title: Effect of PDE5 inhibition on the modulation of sympathetic α-adrenergic vasoconstriction in contracting skeletal muscle of young and older recreationally active humans.
abstract: Aging is associated with an altered regulation of blood flow to contracting skeletal muscle; however, the precise mechanisms remain unclear. We recently demonstrated that inhibition of cGMP-binding phosphodiesterase 5 (PDE5) increased blood flow to contracting skeletal muscle of older but not young human subjects. Here we examined whether this effect of PDE5 inhibition was related to an improved ability to blunt α-adrenergic vasoconstriction (functional sympatholysis) and/or improved efficacy of local vasodilator pathways. A group of young (23 ± 1 yr) and a group of older (72 ± 1 yr) male subjects performed knee-extensor exercise in a control setting and following intake of the highly selective PDE5 inhibitor sildenafil. During both conditions, exercise was performed without and with arterial tyramine infusion to evoke endogenous norepinephrine release and consequently stimulation of α1- and α2-adrenergic receptors. The level of the sympatholytic compound ATP was measured in venous plasma by use of the microdialysis technique. Sildenafil increased (P < 0.05) vascular conductance during exercise in the older group, but tyramine infusion reduced (P < 0.05) this effect by 38 ± 9%. Similarly, tyramine reduced (P < 0.05) the vasodilation induced by arterial infusion of a nitric oxide (NO) donor by 54 ± 9% in the older group, and this effect was not altered by sildenafil. Venous plasma [ATP] did not change with PDE5 inhibition in the older subjects during exercise. Collectively, PDE5 inhibition in older humans was not associated with an improved ability for functional sympatholysis. An improved efficacy of the NO system may be one mechanism underlying the effect of PDE5 inhibition on exercise hyperemia in aging.
authors.affiliation: Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark; mnyberg@nexs.ku.dk.
authors.forename: Michael
authors.initials: M
authors.lastname: Nyberg
authors.affiliation: Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Peter
authors.initials: P
authors.lastname: Piil
authors.affiliation: Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Jon
authors.initials: J
authors.lastname: Egelund
authors.affiliation: Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, St. Louis, Missouri;
authors.forename: Randy S
authors.initials: RS
authors.lastname: Sprague
authors.affiliation: Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; and The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Mortensen
authors.affiliation: Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Ylva
authors.initials: Y
authors.lastname: Hellsten
mesh_terms: D000255:Adenosine Triphosphate / Q000097:blood; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000378:metabolism*; D001783:Blood Flow Velocity; D001808:Blood Vessels / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D006801:Humans; D006940:Hyperemia / Q000378:metabolism / Q000503:physiopathology; D007261:Infusions, Intra-Arterial; D008297:Male; D017551:Microdialysis; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000008:administration & dosage; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D012039:Regional Blood Flow; D000068677:Sildenafil Citrate / Q000008:administration & dosage*; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism; D013566:Sympathomimetics / Q000008:administration & dosage*; D014439:Tyramine / Q000008:administration & dosage*; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*; D055815:Young Adult
chemical_list: C547713:ADRA1A protein, human; C547768:ADRA2A protein, human; D020030:Nitric Oxide Donors; D058986:Phosphodiesterase 5 Inhibitors; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D013566:Sympathomimetics; D000255:Adenosine Triphosphate; D000068677:Sildenafil Citrate; D014439:Tyramine
keywords: ATP; cGMP; exercise; nitric oxide; sildenafil