title: Familial hypercholesterolemia impairs exercise-induced systemic vasodilation due to reduced NO bioavailability.
abstract: Hypercholesterolemia impairs endothelial function [e.g., the nitric oxide (NO)-cyclic GMP-phosphodiesterase 5 (PDE5) pathway], limits shear stress-induced vasodilation, and is therefore expected to reduce exercise-induced vasodilation. To assess the actual effects of hypercholesterolemia on endothelial function and exercise-induced vasodilation, we compared the effects of endothelial NO synthase (eNOS) and PDE5 inhibition in chronically instrumented Yucatan (Control) and Rapacz familial hypercholesterolemic (FH) swine, at rest and during treadmill exercise. The increases in systemic vascular conductance produced by ATP (relative to nitroprusside) and exercise were blunted in FH compared with Control swine. The vasoconstrictor response to eNOS inhibition, with nitro-l-arginine (NLA), was attenuated in FH compared with Control swine, both at rest and during exercise. Furthermore, whereas the vasodilator response to nitroprusside was enhanced slightly, the vasodilator response to PDE5 inhibition, with EMD360527, was reduced in FH compared with Control swine. Finally, in the pulmonary circulation, FH resulted in attenuated vasodilator responses to ATP, while maintaining the responses to both NLA and EMD360527. In conclusion, hypercholesterolemia reduces exercise-induced vasodilation in the systemic but not the pulmonary circulation. This reduction appears to be the principal result of a decrease in NO bioavailability, which is mitigated by a lower PDE5 activity.
authors.affiliation: Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School Erasmus University Rotterdam, Erasmus University Medical Center, Rotterdam, The Netherlands;
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: de Beer
authors.forename: Daphne
authors.initials: D
authors.lastname: Merkus
authors.forename: Shawn B
authors.initials: SB
authors.lastname: Bender
authors.forename: Darla L
authors.initials: DL
authors.lastname: Tharp
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Bowles
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Duncker
authors.forename: M Harold
authors.initials: MH
authors.lastname: Laughlin
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006940:Hyperemia / Q000378:metabolism / Q000503:physiopathology; D006938:Hyperlipoproteinemia Type II / Q000378:metabolism* / Q000503:physiopathology*; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009599:Nitroprusside / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010805:Physical Conditioning, Animal / Q000502:physiology*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology; D013552:Swine; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D052250:Nitric Oxide Synthase Type III; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5
keywords: PDE inhibitors; arginine; endothelium; exercise