Sympatholytic effect of intravascular ATP is independent of nitric oxide, prostaglandins, Na⁺/K⁺‐ATPase and KIR channels in humans

Key points Intravascular ATP attenuates sympathetic vasoconstriction (sympatholysis) similar to what is observed in contracting skeletal muscle of humans, and may be an important contributor to exercise hyperaemia. Similar to exercise, ATP‐mediated vasodilatation occurs via activation of inwardly rectifying potassium channels (K IR ), and synthesis of nitric oxide (NO) and prostaglandins (PG). However, recent evidence suggests that these dilatatory pathways are not obligatory for sympatholysis during exercise; therefore, we tested the hypothesis that the ability of ATP to blunt α 1 ‐adrenergic vasoconstriction in resting skeletal muscle would be independent of K IR , NO, PGs and Na + /K + ‐ATPase activity. Blockade of K IR channels alone or in combination with NO, PGs and Na + /K + ‐ATPase significantly reduced the vasodilatatory response to ATP, although intravascular ATP maintained the ability to attenuate α 1 ‐adrenergic vasoconstriction. This study highlights similarities in the vascular response to ATP and exercise, and further supports a potential role of intravascular ATP in blood flow regulation during exercise in humans. Abstract Exercise and intravascular ATP elicit vasodilatation that is dependent on activation of inwardly rectifying potassium (K IR ) channels, with a modest reliance on nitric oxide (NO) and prostaglandin (PG) synthesis. Both exercise and intravascular ATP attenuate sympathetic α‐adrenergic vasoconstriction (sympatholysis). However, K IR channels, NO, PGs and Na + /K + ‐ATPase activity are not obligatory to observe sympatholysis during exercise. To further determine similarities between exercise and intravascular ATP, we tested the hypothesis that inhibition of K IR channels, NO and PG synthesis, and Na + /K + ‐ATPase would not alter the ability of ATP to blunt α 1 ‐adrenergic vasoconstriction. In healthy subjects, we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to intra‐arterial infusion of phenylephrine (PE; α 1 ‐agonist) during ATP or control vasodilatator infusion, before and after K IR channel inhibition alone (barium chloride; n = 7; Protocol 1); NO ( l ‐NMMA) and PG (ketorolac) inhibition alone, or combined NO, PGs, Na + /K + ‐ATPase (ouabain) and K IR channel inhibition ( n = 6; Protocol 2). ATP attenuated PE‐mediated vasoconstriction relative to adenosine (ADO) and sodium nitroprusside (SNP) (PE‐mediated ΔFVC: ATP: −16 ± 2; ADO: −38 ± 6; SNP: −59 ± 6%; P < 0.05 vs . ADO and SNP). Blockade of K IR channels alone or combined with NO, PGs and Na + /K + ‐ATPase, attenuated ATP‐mediated vasodilatation (∼35 and ∼60% respectively; P < 0.05 vs . control). However, ATP maintained the ability to blunt PE‐mediated vasoconstriction (PE‐mediated ΔFVC: K IR blockade alone: −6 ± 5%; combined blockade:−4 ± 14%; P > 0.05 vs . control). These findings demonstrate that intravascular ATP modulates α 1 ‐adrenergic vasoconstriction via pathways independent of K IR channels, NO, PGs and Na + /K + ‐ATPase in humans, consistent with a role for endothelium‐derived hyperpolarization in functional sympatholysis.