title: Potentiation of the NO-cGMP pathway and blood flow responses during dynamic exercise in healthy humans.
abstract: OBJECTIVE
  Previous work has shown nitric oxide (NO) contributes to ~15% of the hyperemic response to dynamic exercise in healthy humans. This NO-mediated vasodilation occurs, in part, via increases in intracellular cyclic guanosine monophosphate (cGMP), which is catabolized by phosphodiesterase. We sought to examine the effect of phosphodiesterase-5 (PDE-5) inhibition on forearm blood flow (FBF) responses to dynamic handgrip exercise in healthy humans and the role of NO. We hypothesized exercise hyperemia would be augmented by sildenafil citrate (SDF, PDE-5 inhibitor). We further hypothesized any effect of SDF on exercise hyperemia would be abolished with intra-arterial infusion of the NO synthase (NOS) inhibitor L-NG-monomethyl arginine (L-NMMA).
  
  
  METHODS
  FBF (Doppler ultrasound) was assessed at rest and during 5 min of dynamic forearm handgrip exercise at 15% of maximal voluntary contraction under control (saline) conditions and during 3 experimental protocols: (1) oral SDF (n = 10), (2) intra-arterial L-NMMA (n = 20), (3) SDF and L-NMMA (n = 10). FBF responses to intra-arterial sodium nitroprusside (NTP, NO donor) were also assessed.
  
  
  RESULTS
  FBF increased with exercise (p < 0.01). Intra-arterial infusion of L-NMMA resulted in a reduction in exercise hyperemia (17 ± 1 to 15 ± 1 mL/dL/min, p < 0.01). Although the hyperemic response to NTP was augmented by SDF (area under the curve: 41 ± 7 vs 61 ± 11 AU, p < 0.01), there was no effect of SDF on exercise hyperemia (p = 0.33).
  
  
  CONCLUSIONS
  Despite improving NTP-mediated vasodilation, oral SDF failed to augment exercise hyperemia in young, healthy adults. These observations reflect a minor contribution of NO and the cGMP pathway during exercise hyperemia in healthy young humans.
authors.affiliation: Department of Anesthesiology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN, 55905, USA.
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Limberg
authors.affiliation: Department of Anesthesiology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN, 55905, USA.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Malterer
authors.affiliation: Department of Kinesiology, University of Wisconsin, Madison, WI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Mikhail Kellawan
authors.affiliation: Department of Anesthesiology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN, 55905, USA.|Department of Kinesiology, University of Wisconsin, Madison, WI, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Schrage
authors.affiliation: Department of Anesthesiology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN, 55905, USA.
authors.forename: Brad W
authors.initials: BW
authors.lastname: Wilkins
authors.affiliation: Department of Anesthesiology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN, 55905, USA.
authors.forename: Wayne T
authors.initials: WT
authors.lastname: Nicholson
authors.affiliation: Department of Anesthesiology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN, 55905, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Eisenach
authors.affiliation: Department of Anesthesiology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN, 55905, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Joyner
authors.affiliation: Department of Anesthesiology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN, 55905, USA. curry.timothy@mayo.edu.
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Curry
mesh_terms: D000328:Adult; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015444:Exercise / Q000502:physiology*; D005260:Female; D018737:Hand Strength / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006940:Hyperemia / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D000068677:Sildenafil Citrate / Q000008:administration & dosage / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D009712:Nucleotides, Cyclic; D058986:Phosphodiesterase 5 Inhibitors; C584311:cyclic guanosine monophosphate-adenosine monophosphate; D009599:Nitroprusside; D009569:Nitric Oxide; D000068677:Sildenafil Citrate
keywords: Blood flow; Cyclic GMP; Exercise; Nitric oxide; Regional; Sildenafil