Is the Pannexin-1 Channel a Mechanism Underlying Hypertension in Humans? a Translational Study of Human Hypertension

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 alpha-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 (alpha-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 alpha-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 alpha-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.