Sympatholytic effect of intravascular ATP is independent of nitric oxide, prostaglandins, Na⁺/K⁺-ATPase and K_IR 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 α₁-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 α₁-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 α₁-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; α₁-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 α₁-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.