Sympatholytic effect of intravascular ATP is independent of Nitric Oxide, prostaglandins, Na+/K+-ATPase, and KIR channels 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 vasodilator 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.

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