562:Electrocardiography; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006225:Hand / Q000502:physiology; D006358:Hot Temperature; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism*; D006940:Hyperemia / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D017534:Radial Artery / Q000000981:diagnostic imaging / Q000378:metabolism*; D014463:Ultrasonography; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D001337:Autonomic Agents; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D000109:Acetylcholine; D001241:Aspirin