Frank A Dinenno

Colorado State University, Fort Collins, Colorado, United States

Are you Frank A Dinenno?

Claim your profile

Publications (80)395.31 Total impact

  • Anne R Crecelius · Frank A Dinenno
    Channels (Austin, Tex.) 07/2015; DOI:10.1080/19336950.2015.1066142 · 2.32 Impact Factor
  • Frank A Dinenno
    [Show abstract] [Hide abstract]
    ABSTRACT: In humans, the net effect of acute systemic hypoxia in quiescent skeletal muscle is vasodilation despite reflex increases in muscle sympathetic vasoconstrictor nerve activity. This vasodilation increases tissue perfusion and oxygen delivery to maintain tissue oxygen consumption. Although several mechanisms may be involved, we recently tested the roles of two endothelial-derived substances during conditions of sympathoadrenal blockade to isolate local vascular control mechanisms: nitric oxide (NO) and prostaglandins (PGs). Our findings indicate that (1) NO normally plays a role in regulating vascular tone during hypoxia independent of the PG pathway; (2) PGs do not normally contribute to vascular tone during hypoxia, however do impact vascular tone when NO is inhibited; (3) NO and PGs are not independently obligatory to observe hypoxic vasodilation when assessed as a response from rest to steady-state hypoxia; and (4) combined NO and PG inhibition abolishes hypoxic vasodilation in human skeletal muscle. When the stimulus is exacerbated via combined submaximal rhythmic exercise and systemic hypoxia to cause further red blood cell (RBC) deoxygenation, blood flow is augmented compared with normoxic exercise via local dilator mechanisms to maintain oxygen delivery to the active tissue. Data obtained in a follow-up study indicate that combined NO and PG inhibition during hypoxic exercise blunts the augmented vasodilation and hyperemia compared with control (normoxic) conditions ~50%, however the response is not abolished implicating other local substances are involved. Factors associated with greater RBC deoxygenation such as ATP release and/or nitrite reduction to NO likely play a role in regulating this response. Copyright © 2015, Journal of Applied Physiology.
    Journal of Applied Physiology 05/2015; DOI:10.1152/japplphysiol.00256.2015 · 3.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Human aging is associated with reduced skeletal muscle perfusion during exercise which may be a result of impaired endothelium-dependent dilation and/or attenuated ability to blunt sympathetically-mediated vasoconstriction. Intra-arterial infusion of ascorbic acid (AA) increases nitric oxide-mediated vasodilation and forearm blood flow (FBF) during handgrip exercise in older adults, yet it remains unknown whether an acute oral dose can similarly improve FBF or enhance the ability to blunt sympathetic vasoconstriction during exercise. We hypothesized that (1) acute oral AA would improve FBF (Doppler ultrasound) and oxygen consumption (VO2) via local vasodilation during graded rhythmic handgrip exercise in older adults (protocol 1), and (2) AA ingestion would not enhance sympatholysis in older adults during handgrip exercise (protocol 2). In protocol 1 (n=8; 65{±plus minus}3 years), AA did not influence FBF or VO2 during rest or 5% MVC exercise, but increased FBF (199±13 vs. 248±16 ml/min and 343±24 vs. 403± 33 ml/min; P< 0.05) and VO2 (26±2 vs.34±3 ml/min and 43±4 vs. 50±5 ml/min; P< 0.05) at both 15% and 25% MVC, respectively. The increased FBF was due to elevations in forearm vascular conductance (FVC). In protocol 2 (n =10; 63±2 years), following AA, FBF was similarly elevated during 15% MVC (~20%), however, vasoconstriction to reflex increases in sympathetic activity during -40mmHg lower body negative pressure at rest (ΔFVC: -16±3 vs. -16±2%) or during 15% MVC (ΔFVC: -12±2 vs. -11±4%) was unchanged. Our collective results indicate that acute oral ingestion of AA improves muscle blood flow during exercise in older adults via local vasodilation. Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 05/2015; 309(2):ajpheart.00209.2015. DOI:10.1152/ajpheart.00209.2015 · 4.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sympathetic vasoconstriction in contracting skeletal muscle is blunted relative to that which occurs in resting tissue; however, the mechanisms underlying this "functional sympatholysis" remain unclear in humans. We tested the hypothesis that α1 -adrenergic vasoconstriction is augmented during exercise following inhibition of inwardly-rectifying potassium (KIR ) channels and Na(+) /K(+) -ATPase (BaCl2 +ouabain). In young healthy humans, we measured forearm blood flow (Doppler ultrasound) and calculated vascular conductance (FVC) at rest, during steady-state stimulus conditions (pre-PE), and after 2 min of phenylephrine (PE; α1 -adrenoceptor agonist) infusion via brachial artery catheter in response to two different stimuli: moderate (15% maximal voluntary contraction) rhythmic handgrip exercise or adenosine infusion. In Protocol 1 (n = 11) a total of six trials were performed in three conditions: control (saline), combined enzymatic inhibition of nitric oxide (NO) and prostaglandin (PG) synthesis (L-NMMA+ketorolac) and combined inhibition of NO, PGs, KIR channels and Na(+) /K(+) -ATPase (L-NMMA+ketorolac+BaCl2 +ouabain). In Protocol 2 (n = 6) a total of four trials were performed in two conditions: control (saline), and combined KIR channel and Na(+) /K(+) -ATPase inhibition. All trials occurred after local β-adrenoceptor blockade (propranolol). PE-mediated vasoconstriction was calculated (%ΔFVC) in each condition. Contrary to our hypothesis, despite attenuated exercise hyperaemia of ∼30%, inhibition of KIR channels and Na(+) /K(+) -ATPase, combined with inhibition of NO and PGs (Protocol 1) or alone (Protocol 2) did not enhance α1 -mediated vasoconstriction during exercise (Protocol 1: -27 ± 3%; P = 0.2 vs control, P = 0.4 vs L-NMMA+ketorolac; Protocol 2: -21 ± 7%; P = 0.9 vs control). Thus, contracting human skeletal muscle maintains the ability to blunt α1 -adrenergic vasoconstriction during combined KIR channel and Na(+) /K(+) -ATPase inhibition. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    The Journal of Physiology 04/2015; DOI:10.1113/JP270461 · 4.54 Impact Factor
  • Source
    Blood 03/2015; 125(11):1844-1845. DOI:10.1182/blood-2014-11-609610 · 10.43 Impact Factor
  • Anne R Crecelius · Brett S Kirby · Frank A Dinenno
    [Show abstract] [Hide abstract]
    ABSTRACT: Regulation of vascular tone is a complex response that integrates multiple signals which allow for blood flow and oxygen supply to appropriately match oxygen demand. Here, we discuss the potential role of intravascular ATP as a primary factor in these responses and put forth the hypothesis that deficient ATP release contributes to impairments in vascular control exhibited in aged and diseased populations.
    Exercise and Sport Sciences Reviews 11/2014; 43(1). DOI:10.1249/JES.0000000000000031 · 4.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Human ageing is associated with attenuated skeletal muscle blood flow during exercise. It is unknown whether elevated sympathetic nervous system activity with ageing limits skeletal muscle blood flow during exercise. Determining the role of the sympathetic nervous system in regulating blood flow in healthy ageing is clinically relevant as age-related changes in the sympathetic nervous system are exacerbated with many diseases associated with impaired tissue perfusion.In the present study, compared to young adults, older adults demonstrate impaired skeletal muscle blood flow during graded handgrip exercise, and this is due to reductions in vascular conductance.Second, the increase in muscle blood flow and vascular conductance during exercise after removal of sympathetic α-adrenergic vasoconstrictor tone in older adults was lower compared to young adults, similar to what was observed under control conditions.As such, the age-associated impairment in exercising muscle blood flow and vascular conductance persisted during local adrenoreceptor blockade.
    The Journal of Physiology 09/2014; 592(21). DOI:10.1113/jphysiol.2014.278358 · 4.54 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We tested the hypothesis that activation of inwardly-rectifying potassium (KIR) channels and Na(+)/K(+)-ATPase, two pathways that lead to hyperpolarization of vascular cells, contributes to both the onset and steady-state hyperemic response to exercise. We also determined whether after inhibiting these pathways, nitric oxide (NO) and prostaglandins (PGs) are involved in the hyperemic response. Forearm blood flow (FBF; Doppler ultrasound) was determined during rhythmic handgrip exercise at 10% maximal voluntary contraction for 5 minutes in the following conditions: control (saline; T1); combined inhibition of KIR channels and Na(+)/K(+)-ATPase alone [via barium chloride (BaCl2) and ouabain, respectively; T2]; and with additional combined nitric oxide synthase (L-NMMA) and cyclooxygenase inhibition (ketorolac; T3). In T2, the total hyperemic responses were attenuated ~50% from control (P<0.05) at exercise onset, and there was minimal further effect in T3 (Protocol 1; n=11). In Protocol 2 (n=8), steady-state FBF was significantly reduced during T2 vs T1 (133±15 vs 167±17 ml/min; Δ from control: -20±3%; P<0.05), and further reduced during T3 (120±15 ml/min; -29±3%; P<0.05 vs T2). In Protocol 3 (n=8), BaCl2 alone reduced FBF during onset (~50%) and steady-state exercise (~30%) as observed in Protocols 1 and 2, respectively, and addition of ouabain had no further impact. Our data implicate activation of KIR channels as a novel contributing pathway to exercise hyperemia in humans.
    AJP Heart and Circulatory Physiology 06/2014; 307(5). DOI:10.1152/ajpheart.00212.2014 · 4.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Rationale: Reactive hyperemia (RH) in the forearm circulation is an important marker of cardiovascular health yet the underlying vasodilator signaling pathways are controversial and thus remain unclear. Objective: We hypothesized RH occurs via activation of inwardly-rectifying potassium (KIR) channels and Na(+)/K(+)-ATPase and is largely independent of the combined production of the endothelial autocoids nitric oxide (NO) and prostaglandins (PGs) in young healthy humans. Methods and Results: In 24 (23±1 years) subjects, we performed RH trials by measuring forearm blood flow (FBF; venous occlusion plethysmography) following 5 minutes of arterial occlusion. In Protocol 1, we studied 2 groups of 8 subjects and assessed RH in the following conditions; Group 1:control (saline), KIR channel inhibition (barium chloride; BaCl2), combined inhibition of KIR channels and Na(+)/K(+)-ATPase (BaCl2(+)ouabain, respectively), and combined inhibition of KIR channels, Na(+)/K(+)-ATPase, NO and PGs (BaCl2(+)ouabain(+)L-NMMA(+)ketorolac, respectively). Group 2 received ouabain rather than BaCl2 in the 2nd trial. In Protocol 2 (n=8), 3 RH trials were performed: control, L-NMMA(+)ketorolac, and L-NMMA(+)ketorolac(+)BaCl2(+)ouabain. All infusions were intra-arterial (brachial). Compared to control, BaCl2 significantly reduced peak FBF (-50±6%; P<0.05) whereas ouabain and L-NMMA(+)ketorolac did not. Total FBF (area under curve) was attenuated by BaCl2 (-61±3%) and ouabain (-44±12%) alone and this effect was enhanced when combined (-87±4%), nearly abolishing RH. L-NMMA(+)ketorolac did not impact total RH FBF prior to or after administration of BaCl2(+)ouabain. Conclusions: Activation of KIR channels is the primary determinant of peak RH, whereas activation of both KIR channels and Na(+)/K(+)-ATPase explains nearly all of total RH in humans.
    Circulation Research 08/2013; 113(8). DOI:10.1161/CIRCRESAHA.113.301675 · 11.09 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A monophasic increase in skeletal muscle blood flow (BF) is observed following a brief single forearm contraction in humans, yet the underlying vascular signaling pathways remain largely undetermined. Evidence from experimental animals indicates an obligatory role of vasodilation via potassium (K(+))-mediated smooth muscle hyperpolarization and human data suggests little-to-no independent role for nitric oxide (NO) or vasodilating prostaglandins (PGs). We tested the hypothesis that K(+)-mediated vascular hyperpolarization underlies rapid vasodilation in humans and that combined inhibition of NO and PGs would have a minimal effect on this response. We measured forearm BF (Doppler ultrasound) and calculated vascular conductance 10 sec prior to, and for 30 sec after a single 1-sec dynamic forearm contraction at 10, 20, and 40% maximum voluntary contraction (MVC) in 16 young adults. To inhibit K(+)-mediated vasodilation, barium chloride (BaCl2) and ouabain were infused intra-arterially to inhibit KIR channels and Na(+)/K(+)-ATPase, respectively. Combined enzymatic inhibition of NO and PG synthesis occurred via L-NMMA (NO synthase) and ketorolac (cyclooxygenase), respectively. In Protocol 1 (n=8), BaCl2+ouabain reduced peak vasodilation (P<0.05; range = 30-45%) and total post-contraction vasodilation (area under the curve; AUC; ~55-75% from control) at all intensities. Contrary to our hypothesis, L-NMMA+ketorolac had a further impact (peak: ~60% and AUC: ~80% from control). In Protocol 2 (n=8), the order of inhibitors was reversed, and the findings were remarkably similar. We conclude that K(+)-mediated hyperpolarization and NO and PGs, in combination, significantly contribute to contraction-induced rapid vasodilation and inhibition of these signaling pathways nearly abolishes this phenomenon in humans.
    AJP Heart and Circulatory Physiology 05/2013; 305(1). DOI:10.1152/ajpheart.00298.2013 · 4.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Intravascular ATP evokes vasodilation and is implicated in the regulation of skeletal muscle blood flow during exercise. Mechanical stresses to erythrocytes and endothelial cells stimulate ATP release in vitro. How mechanical effects of muscle contractions contribute to increased plasma ATP during exercise is largely unexplored. We tested the hypothesis that simulated mechanical effects of muscle contractions increase [ATP](enous) and ATP effluent in vivo, independent of changes in tissue metabolic demand and further increase plasma ATP when superimposed with mild intensity exercise. In young healthy adults, we measured FBF (Doppler ultrasound) and plasma [ATP](v) (luciferin-luciferase assay) and calculated forearm ATP effluent (FBF×[ATP](v)) during rhythmic forearm compressions (RFC) via a blood pressure cuff at 3 graded pressures (50, 100 and 200 mmHg; Protocol 1; n=10) and during RFC at 100 mmHg, 5% maximal voluntary contraction rhythmic handgrip exercise (RHG), and combined RFC+RHG (Protocol 2; n=10). [ATP](v) increased from rest with each cuff pressure (range 144-161 vs 64±13 nmol/l) and ATP effluent was graded with pressure. In Protocol 2, [ATP](v) increased in each condition compared with rest (RFC:123±33; RHG:51±9; RFC+RHG:96±23 vs Mean Rest:42±4 nmol/l; P<0.05) and ATP effluent was greatest with RFC+RHG (RFC:5.3±1.4; RHG:5.3±1.1; RFC+RHG:11.6±2.7 vs Mean Rest:1.2±0.1 nmol/min; P<0.05). We conclude the mechanical effects of muscle contraction can (a)independently elevate intravascular ATP draining quiescent skeletal muscle without changes in local metabolism, and (b)further augment intravascular ATP during mild exercise associated with increases in metabolism and local deoxgyenation, and therefore is likely one stimulus for increasing intravascular ATP during exercise in humans.
    Journal of Applied Physiology 02/2013; 114(8). DOI:10.1152/japplphysiol.01465.2012 · 3.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Holes within the internal elastic lamina (IEL) of blood vessels are sites of fenestration allowing for passage of diffusible vasoactive substances and interface of endothelial cell membrane projections with underlying vascular smooth muscle. Endothelial projections are sites of dynamic Ca(2+) events leading to endothelium dependent hyperpolarization (EDH)-mediated relaxations and the activity of these events increase as vessel diameter decreases. We tested the hypothesis that IEL fenestration is greater in distal vs. proximal arteries in skeletal muscle, and is unlike other vascular beds (mesentery). We also determined ion channel protein composition within the endothelium of intramuscular and non-intramuscular skeletal muscle arteries. Popliteal arteries, subsequent gastrocnemius feed arteries, and first and second order intramuscular arterioles from rat hindlimb were isolated, cut longitudinally, fixed, and imaged using confocal microscopy. Quantitative analysis revealed a significantly larger total fenestration area in second and first order arterioles vs. feed and popliteal arteries (58% and 16% vs. 5% and 3%; N = 10 images/artery), due to a noticeably greater average size of holes (9.5 and 3.9 µm(2) vs 1.5 and 1.9 µm(2)). Next, we investigated via immunolabeling procedures whether proteins involved in EDH often embedded in endothelial cell projections were disparate between arterial segments. Specific proteins involved in EDH, such as inositol trisphosphate receptors, small and intermediate conductance Ca(2+)-activated K(+) channels, and the canonical (C) transient receptor potential (TRP) channel TRPC3 were present in both popliteal and first order intramuscular arterioles. However due to larger IEL fenestration in first order arterioles, a larger spanning area of EDH proteins is observed proximal to the smooth muscle cell plasma membrane. These observations highlight the robust area of fenestration within intramuscular arterioles and indicate that the anatomical architecture and endothelial cell hyperpolarizing apparatus for distinct vasodilatory signaling is potentially present.
    PLoS ONE 01/2013; 8(1):e54849. DOI:10.1371/journal.pone.0054849 · 3.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: • What is the central question of this study?Plasma ATP increases during exercise in humans, but whether ATP originates predominantly from extravascular (nerves and muscle) or intravascular sources (blood and endothelial cells) is unclear.• What is the main finding and its importance?The collective observations indicate that neither sympathetic nerves nor active skeletal muscle are likely to be the origin of intravascular ATP during dynamic muscle contractions in humans. Furthermore, elevations in skeletal muscle perfusion are requisite to increase and maintain high plasma ATP during exercise, suggesting ATP release from an intravascular cell source.
    Experimental physiology 01/2013; 98(5). DOI:10.1113/expphysiol.2012.071555 · 2.87 Impact Factor
  • Frank A Dinenno · Brett S Kirby
    Circulation Research 09/2012; 111(7):e203-4. DOI:10.1161/CIRCRESAHA.112.279356 · 11.09 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Circulating ATP possesses unique vasomotor properties in humans and has been hypothesized to play a role in vascular control under a variety of physiological conditions. However, the primary downstream signaling mechanisms underlying ATP-mediated vasodilatation remain unclear. The purpose of the present experiment was to determine whether ATP-mediated vasodilatation is independent of nitric oxide (NO) and prostaglandin (PG) synthesis and occurs primarily via the activation of Na+/K+-ATPase and inwardly-rectifying potassium (KIR) channels in humans. In all protocols, young healthy adults were studied and forearm vascular conductance (FVC) was calculated from forearm blood flow (measured via venous occlusion plethysmography) and intra-arterial blood pressure to quantify local vasodilatation. Vasodilator responses (%ΔFVC) during intra-arterial ATP infusions were unchanged following combined inhibition of NO and PGs (n=8; P>0.05) whereas the responses to KCl were greater (P<0.05). Combined infusion of ouabain (to inhibit Na+/K+-ATPase) and barium chloride (BaCl2; to inhibit KIR channels) abolished KCl-mediated vasodilatation (n=6; %ΔFVC=134±13 vs 4±5%; P<0.05), demonstrating effective blockade of direct vascular hyperpolarization. The vasodilator responses to 3 different doses of ATP were inhibited on average 56±5% (n=16) following combined ouabain+BaCl2 infusion. In follow-up studies, BaCl2 alone inhibited the vasodilator responses to ATP on average 51±3% (n=6), which was not different than that observed for combined ouabain+BaCl2 administration. Our novel results indicate that the primary mechanism of ATP-mediated vasodilatation is vascular hyperpolarization via activation of KIR channels. These observations translate in vitro findings to humans in vivo and may help explain the unique vasomotor properties of intravascular ATP in the human circulation.
    The Journal of Physiology 07/2012; 590(21). DOI:10.1113/jphysiol.2012.234245 · 4.54 Impact Factor
  • Brett S Kirby · Anne R Crecelius · Wyatt F Voyles · Frank A Dinenno
    [Show abstract] [Hide abstract]
    ABSTRACT: Skeletal muscle blood flow is coupled with the oxygenation state of hemoglobin in young adults, whereby the erythrocyte functions as an oxygen sensor and releases ATP during deoxygenation to evoke vasodilation. Whether this function is impaired in humans of advanced age is unknown. To test the hypothesis that older adults demonstrate impaired muscle blood flow and lower intravascular ATP during conditions of erythrocyte deoxygenation. We showed impaired forearm blood flow responses during 2 conditions of erythrocyte deoxygenation (systemic hypoxia and graded handgrip exercise) with age, which was caused by reduced local vasodilation. In young adults, both hypoxia and exercise significantly increased venous [ATP] and ATP effluent (forearm blood flow×[ATP]) draining the skeletal muscle. In contrast, hypoxia and exercise did not increase venous [ATP] in older adults, and both venous [ATP] and ATP effluent were substantially reduced compared with young people despite similar levels of deoxygenation. Next, we demonstrated that this could not be explained by augmented extracellular ATP hydrolysis in whole blood with age. Finally, we found that deoxygenation-mediated ATP release from isolated erythrocytes was essentially nonexistent in older adults. Skeletal muscle blood flow during conditions of erythrocyte deoxygenation was markedly reduced in aging humans, and reductions in plasma ATP and erythrocyte-mediated ATP release may be a novel mechanism underlying impaired vasodilation and oxygen delivery during hypoxemia with advancing age. Because aging is associated with elevated risk for ischemic cardiovascular disease and exercise intolerance, interventions that target erythrocyte-mediated ATP release may offer therapeutic potential.
    Circulation Research 05/2012; 111(2):220-30. DOI:10.1161/CIRCRESAHA.112.269571 · 11.09 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We tested the hypothesis that, among conditions of matched contractile work, shorter contraction durations and greater muscle fibre recruitment result in augmented skeletal muscle blood flow and oxygen consumption ( ) during steady-state exercise in humans. To do so, we measured forearm blood flow (FBF; Doppler ultrasound) during 4 min of rhythmic hand-grip exercise in 24 healthy young adults and calculated forearm oxygen consumption ( ) via blood samples obtained from a catheter placed in retrograde fashion into a deep vein draining the forearm muscle. In protocol 1 (n = 11), subjects performed rhythmic isometric hand-grip exercise at mild and moderate intensities during conditions in which time-tension index (isometric analogue of work) was held constant but contraction duration was manipulated. In this protocol, shorter contraction durations led to greater FBF (184 ± 25 versus 164 ± 25 ml min(-1)) and (23 ± 3 versus 17 ± 2 ml min(-1); both P < 0.05) among mild workloads, whereas this was not the case for moderate-intensity exercise. In protocol 2 (n = 13), subjects performed rhythmic dynamic hand-grip exercise at mild and moderate intensities in conditions of matched total work, but muscle fibre recruitment was manipulated. In this protocol, greater muscle fibre recruitment led to significantly greater FBF (152 ± 15 versus 127 ± 13 ml min(-1)) and (20 ± 2 versus 17 ± 2 ml min(-1); both P < 0.05) at mild workloads, and there was a trend for similar responses at the moderate intensity but this was not statistically significant. In both protocols, the ratio of the change in FBF to change in was similar across all exercise intensities and manipulations, and the strongest correlation among all variables was between and blood flow. Our collective data indicate that, among matched workloads, shorter contraction duration and greater muscle fibre recruitment augment FBF and during mild-intensity forearm exercise, and that muscle blood flow is more closely related to metabolic cost ( ) rather than contractile work per se during steady-state exercise in humans.
    Experimental physiology 02/2012; 97(6):750-61. DOI:10.1113/expphysiol.2011.062968 · 2.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: ATP is an endothelium-dependent vasodilator, and findings regarding the underlying signaling mechanisms are equivocal. We sought to determine the independent and interactive roles of nitric oxide (NO) and vasodilating prostaglandins (PGs) in ATP-mediated vasodilation in young, healthy humans and determine whether any potential role was dependent on ATP dose or the timing of inhibition. In protocol 1 (n = 18), a dose-response curve to intrabrachial infusion of ATP was performed before and after both single and combined inhibition of NO synthase [N(G)-monomethyl-L-arginine (L-NMMA)] and cyclooxygenase (ketorolac). Forearm blood flow (FBF) was measured via venous occlusion plethysmography and forearm vascular conductance (FVC) was calculated. In this protocol, neither individual nor combined NO/PG inhibition had any effect on the vasodilatory response (P = 0.22-0.99). In protocol 2 (n = 16), we determined whether any possible contribution of both NO and PGs to ATP vasodilation was greater at low vs. high doses of ATP and whether inhibition during steady-state infusion of the respective dose of ATP impacted the dilation. FBF in this protocol was measured via Doppler ultrasound. In protocol 2, infusion of low (n = 8)- and high-dose (n = 8) ATP for 5 min evoked a significant increase in FVC above baseline (low = 198 ± 24%; high = 706 ± 79%). Infusion of L-NMMA and ketorolac together reduced steady-state FVC during both low- and high-dose ATP (P < 0.05), and in a subsequent trial with continuous NO/PG blockade, the vasodilator response from baseline to 5 min of steady-state infusion was similarly reduced for both low (ΔFVC = -31 ± 11%)- and high-dose ATP (ΔFVC -25 ± 11%; P = 0.70 low vs. high dose). Collectively, our findings indicate a potential modest role for NO and PGs in the vasodilatory response to exogenous ATP in the human forearm that does not appear to be dose or timing dependent; however, this is dependent on the method for assessing forearm vascular responses. Importantly, the majority of ATP-mediated vasodilation is independent of these putative endothelium-dependent pathways in humans.
    AJP Heart and Circulatory Physiology 07/2011; 301(4):H1302-10. DOI:10.1152/ajpheart.00469.2011 · 4.01 Impact Factor
  • Source
    Anne R Crecelius · Brett S Kirby · Wyatt F Voyles · Frank A Dinenno
    [Show abstract] [Hide abstract]
    ABSTRACT: Exercise hyperaemia in hypoxia is augmented relative to the same level of exercise in normoxia. At moderate exercise intensities, the mechanism(s) underlying this augmented response are currently unclear. We tested the hypothesis that endothelium-derived nitric oxide (NO) and vasodilating prostaglandins (PGs) contribute to the augmented muscle blood flow during hypoxic exercise relative to normoxia. In 10 young healthy adults, we measured forearm blood flow (FBF; Doppler ultrasound) and calculated the vascular conductance (FVC) responses during 5 min of rhythmic handgrip exercise at 20% maximal voluntary contraction in normoxia (NormEx) and isocapnic hypoxia (HypEx; O2 saturation ∼85%) before and after local intra-brachial combined blockade of NO synthase (NOS; via N(G)-monomethyl-L-arginine: L-NMMA) and cyclooxygenase (COX; via ketorolac). All trials were performed during local α- and β-adrenoceptor blockade to eliminate sympathoadrenal influences on vascular tone and thus isolate local vasodilatation. Arterial and deep venous blood gases were measured and oxygen consumption (VO2) was calculated. In control (saline) conditions, FBF after 5 min of exercise in hypoxia was greater than in normoxia (345 ± 21 ml min(−1) vs. 297 ± 18 ml min(−1); P < 0.05). After NO–PG block, the compensatory increase in FBF during hypoxic exercise was blunted ∼50% and thus was reduced compared with control hypoxic exercise (312 ± 19 ml min(−1); P < 0.05), but this was not the case in normoxia (289 ± 15 ml min(−1); P = 0.33). The lower FBF during hypoxic exercise was associated with a compensatory increase in O2 extraction, and thus VO2 was maintained at normal control levels (P = 0.64–0.99). We conclude that under the experimental conditions employed, NO and PGs have little role in normoxic exercise hyperaemia whereas combined NO–PG inhibition reduces hypoxic exercise hyperaemia and abolishes hypoxic vasodilatation at rest. Additionally, VO2 of the tissue was maintained in hypoxic conditions at rest and during exercise, despite attenuated oxygen delivery following NO–PG blockade, due to an increase in O2 extraction at the level of the muscle.
    The Journal of Physiology 05/2011; 589(Pt 14):3671-83. DOI:10.1113/jphysiol.2011.209486 · 4.54 Impact Factor
  • Source
    Brett S Kirby · Anne R Crecelius · Wyatt F Voyles · Frank A Dinenno
    [Show abstract] [Hide abstract]
    ABSTRACT: Non-technical summary When muscles contract, a variety of signals interact and ultimately increase blood flow and oxygen delivery to the active muscle. However, when there is simultaneous activation of the sympathetic nervous system, noradrenaline (norepinephrine) is released which tries to cause vasoconstriction in the same blood vessels that are trying to relax (vasodilate). In young adults, we have shown that there is a unique ability of the contracting muscle to limit this vasoconstriction, and also that a circulating factor called ATP mimics the exercise response. In the present study, we demonstrate that older healthy adults have an impaired ability to limit the sympathetic vasoconstrictor signal during exercise; however, this ability is preserved when we administer ATP. Thus, if this impairment in the ability of contracting muscle to limit sympathetic vasoconstriction in older adults is related to ATP, we speculate that circulating levels of ATP may be impaired during exercise. Abstract The ability to modulate sympathetic α-adrenergic vasoconstriction in contracting muscle is impaired with age. In young adults, adenosine triphosphate (ATP) has been shown to blunt sympathetic vasoconstrictor responsiveness similar to exercise. Therefore, we tested the hypothesis that modulation of postjunctional α-adrenergic vasoconstriction to exogenous ATP is impaired in ageing humans. We measured forearm blood flow (FBF; Doppler ultrasound) and calculated vascular conductance (FVC) to intra-arterial infusions of phenylephrine (α1-agonist) and dexmedetomidine (α2-agonist) during rhythmic handgrip exercise (15% MVC), a control non-exercise vasodilator condition (adenosine), and ATP infusion in seven older (64 ± 3 years) and seven young (22 ± 1 years) healthy adults. Forearm hyperaemia was matched across all vasodilatating conditions. During adenosine, forearm vasoconstrictor responses to direct α1-stimulation were lower in older compared with young adults (ΔFVC =−25 ± 3%vs.−41 ± 5%; P < 0.05), whereas the responses to α2-stimulation were not different (−35 ± 6%vs.−44 ± 8%; NS). During exercise, α1-mediated vasoconstriction was significantly blunted compared with adenosine in both young (−9 ± 2%vs.−41 ± 5%) and older adults (−15 ± 2%vs.−25 ± 3%); however, the magnitude of sympatholysis was reduced in older adults (32 ± 13 vs. 74 ± 8%; P < 0.05). Similarly, α2-mediated vasoconstriction during exercise was significantly blunted in both young (−15 ± 4%vs.−44 ± 8%) and older adults (−26 ± 3%vs.−35 ± 6%), however the magnitude of sympatholysis was reduced in older adults (19 ± 8%vs. 60 ± 10%; P < 0.05). During ATP, both α1- and α2-mediated vasoconstriction was nearly abolished in young and older adults (ΔFVC ∼−5%), and the magnitude of sympatholysis was similar in both age groups (∼85–90%). Our findings indicate that the ability to modulate postjunctional α-adrenergic vasoconstriction during exercise is impaired with age, whereas the sympatholytic effect of exogenous ATP is preserved. Thus, if impairments in vascular control during exercise in older adults involve vasoactive ATP, we speculate that circulating ATP is reduced with advancing age.
    The Journal of Physiology 05/2011; 589(Pt 10):2641-53. DOI:10.1113/jphysiol.2010.204081 · 4.54 Impact Factor

Publication Stats

3k Citations
395.31 Total Impact Points

Institutions

  • 2004–2015
    • Colorado State University
      • Department of Health and Exercise Science
      Fort Collins, Colorado, United States
  • 1998–2006
    • University of Colorado at Boulder
      • Department of Integrative Physiology
      Boulder, Colorado, United States
  • 2003–2004
    • Mayo Foundation for Medical Education and Research
      • Department of Anesthesiology
      Scottsdale, AZ, United States
    • Mayo Clinic - Rochester
      • Department of Anesthesiology
      Рочестер, Minnesota, United States