TY - JOUR

T1 - Is the Pannexin-1 channel a mechanism underlying hypertension in humans? A translational study of human hypertension

AU - Gliemann, Lasse

AU - Tamariz-Ellemann, Andrea

AU - Hansen, Camilla Collin

AU - Ehlers, Thomas Svare

AU - Møller, Sophie

AU - Hellsten, Ylva

N1 - CURIS 2022 NEXS 080

PY - 2022

Y1 - 2022

N2 - Background: In preclinical models, the pannexin-1 channel has been shown to be involved in blood pressure regulation through an effect on peripheral vascular resistance. Pannexin-1 releases ATP, which can activate constrictive purinergic receptors on the smooth muscle cells. Pannexin-1 opening is proposed to be mediated by α-adrenergic receptors to potentiate sympathetic constriction. This positions pannexin-1 as a putative pharmacological target in blood pressure regulation in humans. The aim was to provide the first translational evidence for a role of pannexin-1 in essential hypertension in humans by use of an advanced invasive mechanistic approach.Methods: Middle-aged stage-1 hypertensive (n=13; 135.7±6.4 over 83.7±3.7 mm Hg) and normotensive men (n=12; 117.3±5.7 over 72.2±3.5 mm Hg) were included. Blood pressure and leg vascular resistance were determined during femoral arterial infusion of tyramine (α-adrenergic receptor stimulation), sodium nitroprusside, and acetylcholine. Measurements were made during control conditions and with Pannexin-1 blockade (3000 mg probenecid). Expression of  Pannexin-1, purinergic- and α-adrenergic receptors in skeletal muscle biopsies was determined by Western blot.Results: The changes in leg vascular resistance in response to tyramine (+289% versus +222%), sodium nitroprusside (-82% versus -78%) and acetylcholine (-40% versus -44%) infusion were not different between the 2 groups (P>0.05) and Pannexin-1 blockade did not alter these variables (P>0.05). Expression of Pannexin-1 and of purinergic- and α-adrenergic receptors was not different between the 2 groups (P>0.05).Conclusions: Contrary to our hypothesis, the data demonstrate that pannexin-1 does not contribute to the elevated blood pressure in essential hypertension, a finding, which also opposes that reported in preclinical models.

AB - Background: In preclinical models, the pannexin-1 channel has been shown to be involved in blood pressure regulation through an effect on peripheral vascular resistance. Pannexin-1 releases ATP, which can activate constrictive purinergic receptors on the smooth muscle cells. Pannexin-1 opening is proposed to be mediated by α-adrenergic receptors to potentiate sympathetic constriction. This positions pannexin-1 as a putative pharmacological target in blood pressure regulation in humans. The aim was to provide the first translational evidence for a role of pannexin-1 in essential hypertension in humans by use of an advanced invasive mechanistic approach.Methods: Middle-aged stage-1 hypertensive (n=13; 135.7±6.4 over 83.7±3.7 mm Hg) and normotensive men (n=12; 117.3±5.7 over 72.2±3.5 mm Hg) were included. Blood pressure and leg vascular resistance were determined during femoral arterial infusion of tyramine (α-adrenergic receptor stimulation), sodium nitroprusside, and acetylcholine. Measurements were made during control conditions and with Pannexin-1 blockade (3000 mg probenecid). Expression of  Pannexin-1, purinergic- and α-adrenergic receptors in skeletal muscle biopsies was determined by Western blot.Results: The changes in leg vascular resistance in response to tyramine (+289% versus +222%), sodium nitroprusside (-82% versus -78%) and acetylcholine (-40% versus -44%) infusion were not different between the 2 groups (P>0.05) and Pannexin-1 blockade did not alter these variables (P>0.05). Expression of Pannexin-1 and of purinergic- and α-adrenergic receptors was not different between the 2 groups (P>0.05).Conclusions: Contrary to our hypothesis, the data demonstrate that pannexin-1 does not contribute to the elevated blood pressure in essential hypertension, a finding, which also opposes that reported in preclinical models.

KW - Faculty of Science

KW - Acetylcholine

KW - Blood pressure

KW - Cardiac output

KW - Probenecid

KW - Tyramine

U2 - 10.1161/HYPERTENSIONAHA.121.18549

DO - 10.1161/HYPERTENSIONAHA.121.18549

M3 - Journal article

C2 - 35291811

VL - 79

SP - 1132

EP - 1143

JO - Hypertension

JF - Hypertension

SN - 0194-911X

IS - 5

ER -