Frank A Dinenno

CSU Mentor, Long Beach, California, United States

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Publications (72)323.42 Total impact

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    ABSTRACT: In healthy humans, ageing is typically associated with reduced skeletal muscle blood flow and vascular conductance during exercise. Further, there is a marked increase in resting sympathetic nervous system (SNS) activity with age, yet whether augmented SNS mediated α-adrenergic vasoconstriction contributes to the age-associated impairment in exercising muscle blood flow and vascular tone in humans is unknown. We tested the hypothesis that SNS-mediated vasoconstriction is greater in older compared with young adults and limits muscle (forearm) blood flow (FBF) during graded handgrip exercise (5, 15, 25% maximal voluntary contraction (MVC)). FBF was measured (Doppler ultrasound) and forearm vascular conductance (FVC) was calculated in 11 young (21±1 years) and 12 older (62±2 years) adults in control conditions and during combined local α- and β-adrenoreceptor blockade via intra-arterial infusions of phentolamine and propranolol, respectively. Under control conditions, older adults exhibited significantly lower FBF and FVC at 15% (22.6±1.3 vs. 29±3.3 ml min−1 100g FFM−1 and 21.7±1.2 vs. 33.6±4.0 ml min−1 100g FFM−1 100 mmHg−1; P<0.05) and 25% (37.4±1.4 vs. 46.0±4.9 ml min−1 100g FFM−1 and 33.7±1.4 vs. 49.0±5.7 ml min−1 100g FFM−1 100 mmHg−1; P<0.05), whereas there was no age-group difference at 5% MVC exercise. Local adrenoreceptor blockade increased FBF and FVC at rest and during exercise in both groups, however the increase in FBF and FVC from rest to steady-state exercise was similar in young and older adults across exercise intensities, and thus the age-associated impairment in FBF and FVC persisted. Our data indicate that during graded intensity handgrip exercise, the reduced FVC and subsequently lower skeletal muscle blood flow in older healthy adults is not due to augmented sympathetic vasoconstriction, but rather due to impairments in local signaling or structural limitations in the peripheral vasculature with advancing age.This article is protected by copyright. All rights reserved
    The Journal of Physiology 09/2014; · 4.38 Impact Factor
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    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.
    American journal of physiology. Heart and circulatory physiology. 06/2014;
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    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; · 11.86 Impact Factor
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    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; · 4.01 Impact Factor
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    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; · 3.48 Impact Factor
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    ABSTRACT: Exercise hyperemia is regulated by several factors and one factor known to increase with exercise that evokes powerful vasomotor action is extracellular ATP. The origination of ATP detectable in plasma from exercising muscle of humans is, however, a matter of debate and ATP has been suggested to arise from sympathetic nerves, blood sources (e.g. erythrocytes), endothelial cells, and skeletal myocytes, among others. Therefore, we tested the hypothesis that acute augmentation of sympathetic nervous system activity (SNA) results in elevated plasma ATP draining skeletal muscle, and that SNA superimposition during exercise further increases ATP vs exercise alone. We show that increased SNA via -40mmHg lower body negative pressure (LBNP) at rest does not increase plasma ATP (51±8 vs 58±7 nmol/L with LBNP), nor does it increase [ATP] above levels observed during rhythmic handgrip exercise (79±11 exercise alone vs 71±8 nmol/L with LBNP). Secondly, we tested the hypothesis that active perfusion of skeletal muscle is essential to observe increased plasma ATP during exercise. We identify that complete obstruction of blood flow to contracting muscle abolishes exercise-mediated increases in plasma ATP (90±19 to 49±12 nmol/L), and further, that cessation of blood flow prior to exercise completely inhibits the typical rise in ATP (3 vs 61%; obstructed vs intact perfusion). The lack of ATP change during occlusion occurred in the face of continued muscle work and elevated SNA, indicating the rise of intravascular ATP is not resultant from these extravascular sources. Our collective observations indicate that the elevation in extracellular ATP observed in blood during exercise is unlikely to originate from sympathetic nerves or the contacting muscle itself, but rather is dependent on intact skeletal muscle perfusion. We conclude that an intravascular source for ATP is essential and points toward an important role for blood sources (e.g. red blood cells) in augmenting and maintaining elevated plasma ATP during exercise.
    Experimental physiology 01/2013; · 3.17 Impact Factor
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    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. · 3.53 Impact Factor
  • Frank A Dinenno, Brett S Kirby
    Circulation Research 09/2012; 111(7):e203-4. · 11.86 Impact Factor
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    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; · 4.38 Impact Factor
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    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. · 11.86 Impact Factor
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    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. · 3.17 Impact Factor
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    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. · 4.01 Impact Factor
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    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. · 4.38 Impact Factor
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    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. · 4.38 Impact Factor
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    ABSTRACT: We tested the hypothesis that nitric oxide (NO) and vasodilating prostaglandins (PGs) contribute independently to hypoxic vasodilatation, and that combined inhibition would reveal a synergistic role for these two pathways in the regulation of peripheral vascular tone. In 20 healthy adults, we measured forearm blood flow (Doppler ultrasound) and calculated forearm vascular conductance (FVC) responses to steady-state (SS) isocapnic hypoxia (O₂ saturation ~85%). All trials were performed during local α- and β-adrenoceptor blockade (via a brachial artery catheter) to eliminate sympathoadrenal influences on vascular tone and thus isolate local vasodilatory mechanisms. The individual and combined effects of NO synthase (NOS) and cyclooxygenase (COX) inhibition were determined by quantifying the vasodilatation from rest to SS hypoxia, as well as by quantifying how each inhibitor reduced vascular tone during hypoxia. Three hypoxia trials were performed in each subject. In group 1 (n = 10), trial 1, 5 min of SS hypoxia increased FVC from baseline (21 ± 3%; P < 0.05). Infusion of N(G)-nitro-L-arginine methyl ester (L-NAME) for 5 min to inhibit NOS during continuous SS hypoxia reduced FVC by -33 ± 3% (P < 0.05). In Trial 2 with continuous NOS inhibition, the increase in FVC from baseline to SS hypoxia was similar to control conditions (20 ± 3%), and infusion of ketorolac for 5 min to inhibit COX during continuous SS hypoxia reduced FVC by -15 ± 3% (P < 0.05). In Trial 3 with combined NOS and COX inhibition, the increase in FVC from baseline to SS hypoxia was abolished (~3%; NS vs. zero). In group 2 (n = 10), the order of NOS and COX inhibition was reversed. In trial 1, five minutes of SS hypoxia increased FVC from baseline (by 24 ± 5%; P < 0.05), and infusion of ketorolac during SS hypoxia had minimal impact on FVC (-4 ± 3%; NS). In Trial 2 with continuous COX inhibition, the increase in FVC from baseline to SS hypoxia was similar to control conditions (27 ± 4%), and infusion of L-NAME during continuous SS hypoxia reduced FVC by -36 ± 7% (P < 0.05). In Trial 3 with combined NOS and COX inhibition, the increase in FVC from baseline to SS hypoxia was abolished (~3%; NS vs. zero). Our collective findings indicate that (1) neither NO nor PGs are obligatory to observe the normal local vasodilatory response from rest to SS hypoxia; (2) NO regulates vascular tone during hypoxia independent of the COX pathway, whereas PGs only regulate vascular tone during hypoxia when NOS is inhibited; and (3) combined inhibition of NO and PGs abolishes local hypoxic vasodilatation (from rest to SS hypoxia) in the forearm circulation of healthy humans during systemic hypoxia.
    The Journal of Physiology 04/2011; 589(Pt 8):1979-90. · 4.38 Impact Factor
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    ABSTRACT: Acute ascorbic acid (AA) administration increases muscle blood flow during dynamic exercise in older adults, and this is associated with improved endothelium-dependent vasodilation. We directly tested the hypothesis that increase in muscle blood flow during AA administration is mediated via endothelium-derived vasodilators nitric oxide (NO) and prostaglandins (PGs). In 14 healthy older adults (64 ± 3 yr), we measured forearm blood flow (FBF; Doppler ultrasound) during rhythmic handgrip exercise at 10% maximum voluntary contraction. After 5-min steady-state exercise with saline, AA was infused via brachial artery catheter for 10 min during continued exercise, and this increased FBF ∼25% from 132 ± 16 to 165 ± 20 ml/min (P < 0.05). AA was infused for the remainder of the study. Next, subjects performed a 15-min exercise bout in which AA + saline was infused for 5 min, followed by 5 min of the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-l-arginine (l-NMMA) and then 5 min of the cyclooxygenase inhibitor ketorolac (group 1). The order of inhibition was reversed in eight subjects (group 2). In group 1, independent NOS inhibition reduced steady-state FBF by ∼20% (P < 0.05), and subsequent PG inhibition had no impact on FBF (Δ 3 ± 5%). Similarly, in group 2, independent PG inhibition had little effect on FBF (Δ -4 ± 4%), whereas subsequent NO inhibition significantly decreased FBF by ∼20% (P < 0.05). In a subgroup of five subjects, we inhibited NO and PG synthesis before AA administration. In these subjects, there was a minimal nonsignificant improvement in FBF with AA infusion (Δ 7 ± 3%; P = nonsignificant vs. zero). Together, our data indicate that the increase in muscle blood flow during dynamic exercise with acute AA administration in older adults is mediated primarily via an increase in the bioavailability of NO derived from the NOS pathway.
    AJP Heart and Circulatory Physiology 11/2010; 299(5):H1633-41. · 4.01 Impact Factor
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    ABSTRACT: Endothelium-dependent vasodilatation is reduced with advancing age in humans, as evidenced by blunted vasodilator responsiveness to acetylcholine (ACh). Circulating adenosine triphosphate (ATP) has been implicated in the control of skeletal muscle vascular tone during mismatches in oxygen delivery and demand (e.g. exercise) via binding to purinergic receptors (P2Y) on the endothelium evoking subsequent vasodilatation, and ageing is typically associated with reductions in muscle blood flow under such conditions. Therefore, we tested the hypothesis that ATP-mediated vasodilatation is impaired with age in healthy humans. We measured forearm blood flow (venous occlusion plethysmography) and calculated vascular conductance (FVC) responses to local intra-arterial infusions of ACh, ATP, and sodium nitroprusside (SNP) before and during ascorbic acid (AA) infusion in 13 young and 13 older adults. The peak increase in FVC to ACh was significantly impaired in older compared with young adults (262 ± 71% vs. 618 ± 97%; P < 0.05), and this difference was abolished during AA infusion (510 ± 82% vs. 556 ± 71%; not significant, NS). In contrast, peak FVC responses were not different between older and young adults to either ATP (675 ± 105% vs. 734 ± 126%) or SNP (1116 ± 111% vs. 1138 ± 148%) and AA infusion did not alter these responses in either age group (both NS). In another group of six young and six older adults, we determined whether vasodilator responses to adenosine and ATP were influenced by P1-receptor blockade via aminophylline. The peak FVC responses to adenosine were not different in young (350 ± 65%) versus older adults (360 ± 80%), and aminophylline blunted these responses by ∼50% in both groups. The peak FVC responses to ATP were again not different in young and older adults, and aminophylline did not impact the vasodilatation in either group. Thus, in contrast to the observed impairments in ACh responses, the vasodilatory response to exogenous ATP is not reduced with age in healthy humans. Further, our data also indicate that adenosine mediated vasodilatation is not reduced with age, and that ATP-mediated vasodilatation is independent of P1-receptor stimulation in both young and older adults.
    The Journal of Physiology 10/2010; 588(Pt 20):4017-27. · 4.38 Impact Factor
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    ABSTRACT: Age-related increases in oxidative stress impair endothelium-dependent vasodilatation in humans, leading to the speculation that endothelial dysfunction contributes to impaired muscle blood flow and vascular control during exercise in older adults. We directly tested this hypothesis in 14 young (22 +/- 1 years) and 14 healthy older men and women (65 +/- 2 years). We measured forearm blood flow (FBF; Doppler ultrasound) and calculated vascular conductance (FVC) responses to single muscle contractions at 10, 20 and 40% maximum voluntary contraction (MVC) before and during ascorbic acid (AA) infusion, and we also determined the effects of AA on muscle blood flow during mild (10% MVC) continuous rhythmic handgrip exercise. For single contractions, the peak rapid hyperaemic responses to all contraction intensities were impaired approximately 45% in the older adults (all P < 0.05), and AA infusion did not impact the responses in either age group. For the rhythmic exercise trial, FBF (approximately 28%) and FVC (approximately 31%) were lower (P = 0.06 and 0.05) in older versus young adults after 5 min of steady-state exercise with saline. Subsequently, AA was infused via brachial artery catheter for 10 min during continued exercise. AA administration did not significantly influence FBF or FVC in young adults (1-3%; P = 0.24-0.59), whereas FBF increased 34 +/- 7% in older adults at end-exercise, and this was due to an increase in FVC (32 +/- 7%; both P < 0.05). This increase in FBF and FVC during exercise in older adults was associated with improvements in vasodilator responses to acetylcholine (ACh; endothelium dependent) but not sodium nitroprusside (SNP; endothelium independent). AA had no effect on ACh or SNP responses in the young. We conclude that acute AA administration does not impact the observed age-related impairment in the rapid hyperaemic response to brief muscle contractions in humans; however, it does significantly increase muscle blood flow during continuous dynamic exercise in older adults, and this is probably due (in part) to an improvement in endothelium-dependent vasodilatation.
    The Journal of Physiology 04/2009; 587(Pt 9):1989-2003. · 4.38 Impact Factor
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    ABSTRACT: Recent evidence suggests that adenosine triphosphate (ATP) can inhibit vasoconstrictor responses to endogenous noradrenaline release via tyramine in the skeletal muscle circulation, similar to what is observed in contracting muscle. Whether this involves direct modulation of postjunctional alpha-adrenoceptor responsiveness, or is selective for alpha(1)- or alpha(2)-receptors remains unclear. Therefore, in Protocol 1, we tested the hypothesis that exogenous ATP can blunt direct postjunctional alpha-adrenergic vasoconstriction in humans. We measured forearm blood flow (FBF; Doppler ultrasound) and calculated the vascular conductance (FVC) responses to local intra-arterial infusions of phenylephrine (alpha(1)-agonist) and dexmedetomidine (alpha(2)-agonist) during moderate rhythmic handgrip exercise (15% maximum voluntary contraction), during a control non-exercise vasodilator condition (adenosine), and during ATP infusion in eight young adults. Forearm hyperaemia was matched across all conditions. Forearm vasoconstrictor responses to direct alpha(1)-receptor stimulation were blunted during exercise versus adenosine (DeltaFVC = -11 +/- 3% versus -39 +/- 5%; P< 0.05), and were abolished during ATP infusion (-3 +/- 2%). Similarly, vasoconstrictor responses to alpha(2)-receptor stimulation were blunted during exercise versus adenosine (-13 +/- 4% versus -40 +/- 8%; P< 0.05), and were abolished during ATP infusion (-4 +/- 4%). In Prototol 2 (n = 10), we tested the hypothesis that graded increases in ATP would reduce alpha(1)-mediated vasoconstriction in a dose-dependent manner compared with vasodilatation evoked via adenosine. Forearm vasoconstrictor responses during low dose adenosine (-38 +/- 3%) and ATP (-33 +/- 2%) were not significantly different from rest (-40 +/- 3%; P> 0.05). In contrast, vasoconstrictor responses during moderate (-22 +/- 6%) and high dose ATP (-8 +/- 5%) were significantly blunted compared with rest, whereas the responses during adenosine became progressively greater (moderate = -48 +/- 4%, P = 0.10; high = -53 +/- 6%, P< 0.05). We conclude that exogenous ATP is capable of blunting direct postjunctional alpha-adrenergic vasoconstriction, that this involves both alpha(1)- and alpha(2)-receptor subtypes, and that this is graded with ATP concentrations. Collectively, these data are consistent with the conceptual framework regarding how muscle blood flow and vascular tone are regulated in contracting muscles of humans.
    The Journal of Physiology 07/2008; 586(Pt 17):4305-16. · 4.38 Impact Factor
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    ABSTRACT: We tested the hypothesis that aging is associated with an impaired contraction-induced rapid vasodilation in healthy adults. We reasoned that employing single contractions of a small muscle mass would allow us to isolate the local rapid vasodilatory responses independent of systemic hemodynamic and sympathetic neural influences on forearm hemodynamics. We measured forearm blood flow (Doppler ultrasound) and arterial blood pressure (Finapres) on a beat-by-beat basis and calculated the changes in forearm vascular conductance (DeltaFVC) in response to forearm contractions in 18 young (24 +/- 1 yr) and 13 older (62 +/- 2 yr) healthy subjects. Single, 1-s dynamic forearm contractions were performed with the experimental arm slightly above heart level at 5, 10, 20, and 40% of the subjects' maximal voluntary contraction (MVC) in random order. In general, muscle contractions evoked a rapid increase in FVC that reached a peak within approximately four to five cardiac cycles postcontraction in both age groups. At 5% MVC, there were no significant age-related differences in contraction-induced forearm vasodilation. However, the peak vasodilatory responses were impaired approximately 40-45% in older adults at 10, 20, and 40% MVC, as were the total vasodilatory responses (area under curve approximately 40-50%; all P < 0.05). Additionally, the immediate vasodilation (first cardiac cycle postcontraction) for the 20% and 40% MVC trials was also impaired approximately 50% with age (P < 0.05). There were no significant age-group differences in MVC or forearm fat-free mass, and these variables were not correlated with local vasodilation within a given exercise intensity. Under the experimental conditions employed, the blunted responses with age reflect impaired local contraction-induced rapid vasodilation.
    AJP Heart and Circulatory Physiology 04/2008; 294(4):H1963-70. · 4.01 Impact Factor

Publication Stats

2k Citations
323.42 Total Impact Points

Institutions

  • 2013
    • CSU Mentor
      Long Beach, California, United States
    • Duke University
      Durham, North Carolina, United States
  • 2004–2012
    • Colorado State University
      • Department of Health and Exercise Science
      Fort Collins, CO, United States
  • 2002–2004
    • Mayo Foundation for Medical Education and Research
      • Department of Anesthesiology
      Scottsdale, AZ, United States
  • 1998–2004
    • University of Colorado at Boulder
      • Department of Integrative Physiology
      Boulder, CO, United States
  • 2003
    • Mayo Clinic - Rochester
      • Department of Anesthesiology
      Rochester, Minnesota, United States