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

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 -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 (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; (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 FVC: ATP: -162; ADO: -386; SNP: -596%; 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 (approximate to 35 and approximate to 60% respectively; P<0.05 vs. control). However, ATP maintained the ability to blunt PE-mediated vasoconstriction (PE-mediated FVC: K-IR blockade alone: -65%; combined blockade:-414%; P>0.05 vs. control). These findings demonstrate that intravascular ATP modulates (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.