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

Abstract

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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“…ATP and adenosine have been known to induce vasodilation following release from the erythrocytes via production of nitric oxide and prostacyclin (Nyberg et al 2010;Sprague et al 2011), and it has been recently demonstrated that exogenous ATP supplementation is capable of increasing exercise-induced blood flow (Jäger et al 2014). Improved blood flow may increase nutrient delivery.…”

Exercise Training Alters the Balance Between Vasoactive Compounds in Skeletal Muscle of Individuals With Essential Hypertension

“…Most of the proteins measured in our study are known to be endothelial cell specific, 17,22,24,28,32 and it is likely that the protein levels assessed in the muscle primarily reflected levels in microvascular endothelial cells, but with a potential contribution from other cells associated with the interstitium, including skeletal muscle cells. As our intention was to determine protein levels of vasoactive systems in cells that can contribute to the muscle interstitial levels of vasoactive compounds, determination in muscle biopsies seemed to be the most appropriate.…”

Mechanisms of rapid vasodilation after a brief contraction in human skeletal muscle

“…Recently, extracellular production of adenosine, resulting from the degradation of adenine nucleotides via ecto 5=-nucleotidase, has been shown to contribute to rapid vasodilation after electrically stimulated contraction of the hamster cremaster muscle (59). Previous evidence also suggests that adenosine is capable of stimulating NO and PG production in humans (52,57). It is also possible that ACh, released at the neuromuscular junction, could diffuse to nearby capillaries and stimulate NO and PG production (25).…”