Nitric oxide (NO) does not contribute to the generation or action of adenosine during exercise hyperaemia in rat hindlimb

Ray, Clare J.; Marshall, Janice M.

doi:10.1113/jphysiol.2008.163691

Cited by 13 publications

(16 citation statements)

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“…In contrast, other studies have shown that NOS inhibition does not affect the increase of blood flow evoked in forearm or leg exercise in humans, rats, and rabbits [27–30]. Also, Ray and Marshall [31] reported that during exercise, adenosine originates from skeletal muscle fibers independently of NO and acts directly on adenosine A 2A AR on the vascular smooth muscle to evoke vasodilatation. As far as the absence of eNOS in eNOS −/− mice, the coronary flow is also not altered [14], and it has been suggested that either up-regulation of different NOS isoform (s) or enzyme(s) that produce other vasodilators as an alternate mechanism proposed for the unaltered coronary flow in eNOS null mice [14].…”

Section: Discussionmentioning

confidence: 99%

Salt modulates vascular response through adenosine A2A receptor in eNOS-null mice: role of CYP450 epoxygenase and soluble epoxide hydrolase

et al. 2010

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High salt (HS) intake can change the arterial tone in mice, and the nitric oxide (NO) acts as a mediator to some of the receptors mediated vascular response. The main aim of this study was to explore the mechanism behind adenosine-induced vascular response in HS-fed eNOS+/+ and eNOS−/− mice The modulation of vascular response by HS was examined using aortas from mice (eNOS+/+ and eNOS−/−) fed 4% (HS) or 0.45% (NS) NaCl-diet through acetylcholine (ACh), NECA (adenosine-analog), CGS 21680 (A2A AR-agonist), MS-PPOH (CYP epoxygenase-blocker; 10−5 M), AUDA (sEH-blocker; 10−5 M), and DDMS (CYP4A-blocker; 10−5 M). ACh-response was greater in HS-eNOS+/+ (+59.3 ± 6.3%) versus NS-eNOS+/+ (+33.3 ± 8.0%; P < 0.05). However, there was no response in both HS-eNOS−/− and NS-eNOS−/−. NECA-response was greater in HS-eNOS−/− (+37.4 ± 3.2%) versus NS-eNOS−/− (+7.4.0 ± 3.8%; P < 0.05). CGS 21680-response was also greater in HS-eNOS−/− (+45.4 ± 5.2%) versus NS-eNOS−/−(+5.1 ± 5.0%; P < 0.05). In HS-eNOS−/−, the CGS 21680-response was reduced by MS-PPOH (+7.3 ± 3.2%; P < 0.05). In NS-eNOS−/−, the CGS 21680-response was increased by AUDA (+38.2 ± 3.3%; P < 0.05) and DDMS (+30.1 ± 4.1%; P < 0.05). Compared to NS, HS increased CYP2J2 in eNOS+/+ (35%; P < 0.05) and eNOS−/− (61%; P < 0.05), but decreased sEH in eNOS+/+ (74%; P < 0.05) and eNOS−/− (40%; P < 0.05). Similarly, CYP4A decreased in HS-eNOS+/+ (35%; P < 0.05) and HS-eNOS−/− (34%; P < 0.05). These data suggest that NS causes reduced-vasodilation in both eNOS+/+ and eNOS−/− via sEH and CYP4A. However, HS triggers possible A2AAR-induced relaxation through CYP epoxygenase in both eNOS+/+ and eNOS−/−.

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Section: Discussionmentioning

confidence: 99%

Salt modulates vascular response through adenosine A2A receptor in eNOS-null mice: role of CYP450 epoxygenase and soluble epoxide hydrolase

et al. 2010

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“…28 This suggestion was based on the observation that adenosine made a substantial contribution to muscle vasodilation when NOS was inhibited. Because the vasodilatory effect of adenosine depends not only on NO formation but also on prostanoid formation, 3 the vasodilatory effect of adenosine during NOS blockade in the study by Ray and Marshall 28 may well reflect PGI 2 -mediated vasodilation.…”

Section: Discussionmentioning

confidence: 99%

Interstitial and Plasma Adenosine Stimulate Nitric Oxide and Prostacyclin Formation in Human Skeletal Muscle

Nyberg

Mortensen²,

Thaning³

et al. 2010

Hypertension

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Abstract-One major unresolved issue in muscle blood flow regulation is that of the role of circulating versus interstitial vasodilatory compounds. The present study determined adenosine-induced formation of NO and prostacyclin in the human muscle interstitium versus in femoral venous plasma to elucidate the interaction and importance of these vasodilators in the 2 compartments. To this end, we performed experiments on humans using microdialysis technique in skeletal muscle tissue, as well as the femoral vein, combined with experiments on cultures of microvascular endothelial versus skeletal muscle cells. In young healthy humans, microdialysate was collected at rest, during arterial infusion of adenosine, and during interstitial infusion of adenosine through microdialysis probes inserted into musculus vastus lateralis. Muscle interstitial NO and prostacyclin increased with arterial and interstitial infusion of adenosine. The addition of adenosine to skeletal muscle cells increased NO formation (fluorochrome 4-amino-5-methylamino-2Ј,7-difluorescein fluorescence), whereas prostacyclin levels remained unchanged. The addition of adenosine to microvascular endothelial cells induced an increase in NO and prostacyclin levels. These findings provide novel insight into the role of adenosine in skeletal muscle blood flow regulation and vascular function by revealing that both interstitial and plasma adenosine have a stimulatory effect on NO and prostacyclin formation. In addition, both skeletal muscle and microvascular endothelial cells are potential mediators of adenosine-induced formation of NO in vivo, whereas only endothelial cells appear to play a role in adenosineinduced formation of prostacyclin. keletal muscle blood flow is closely regulated to match O 2 delivery to the metabolic demand of the contracting muscle. 1 This precise regulation of muscle blood flow is believed to be regulated by a balance between vasoconstrictor activity and locally derived vasoactive substances. 2 Three such vasoactive compounds shown to be of importance for muscle blood flow regulation are adenosine, NO, and prostacyclin (PGI 2 ). Accordingly, it has been shown that blockade of adenosine receptors reduces exercise hyperemia by Ϸ15% to 20% 3,4 and simultaneous inhibition of the enzymes NO synthase (NOS), which catalyzes the formation of NO, and cyclooxygenase (COX), which initiates the conversion of arachidonic acid to PGI 2 , reduces exercise hyperemia in both the forearm and leg by Ϸ30%. 3,5-8 Importantly, these 3 vasoactive compounds show a close interaction in that the vasodilator effect of adenosine primarily appears to be mediated via the formation of NO and PGI 2 , as evidenced by markedly reduced vasodilation in response to arterially infused adenosine when NOS 3,9 and COX 3 are inhibited. Moreover, adenosine receptor blockade does not further reduce exercise hyperemia when combined with inhibition of NOS and COX, 3 suggesting that the vasodilator effect of endogenous adenosine is NO and PGI 2 dependent. However, because pharmac...

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“…In A , n = 10; in B and C , n = 12 rats. Modified from Ray & Marshall (2009 a , b ). In D , the effects on FVC of breathing air or 40% O 2 without or with 8‐SPT are compared.…”

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confidence: 99%

“…1). Furthermore, when an NO donor or cell‐permeant cGMP was infused after NOS inhibition so as to restore the tonic dilator effect of NO and cGMP levels in the vascular smooth muscle, exercise hyperaemia was fully restored and A 2A receptor blockade had the same effect as before NOS inhibition (Ray & Marshall, 2009 b ; Fig. 1).…”

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confidence: 99%

“…Thus, release of adenosine in exercise cannot be attributed to the interaction of NO and O 2 at cyta 3 in endothelial cells or muscle fibres, consistent with the evidence discussed above that adenosine is generated extracellularly from ATP. Furthermore, in the rat, NO does not mediate the A 2A component of exercise hyperaemia (Ray & Marshall, 2009 b ). This is consistent with evidence that NOS inhibition in humans has little effect on the maintained phase of exercise hyperaemia or (Frandsen et al 2001; Schrage et al 2004; Mortensen et al 2007).…”

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confidence: 99%

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Contribution of non‐endothelium‐dependent substances to exercise hyperaemia: are they O₂ dependent?

Marshall

Ray

2012

The Journal of Physiology

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This review considers the contributions to exercise hyperaemia of substances released into the interstitial fluid, with emphasis on whether they are endothelium dependent or O 2 dependent. The early phase of exercise hyperaemia is attributable to K + released from contracting muscle fibres and acting extraluminally on arterioles. Hyperpolarization of vascular smooth muscle and endothelial cells induced by K + may also facilitate the maintained phase, for example by facilitating conduction of dilator signals upstream. ATP is released into the interstitium from muscle fibres, at least in part through cystic fibrosis transmembrane conductance regulator-associated channels, following the fall in intracellular H + . ATP is metabolized by ectonucleotidases to adenosine, which dilates arterioles via A 2A receptors, in a nitric oxide-independent manner. Evidence is presented that the rise in arterial P O 2 achieved by breathing 40% O 2 attenuates efflux of H + and lactate, thereby decreasing the contribution that adenosine makes to exercise hyperaemia; efflux of inorganic phosphate and its contribution may likewise be attenuated. Prostaglandins (PGs), PGE 2 and PGI 2 , also accumulate in the interstitium during exercise, and breathing 40% O 2 abolished the contribution of PGs to exercise hyperaemia. This suggests that PGE 2 released from muscle fibres and PGI 2 released from capillaries and venular endothelium by a fall in their local P O 2 act extraluminally to dilate arterioles. Although modest hyperoxia attenuates exercise hyperaemia by improving O 2 supply, limiting the release of O 2 -dependent adenosine and PGs, higher O 2 concentrations may have adverse effects. Evidence is presented that breathing 100% O 2 limits exercise hyperaemia by generating O 2 − , which inactivates nitric oxide and decreases PG synthesis.

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Nitric oxide (NO) does not contribute to the generation or action of adenosine during exercise hyperaemia in rat hindlimb

Cited by 13 publications

References 40 publications

Salt modulates vascular response through adenosine A2A receptor in eNOS-null mice: role of CYP450 epoxygenase and soluble epoxide hydrolase

Salt modulates vascular response through adenosine A2A receptor in eNOS-null mice: role of CYP450 epoxygenase and soluble epoxide hydrolase

Interstitial and Plasma Adenosine Stimulate Nitric Oxide and Prostacyclin Formation in Human Skeletal Muscle

Contribution of non‐endothelium‐dependent substances to exercise hyperaemia: are they O₂ dependent?

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Nitric oxide (NO) does not contribute to the generation or action of adenosine during exercise hyperaemia in rat hindlimb

Cited by 13 publications

References 40 publications

Salt modulates vascular response through adenosine A2A receptor in eNOS-null mice: role of CYP450 epoxygenase and soluble epoxide hydrolase

Salt modulates vascular response through adenosine A2A receptor in eNOS-null mice: role of CYP450 epoxygenase and soluble epoxide hydrolase

Interstitial and Plasma Adenosine Stimulate Nitric Oxide and Prostacyclin Formation in Human Skeletal Muscle

Contribution of non‐endothelium‐dependent substances to exercise hyperaemia: are they O2 dependent?

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Contribution of non‐endothelium‐dependent substances to exercise hyperaemia: are they O₂ dependent?