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

Christopher M. Hearon, Jennifer C. Richards, Mathew L. Racine, Gary J. Luckasen, Dennis G. Larson, Michael Joseph Joyner, Frank A. Dinenno

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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 (KIR), 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 KIR, NO, PGs and Na+/K+-ATPase activity. Blockade of KIR 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 (KIR) 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, KIR 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 KIR 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 KIR 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 KIR 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 KIR 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: KIR 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 KIR channels, NO, PGs and Na+/K+-ATPase in humans, consistent with a role for endothelium-derived hyperpolarization in functional sympatholysis.

Original languageEnglish (US)
Pages (from-to)5175-5190
Number of pages16
JournalJournal of Physiology
Volume595
Issue number15
DOIs
StatePublished - Aug 1 2017

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Sympatholytics
Prostaglandins
Nitric Oxide
Adenosine Triphosphate
Vasoconstriction
Exercise
Adrenergic Agents
Inwardly Rectifying Potassium Channel
sodium-translocating ATPase
Nitroprusside
Vasodilation
Adenosine
Blood Vessels
Skeletal Muscle
Ketorolac
Doppler Ultrasonography
Intra Arterial Infusions
Hyperemia

Keywords

  • adenosine triphosphate
  • blood flow control
  • sympatholysis

ASJC Scopus subject areas

  • Physiology

Cite this

Sympatholytic effect of intravascular ATP is independent of nitric oxide, prostaglandins, Na+/K+-ATPase and KIR channels in humans. / Hearon, Christopher M.; Richards, Jennifer C.; Racine, Mathew L.; Luckasen, Gary J.; Larson, Dennis G.; Joyner, Michael Joseph; Dinenno, Frank A.

In: Journal of Physiology, Vol. 595, No. 15, 01.08.2017, p. 5175-5190.

Research output: Contribution to journalArticle

Hearon, Christopher M. ; Richards, Jennifer C. ; Racine, Mathew L. ; Luckasen, Gary J. ; Larson, Dennis G. ; Joyner, Michael Joseph ; Dinenno, Frank A. / Sympatholytic effect of intravascular ATP is independent of nitric oxide, prostaglandins, Na+/K+-ATPase and KIR channels in humans. In: Journal of Physiology. 2017 ; Vol. 595, No. 15. pp. 5175-5190.
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abstract = "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 (KIR), 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 KIR, NO, PGs and Na+/K+-ATPase activity. Blockade of KIR 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 (KIR) 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, KIR 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 KIR 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 KIR 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 KIR 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 KIR 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: KIR 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 KIR channels, NO, PGs and Na+/K+-ATPase in humans, consistent with a role for endothelium-derived hyperpolarization in functional sympatholysis.",
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T1 - Sympatholytic effect of intravascular ATP is independent of nitric oxide, prostaglandins, Na+/K+-ATPase and KIR channels in humans

AU - Hearon, Christopher M.

AU - Richards, Jennifer C.

AU - Racine, Mathew L.

AU - Luckasen, Gary J.

AU - Larson, Dennis G.

AU - Joyner, Michael Joseph

AU - Dinenno, Frank A.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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 (KIR), 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 KIR, NO, PGs and Na+/K+-ATPase activity. Blockade of KIR 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 (KIR) 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, KIR 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 KIR 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 KIR 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 KIR 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 KIR 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: KIR 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 KIR channels, NO, PGs and Na+/K+-ATPase in humans, consistent with a role for endothelium-derived hyperpolarization in functional sympatholysis.

AB - 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 (KIR), 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 KIR, NO, PGs and Na+/K+-ATPase activity. Blockade of KIR 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 (KIR) 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, KIR 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 KIR 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 KIR 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 KIR 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 KIR 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: KIR 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 KIR channels, NO, PGs and Na+/K+-ATPase in humans, consistent with a role for endothelium-derived hyperpolarization in functional sympatholysis.

KW - adenosine triphosphate

KW - blood flow control

KW - sympatholysis

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