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

Abstract

Exercise and intravascular ATP elicit vasodilatation that is dependent on activation of inwardly rectifying potassium (K ) 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 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 channels, NO and PG synthesis, and Na /K -ATPase would not alter the ability of ATP to blunt α -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 -agonist) during ATP or control vasodilatator infusion, before and after K 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 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 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 blockade alone: -6 ± 5%; combined blockade:-4 ± 14%; P > 0.05 vs. control). These findings demonstrate that intravascular ATP modulates α -adrenergic vasoconstriction via pathways independent of K channels, NO, PGs and Na /K -ATPase in humans, consistent with a role for endothelium-derived hyperpolarization in functional sympatholysis.

Probenecid Inhibits α-Adrenergic Receptor–Mediated Vasoconstriction in the Human Leg Vasculature

“…23 Hence, Panx1 channels may provide 1 point of intercept for vasodilator substances in contracting skeletal muscle. 24 As the mechanisms underlying the sympatholytic properties of intravascular ATP remain undisclosed, 25 it is tempting to speculate that ATP acting on luminal endothelial purinergic receptors may ultimately lead to reduced Panx1 activity and α-adrenergic mediated vasoconstriction. One such mode of action could be hyperpolarization of endothelial and adjacent smooth muscle cells, thus leading to altered smooth muscle Panx1 conformation and activity.…”

Inhibition of Na+/K+‐ATPase and KIR channels abolishes hypoxic hyperaemia in resting but not contracting skeletal muscle of humans

“…As such, the vasodilatory response to intravascular ATP that persists following combined inhibition of NO, PGs, Na + /K + ‐ATPase and K IR channels (∼40% based on Hearon et al . ) may have contributed to the remaining augmented hyperaemia during hypoxic exercise. RBCs can also act as an endothelium‐independent source of NO through the formation of S ‐nitrosohemoglobin in the lung (Jia et al .…”

Difference in the integrated effects of sympathetic vasoconstriction and local vasodilation in human skeletal muscle and skin microvasculature

“…; Hearon et al. ). This effect, termed functional sympatholysis, ensures adequate blood flow to active skeletal muscle, despite elevated sympathetic vasoconstrictor activity (Thomas et al.…”

“…; Hearon et al. ). However, it is unknown whether the sympathetically mediated inhibition of dilation of skeletal muscle microvessels during PORH is affected by the levels of local vasodilatory stimuli.…”