Nitric oxide and prostaglandins influence local skeletal muscle blood flow during exercise in humans: coupling between local substrate uptake and blood flow

Kalliokoski, Kari K.; Langberg, Henning; Ryberg, Ann Kathrine; Scheede‐Bergdahl, Celena; Doessing, Simon; Kjær, Andreas; Kjær, Michael; Boushel, Robert

doi:10.1152/ajpregu.00808.2005

Cited by 23 publications

(23 citation statements)

References 62 publications

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“…[91][92][93][94][95][96][97][98] These transmitters also play a role in the adjustments of energy metabolism to muscle contractions (figure 4). [99][100][101][102][103][104][105] Because the effects of kinins are attenuated by inhibitors of the three enzymes mentioned above, causing diminished concentrations of downstream factors, [106][107][108][109][110] it has been postulated that kinins signal through NO, prostaglandins, and EDHF. 78 The molecular mode of action of these mediators has been described in detail by others.…”

Section: O P Y R I G H T J R a A S L I M I T E D R E P R O D U C T mentioning

confidence: 99%

“…76,120 Prostaglandins, such as PGE 2 and PGI 2 , may also participate in the control of vasodilation in SMT. 7,102,103,105 Prostaglandins are formed and released during contractions in the venous effluent. Their concentrations increase in the intercellular space, and they contribute to contraction-induced vasodilation in humans.…”

Section: O P Y R I G H T J R a A S L I M I T E D R E P R O D U C T mentioning

confidence: 99%

“…Their concentrations increase in the intercellular space, and they contribute to contraction-induced vasodilation in humans. 99,103,105,121,122 In eNOSdeficient knockout mice, prostaglandins may compensate for the lost vasodilatory potential of the vasculature. 123,124 A limited number of investigations in the last 30 years have focused on the effects of prostaglandins on glucose metabolism in SMT, in some cases with conflicting results.…”

Section: O P Y R I G H T J R a A S L I M I T E D R E P R O D U C T mentioning

confidence: 99%

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Review: Angiotensin-converting enzyme in skeletal muscle: sentinel of blood pressure control and glucose homeostasis

Dietze¹,

Henriksen

2008

J Renin Angiotensin Aldosterone Syst

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Recent evidence suggests a coordinated regulation by the local renin-angiotensin system (RAS) and tissue kallikrein-kinin system (TKKS) of blood flow and substrate supply in oxidative red myofibres of skeletal muscle tissue during endurance exercise.The performance of these myofibres is dependent on the increased oxidation of substrates facilitated by augmenting nutritive blood flow and glucose uptake. Humoral factors released by the contracting fibres, such as adenosine and kinins, are suggested to be responsible for this metabolic adjustment.The considerable drain of blood volume and the enormous consumption of glucose during endurance exercise require a control mechanism for the maintenance of blood pressure (BP) and glucose homeostasis. This is achieved by the sympathetic nervous system and its subordinate RAS, which is located in the nutritive vessels and parenchyma of the red myofibres. The angiotensin-converting enzyme (ACE) is the primary enzyme responsible for kinin degradation during exercise, underscoring the important interrelationship between the RAS and the TKKS in the critical role of kinins in the multifactorial regulation of muscle bioenergetics and glucose and BP homeostasis. Importantly, overactivity of the ACE, as occurs in individuals displaying risk factors such as overweight, causes exaggerated BP response and reduced glucose disposal. If they persist over years, compensatory responses to this ACE overactivity, such as hypersecretion of insulin and compliance of the vessel walls, will inevitably be exhausted, leading ultimately to the manifestation of type 2 diabetes and hypertension. This concept also provides a unifying explanation for the beneficial effects of ACE-inhibitors and Angiotensin II receptor antagonists in the treatment of hypertension and insulin resistance.Need for control of blood pressure and glucose homeostasis during endurance exercise performance The regulation of muscle bioenergetics during exercise has been studied for more than 100 years.

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Section: O P Y R I G H T J R a A S L I M I T E D R E P R O D U C T mentioning

confidence: 99%

Section: O P Y R I G H T J R a A S L I M I T E D R E P R O D U C T mentioning

confidence: 99%

Section: O P Y R I G H T J R a A S L I M I T E D R E P R O D U C T mentioning

confidence: 99%

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Review: Angiotensin-converting enzyme in skeletal muscle: sentinel of blood pressure control and glucose homeostasis

Dietze¹,

Henriksen

2008

J Renin Angiotensin Aldosterone Syst

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“…Nitric oxide [NO; synthesized via nitric oxide synthase (NOS)] and vasodilating prostaglandins [PGs; synthesized via cyclooxygenase (COX)] are two endothelium-derived vasodilatory substances that contribute to the hyperemic response during dynamic knee-extensor exercise in young healthy humans (1,14,21,22). In the forearm model, combined inhibition of NO and PG synthesis during exercise in young adults results in a significant decrease in forearm blood flow (FBF; ϳ20%), primarily mediated through NOS inhibition (30).…”

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confidence: 99%

Nitric oxide, but not vasodilating prostaglandins, contributes to the improvement of exercise hyperemia via ascorbic acid in healthy older adults

Crecelius

Kirby

Voyles

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Crecelius AR, Kirby BS, Voyles WF, Dinenno FA. Nitric oxide, but not vasodilating prostaglandins, contributes to the improvement of exercise hyperemia via ascorbic acid in healthy older adults. Am J Physiol Heart Circ Physiol 299: H1633-H1641, 2010. First published September 3, 2010; doi:10.1152/ajpheart.00614.2010.-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 Ϯ 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 ϳ25% from 132 Ϯ 16 to 165 Ϯ 20 ml/min (P Ͻ 0.05). AA was infused for the remainder of the study. Next, subjects performed a 15-min exercise bout in which AA ϩ 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 ϳ20% (P Ͻ 0.05), and subsequent PG inhibition had no impact on FBF (⌬ 3 Ϯ 5%). Similarly, in group 2, independent PG inhibition had little effect on FBF (⌬ Ϫ4 Ϯ 4%), whereas subsequent NO inhibition significantly decreased FBF by ϳ20% (P Ͻ 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 (⌬ 7 Ϯ 3%; P ϭ 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. blood flow; aging; muscle contractions THE REGULATION OF BLOOD FLOW and oxygen delivery to contracting muscle is a complex response that involves mechanical factors, the sympathetic nervous system, and local metabolic and endothelium-derived substances that can influence vascular tone (28). In aging humans, an imbalance occurs in these regulatory mechanisms that typically results in impaired vasodilation and attenuated muscle blood flow during exercise (17,19,25,26). Investigators have hypothesized that impaired endothelial vasodilator function contributes to the age-related impairment in muscle blood flow during exercise (8,27). Recently, our laboratory demonstrated (17) that improving endothelium-dependent vasodilation via the potent antioxidant ascorbic acid also improved muscle blood flow during rhythmic handgrip exercise in older adults, providing the...

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“…Some animal studies have subsequently found evidence that NO tonically inhibits mitochondrial respiration in vivo (33-35), but there has not been evidence for this in humans (10,27,31). It is well shown with various methods that prostanoids can act synergistically with NO to regulate vascular function in health and disease (2,19,23,30,31), but COX inhibition may also have direct effects on cellular aerobic respiration by affecting uncoupling (17,20,23).Positron emission tomography (PET) is a noninvasive imaging method based on short-lived radioisotopes that can be applied to measure blood flow and its distribution in muscle. Muscle blood flow by PET can be quantified with [ 15 O]H 2 O (radiowater), which is an intravenously infused inert and freely diffusible tracer.…”

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Skeletal muscle blood flow and oxygen uptake at rest and during exercise in humans: a pet study with nitric oxide and cyclooxygenase inhibition

Heinonen

Saltin

Kemppainen

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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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, 2011. First published January 21, 2011; doi:10.1152/ajpheart.00996.2010.-The aim of the present study was to determine the effect of nitric oxide and prostanoids on microcirculation and oxygen uptake, specifically in the active skeletal muscle by use of positron emission tomography (PET). Healthy males performed three 5-min bouts of light knee-extensor exercise. Skeletal muscle blood flow and oxygen uptake were measured at rest and during the exercise using PET with H 2O 15 and 15 O2 during: 1) control conditions; 2) nitric oxide synthase (NOS) inhibition by arterial infusion of N G -monomethyl-L-arginine (L-NMMA), and 3) combined NOS and cyclooxygenase (COX) inhibition by arterial infusion of L-NMMA and indomethacin. At rest, inhibition of NOS alone and in combination with indomethacin reduced (P Ͻ 0.05) muscle blood flow. NOS inhibition increased (P Ͻ 0.05) limb oxygen extraction fraction (OEF) more than the reduction in muscle blood flow, resulting in an ϳ20% increase (P Ͻ 0.05) in resting muscle oxygen consumption. During exercise, muscle blood flow and oxygen uptake were not altered with NOS inhibition, whereas muscle OEF was increased (P Ͻ 0.05). NOS and COX inhibition reduced (P Ͻ 0.05) blood flow in working quadriceps femoris muscle by 13%, whereas muscle OEF and oxygen uptake were enhanced by 51 and 30%, respectively. In conclusion, by specifically measuring blood flow and oxygen uptake by the use of PET instead of whole limb measurements, the present study shows for the first time in humans that inhibition of NO formation enhances resting muscle oxygen uptake and that combined inhibition of NOS and COX during exercise increases muscle oxygen uptake. skeletal muscle; blood flow; oxygen consumption; nitric oxide NITRIC OXIDE (NO) is involved in a host of signaling and regulatory pathways of mammals. Its role as an important tonic regulator of baseline vessel tone (37) and blood pressure (28) is well established. Additionally, exercise hyperemia also depends on NO since it, in synergy with other compounds, regulates blood flow of the working limb (2,15,19,23,30,31). NO also plays a role in the regulation of muscle metabolism. By use of in vitro preparations, it has been demonstrated that the primary effect of exogenous NO on mitochondrial activity is a reversible and competitive inhibition of cytochrome oxidase activity (5,6,32). Some animal studies have subsequently found evidence that NO tonically inhibits mitochondrial respiration in vivo (33-35), but there has not been evidence for this in humans (10,27,31). It is well shown with various methods that prostanoids can act synergistically with NO to regulate vascular function in health and disease (2,19,23,30,31), but COX inhibition may also have direct effects on cellular aerobic respiration by affecting uncoupling (17,20,23).Positron emission tomography (PET) ...

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Nitric oxide and prostaglandins influence local skeletal muscle blood flow during exercise in humans: coupling between local substrate uptake and blood flow

Cited by 23 publications

References 62 publications

Review: Angiotensin-converting enzyme in skeletal muscle: sentinel of blood pressure control and glucose homeostasis

Review: Angiotensin-converting enzyme in skeletal muscle: sentinel of blood pressure control and glucose homeostasis

Nitric oxide, but not vasodilating prostaglandins, contributes to the improvement of exercise hyperemia via ascorbic acid in healthy older adults

Skeletal muscle blood flow and oxygen uptake at rest and during exercise in humans: a pet study with nitric oxide and cyclooxygenase inhibition

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