Abstract
We tested the hypothesis that nitric oxide (NO) and adenosine contribute to the onset of vasodilation during dynamic forearm exercise. Twenty-two subjects performed rhythmic forearm exercise (20 % of maximum) during control and NO synthase (NOS) inhibition (N G-monomethyl-l-arginine; l-NMMA) trials. A subset of subjects performed a third trial of forearm exercise during combined inhibition of NOS and adenosine (aminophylline; n = 9). Additionally, a separate group of subjects (n = 7) performed rhythmic forearm exercise during control, inhibition of adenosine alone and combined inhibition of adenosine and NOS. Forearm vascular conductance (FVC; ml min−1 · 100 mmHg−1) was calculated from blood flow and mean arterial pressure (mmHg). The onset of vasodilation was assessed by calculating the slope of the FVC response for every duty cycle between baseline and steady state, and the number of duty cycles (1-s contraction/2-s relaxation) to reach steady state. NOS inhibition blunted vasodilation at the onset of exercise (11.1 ± 0.8 vs. 8.5 ± 0.6 FVC units/duty cycle; P < 0.001 vs. control) and increased the time to reach steady state (25 ± 1 vs. 32 ± 1 duty cycles; P < 0.001 vs. control). Vasodilation was blunted further with combined inhibition of NOS and adenosine (7.5 ± 0.6 vs. 6.2 ± 0.8 FVC units/duty cycle; P < 0.05 vs. l-NMMA alone), but not with aminophylline alone (16.0 ± 2.2 vs. 14.7 ± 2.0 FVC units/duty cycle; P = 0.67 vs. control). Our data indicate that NO and adenosine (in the absence of NO) contribute to the onset of vasodilation during dynamic forearm exercise.
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References
Behnke BJ, Delp MD (2010) Aging blunts the dynamics of vasodilation in isolated skeletal muscle resistance vessels. J Appl Physiol 108:14–20
Brock RW, Tschakovsky ME, Shoemaker JK, Halliwill JR, Joyner MJ, Hughson RL (1998) Effects of acetylcholine and nitric oxide on forearm blood flow at rest and after a single muscle contraction. J Appl Physiol 85:2249–2254
Carlson RE, Kirby BS, Voyles WF, Dinenno FA (2008) Evidence for impaired skeletal muscle contraction-induced rapid vasodilation in aging humans. Am J Physiol Heart Circ Physiol 294:H1963–H1970
Casey DP, Joyner MJ (2009) NOS inhibition blunts and delays the compensatory dilation in hypoperfused contracting human muscles. J Appl Physiol 107:1685–1692
Casey DP, Joyner MJ (2011a) Contribution of adenosine to compensatory dilation in hypoperfused contracting human muscles is independent of nitric oxide. J Appl Physiol 110:1181–1189
Casey DP, Joyner MJ (2011b) Prostaglandins do not contribute to the nitric oxide-mediated compensatory vasodilation in hypoperfused exercising muscle. Am J Physiol Heart Circ Physiol 301:H261–H268
Casey DP, Madery BD, Pike TL, Eisenach JH, Dietz NM, Joyner MJ, Wilkins BW (2009) Adenosine receptor antagonist and augmented vasodilation during hypoxic exercise. J Appl Physiol 107:1128–1137
Casey DP, Madery BD, Curry TB, Eisenach JH, Wilkins BW, Joyner MJ (2010) Nitric oxide contributes to the augmented vasodilatation during hypoxic exercise. J Physiol 588:373–385
Chavoshan B, Sander M, Sybert TE, Hansen J, Victor RG, Thomas GD (2002) Nitric oxide-dependent modulation of sympathetic neural control of oxygenation in exercising human skeletal muscle. J Physiol 540:377–386
Clifford PS, Hellsten Y (2004) Vasodilatory mechanisms in contracting skeletal muscle. J Appl Physiol 97:393–403
Dietz NM, Rivera JM, Eggener SE, Fix RT, Warner DO, Joyner MJ (1994) Nitric oxide contributes to the rise in forearm blood flow during mental stress in humans. J Physiol 480(Pt 2):361–368
Dinenno FA, Joyner MJ (2003) Blunted sympathetic vasoconstriction in contracting skeletal muscle of healthy humans: is nitric oxide obligatory? J Physiol 553:281–292
Engelke KA, Halliwill JR, Proctor DN, Dietz NM, Joyner MJ (1996) Contribution of nitric oxide and prostaglandins to reactive hyperemia in human forearm. J Appl Physiol 81:1807–1814
Frandsenn U, Bangsbo J, Sander M, Hoffner L, Betak A, Saltin B, Hellsten Y (2001) Exercise-induced hyperaemia and leg oxygen uptake are not altered during effective inhibition of nitric oxide synthase with N(G)-nitro-l-arginine methyl ester in humans. J Physiol 531:257–264
Furchgott RF (1996) The 1996 Albert Lasker Medical Research Awards. The discovery of endothelium-derived relaxing factor and its importance in the identification of nitric oxide. JAMA 276:1186–1188
Harper AJ, Ferreira LF, Lutjemeier BJ, Townsend DK, Barstow TJ (2006) Human femoral artery and estimated muscle capillary blood flow kinetics following the onset of exercise. Exp Physiol 91:661–671
Heinonen I, Saltin B, Kemppainen J, Sipila HT, Oikonen V, Nuutila P, Knuuti J, Kalliokoski K, Hellsten Y (2011) Skeletal muscle blood flow and oxygen uptake at rest and during exercise in humans: a pet study with nitric oxide and cyclooxygenase inhibition. Am J Physiol Heart Circ Physiol 300:H1510–H1517
Hellsten Y, Maclean D, Radegran G, Saltin B, Bangsbo J (1998) Adenosine concentrations in the interstitium of resting and contracting human skeletal muscle. Circulation 98:6–8
Hester RL, Eraslan A, Saito Y (1993) Differences in EDNO contribution to arteriolar diameters at rest and during functional dilation in striated muscle. Am J Physiol 265:H146–H151
Hirai T, Visneski MD, Kearns KJ, Zelis R, Musch TI (1994) Effects of NO synthase inhibition on the muscular blood flow response to treadmill exercise in rats. J Appl Physiol 77:1288–1293
Laughlin MH, Klabunde RE, Delp MD, Armstrong RB (1989) Effects of dipyridamole on muscle blood flow in exercising miniature swine. Am J Physiol 257:H1507–H1515
Martin EA, Nicholson WT, Eisenach JH, Charkoudian N, Joyner MJ (2006a) Bimodal distribution of vasodilator responsiveness to adenosine due to difference in nitric oxide contribution: implications for exercise hyperemia. J Appl Physiol 101:492–499
Martin EA, Nicholson WT, Eisenach JH, Charkoudian N, Joyner MJ (2006b) Influences of adenosine receptor antagonism on vasodilator responses to adenosine and exercise in adenosine responders and nonresponders. J Appl Physiol 101:1678–1684
Maxwell AJ, Schauble E, Bernstein D, Cooke JP (1998) Limb blood flow during exercise is dependent on nitric oxide. Circulation 98:369–374
Metting PJ, Weldy DL, Ronau TF, Britton SL (1986) Effect of aminophylline on hindlimb blood flow autoregulation during increased metabolism in dogs. J Appl Physiol 60:1857–1864
Mortensen SP, Nyberg M, Thaning P, Saltin B, Hellsten Y (2009) Adenosine contributes to blood flow regulation in the exercising human leg by increasing prostaglandin and nitric oxide formation. Hypertension 53:993–999
Musch TI, McAllister RM, Symons JD, Stebbins CL, Hirai T, Hageman KS, Poole DC (2001) Effects of nitric oxide synthase inhibition on vascular conductance during high speed treadmill exercise in rats. Exp Physiol 86:749–757
Naik JS, Valic Z, Buckwalter JB, Clifford PS (1999) Rapid vasodilation in response to a brief tetanic muscle contraction. J Appl Physiol 87:1741–1746
Padilla J, Sheldon RD, Sitar DM, Newcomer SC (2009) Impact of acute exposure to increased hydrostatic pressure and reduced shear rate on conduit artery endothelial function: a limb-specific response. Am J Physiol Heart Circ Physiol 297:H1103–H1108
Radegran G, Calbet JA (2001) Role of adenosine in exercise-induced human skeletal muscle vasodilatation. Acta Physiologica Scand 171:177–185
Radegran G, Saltin B (1998) Muscle blood flow at onset of dynamic exercise in humans. Am J Physiol 274:H314–H322
Radegran G, Saltin B (1999) Nitric oxide in the regulation of vasomotor tone in human skeletal muscle. Am J Physiol 276:H1951–H1960
Roseguini BT, Davis MJ, Harold Laughlin M (2010) Rapid vasodilation in isolated skeletal muscle arterioles: impact of branch order. Microcirculation 17:83–93
Saltin B, Radegran G, Koskolou MD, Roach RC (1998) Skeletal muscle blood flow in humans and its regulation during exercise. Acta Physiologica Scand 162:421–436
Schrage WG, Joyner MJ, Dinenno FA (2004) Local inhibition of nitric oxide and prostaglandins independently reduces forearm exercise hyperaemia in humans. J Physiol 557:599–611
Shepherd JT (1983) Circulation to skeletal muscle. In: Handbook of physiology. The cardiovascular system. Peripheral circulation and organ blood flow (sec 2, vol 3), pp 319–370
Sheriff DD, Rowell LB, Scher AM (1993) Is rapid rise in vascular conductance at onset of dynamic exercise due to muscle pump? Am J Physiol 265:H1227–H1234
Sheriff DD, Nelson CD, Sundermann RK (2000) Does autonomic blockade reveal a potent contribution of nitric oxide to locomotion-induced vasodilation? Am J Physiol Heart Circ Physiol 279:H726–H732
Shoemaker JK, Halliwill JR, Hughson RL, Joyner MJ (1997) Contributions of acetylcholine and nitric oxide to forearm blood flow at exercise onset and recovery. Am J Physiol 273:H2388–H2395
Shoemaker JK, Tschakovsky ME, Hughson RL (1998) Vasodilation contributes to the rapid hyperemia with rhythmic contractions in humans. Can J Physiol Pharmacol 76:418–427
Taddei S, Pedrinelli R, Salvetti A (1991) Theophylline is an antagonist of adenosine in human forearm arterioles. Am J Hypertens 4:256–259
Tschakovsky ME, Shoemaker JK, Hughson RL (1996) Vasodilation and muscle pump contribution to immediate exercise hyperemia. Am J Physiol 271:H1697–H1701
Tschakovsky ME, Sujirattanawimol K, Ruble SB, Valic Z, Joyner MJ (2002) Is sympathetic neural vasoconstriction blunted in the vascular bed of exercising human muscle? J Physiol 541:623–635
Wunsch SA, Muller-Delp J, Delp MD (2000) Time course of vasodilatory responses in skeletal muscle arterioles: role in hyperemia at onset of exercise. Am J Physiol Heart Circ Physiol 279:H1715–H1723
Acknowledgments
We thank Branton Walker, Shelly Roberts, Jean Knutson, Karen Krucker, Chistopher Johnson and Pam Engrav for their technical assistance. We also thank the volunteers for their time. This study was supported by the National Institutes of Health research grants HL-46493 (to M.J. Joyner), AR-55819 (to D.P. Casey) and by CTSA RR-024150. The Caywood Professorship via the Mayo Foundation also supported this research.
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Communicated by Massimo Pagani.
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Casey, D.P., Mohamed, E.A. & Joyner, M.J. Role of nitric oxide and adenosine in the onset of vasodilation during dynamic forearm exercise. Eur J Appl Physiol 113, 295–303 (2013). https://doi.org/10.1007/s00421-012-2439-0
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DOI: https://doi.org/10.1007/s00421-012-2439-0