TY - JOUR
T1 - Phosphodiesterase-5 inhibition preserves exercise-onset vasodilator kinetics when NOS activity is reduced
AU - Kellawan, J. Mikhail
AU - Limberg, Jacqueline K.
AU - Scruggs, Zachariah M.
AU - Nicholson, Wayne T.
AU - Schrage, William G.
AU - Joyner, Michael J.
AU - Curry, Timothy B.
N1 - Publisher Copyright:
Copyright © 2018 American Physiological Society. All rights reserved.
PY - 2018/2
Y1 - 2018/2
N2 - 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.
AB - 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.
KW - Cyclic GMP
KW - Exercise onset
KW - Nitric oxide
KW - Sildenafil
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U2 - 10.1152/japplphysiol.00483.2017
DO - 10.1152/japplphysiol.00483.2017
M3 - Article
C2 - 28982942
AN - SCOPUS:85043503588
SN - 8750-7587
VL - 124
SP - 276
EP - 282
JO - Journal of applied physiology
JF - Journal of applied physiology
IS - 2
ER -