Probenecid inhibits α-adrenergic receptor-mediated vasoconstriction in the human leg vasculature
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Probenecid inhibits α-adrenergic receptor-mediated vasoconstriction in the human leg vasculature. / Nyberg, Michael Permin; Piil, Peter Bergmann; Kiehn, Oliver Thistrup; Maagaard, Christian; Jørgensen, Tue Sparholt; Egelund, Jon; Isakson, Brant E; Nielsen, Morten Schak; Gliemann, Lasse; Hellsten, Ylva.
In: Hypertension, Vol. 71, No. 1, 2018, p. 151-159.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Probenecid inhibits α-adrenergic receptor-mediated vasoconstriction in the human leg vasculature
AU - Nyberg, Michael Permin
AU - Piil, Peter Bergmann
AU - Kiehn, Oliver Thistrup
AU - Maagaard, Christian
AU - Jørgensen, Tue Sparholt
AU - Egelund, Jon
AU - Isakson, Brant E
AU - Nielsen, Morten Schak
AU - Gliemann, Lasse
AU - Hellsten, Ylva
N1 - CURIS 2018 NEXS 011
PY - 2018
Y1 - 2018
N2 - Coordination of vascular smooth muscle cell tone in resistance arteries plays an essential role in the regulation of peripheral resistance and overall blood pressure. Recent observations in animals have provided evidence for a coupling between adrenoceptors and Panx1 (pannexin-1) channels in the regulation of sympathetic nervous control of peripheral vascular resistance and blood pressure; however, evidence for a functional coupling in humans is lacking. We determined Panx1 expression and effects of treatment with the pharmacological Panx1 channel inhibitor probenecid on the vasoconstrictor response to α1- and α2-adrenergic receptor stimulation in the human forearm and leg vasculature of young healthy male subjects (23±3 years). By use of immunolabeling and confocal microscopy, Panx1 channels were found to be expressed in vascular smooth muscle cells of arterioles in human leg skeletal muscle. Probenecid treatment increased (P<0.05) leg vascular conductance at baseline by ≈15% and attenuated (P<0.05) the leg vasoconstrictor response to arterial infusion of tyramine (α1- and α2-adrenergic receptor stimulation) by ≈15%, whereas the response to the α1-agonist phenylephrine was unchanged. Inhibition of α1-adrenoceptors prevented the probenecid-induced increase in baseline leg vascular conductance, but did not alter the effect of probenecid on the vascular response to tyramine. No differences with probenecid treatment were detected in the forearm. These observations provide the first line of evidence in humans for a functional role of Panx1 channels in setting resting tone via α1-adrenoceptors and in the constrictive effect of noradrenaline via α2-adrenoceptors, thereby contributing to the regulation of peripheral vascular resistance and blood pressure in humans.
AB - Coordination of vascular smooth muscle cell tone in resistance arteries plays an essential role in the regulation of peripheral resistance and overall blood pressure. Recent observations in animals have provided evidence for a coupling between adrenoceptors and Panx1 (pannexin-1) channels in the regulation of sympathetic nervous control of peripheral vascular resistance and blood pressure; however, evidence for a functional coupling in humans is lacking. We determined Panx1 expression and effects of treatment with the pharmacological Panx1 channel inhibitor probenecid on the vasoconstrictor response to α1- and α2-adrenergic receptor stimulation in the human forearm and leg vasculature of young healthy male subjects (23±3 years). By use of immunolabeling and confocal microscopy, Panx1 channels were found to be expressed in vascular smooth muscle cells of arterioles in human leg skeletal muscle. Probenecid treatment increased (P<0.05) leg vascular conductance at baseline by ≈15% and attenuated (P<0.05) the leg vasoconstrictor response to arterial infusion of tyramine (α1- and α2-adrenergic receptor stimulation) by ≈15%, whereas the response to the α1-agonist phenylephrine was unchanged. Inhibition of α1-adrenoceptors prevented the probenecid-induced increase in baseline leg vascular conductance, but did not alter the effect of probenecid on the vascular response to tyramine. No differences with probenecid treatment were detected in the forearm. These observations provide the first line of evidence in humans for a functional role of Panx1 channels in setting resting tone via α1-adrenoceptors and in the constrictive effect of noradrenaline via α2-adrenoceptors, thereby contributing to the regulation of peripheral vascular resistance and blood pressure in humans.
KW - Forearm
KW - Hypertension
KW - Norepinephrine
KW - Sympathetic nervous system
KW - Tyramine
U2 - 10.1161/HYPERTENSIONAHA.117.10251
DO - 10.1161/HYPERTENSIONAHA.117.10251
M3 - Journal article
C2 - 29084879
VL - 71
SP - 151
EP - 159
JO - Hypertension
JF - Hypertension
SN - 0194-911X
IS - 1
ER -
ID: 185509020