Phosphodiesterase-5 inhibition preserves exercise-onset vasodilator kinetics when NOS activity is reduced

J. Mikhail Kellawan, Jacqueline K. Limberg, Zachariah M. Scruggs, Wayne T. Nicholson, William G. Schrage, Michael J. Joyner, Timothy B. Curry

Research output: Contribution to journalArticle

4 Scopus citations


Nitricoxide (NO)-mediated vasodilation contributes to the rapid rise in muscle blood flow at exercise onset. This occurs via increased cyclic guanos-ine monophosphate (cGMP), which is catabolized by phosphodiesterase-5 (PDE-5). Whether PDE-5 limits exercise vasodilation onset kinetics is unknown. We hypothesized the time course of exercise vasodilation would be 1) accelerated during PDE-5 inhibition (sildenafil citrate, SDF) and 2) decelerated during NO synthase inhibition (N G-monomethyl-L-arginine, L-NMMA), and 3) the effect of SDF on vasodilation onset kinetics would be attenuated with concurrent L-NMMA. Data from 29 healthy adults were analyzed. Individuals completed 5 min of moderate-intensity forearm exercise under control conditions and during 1) oral SDF (n = 8), 2) intra-arterial L-NMMA (n = 15), or 3) combined SDF + L-NMMA (n = 6). Forearm blood flow (FBF; Doppler ultrasound of the brachial artery) and mean brachial artery blood pressure (MAP) were measured continuously. Forearm vascular conductance (FVC, FBF ÷ MAP) was curve-fit with a monoexponential model, and vasodilation onset kinetics were assessed by mean response time (MRT, time to achieve 63% of steady state). SDF had no effect on MRT (P = 0.90). NOS inhibition increased MRT (P = 0.01). MRT during SDF+L-NMMA was not different from control exercise (P = 0.76). PDE-5 inhibition alone has no effect on rapid-onset vasodilation. Whereas NOS inhibition decelerates vasodilator kinetics, when combined with SDF, vasodilator kinetics do not differ from control. These data suggest NO-indepen-dent activation of cGMP occurs at exercise onset; thus PDE-5 inhibition may improve vasodilation in pathologies where NO bioavailability is impaired.

Original languageEnglish (US)
Pages (from-to)276-282
Number of pages7
JournalJournal of applied physiology
Issue number2
StatePublished - Feb 2018


  • Cyclic GMP
  • Exercise onset
  • Nitric oxide
  • Sildenafil

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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