Probenecid inhibits α-adrenergic receptor-mediated vasoconstriction in the human leg vasculature

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 - 2018/1/1

Y1 - 2018/1/1

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 a1- and a2-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 Ĩ5% and attenuated (P<0.05) the leg vasoconstrictor response to arterial infusion of tyramine (a1- and a2-adrenergic receptor stimulation) by Ĩ5%, whereas the response to the a1-agonist phenylephrine was unchanged. Inhibition of a1-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 a1-adrenoceptors and in the constrictive effect of noradrenaline via a2-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 a1- and a2-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 Ĩ5% and attenuated (P<0.05) the leg vasoconstrictor response to arterial infusion of tyramine (a1- and a2-adrenergic receptor stimulation) by Ĩ5%, whereas the response to the a1-agonist phenylephrine was unchanged. Inhibition of a1-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 a1-adrenoceptors and in the constrictive effect of noradrenaline via a2-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

SN - 0194-911X

VL - 71

SP - 151

EP - 159

JO - Hypertension

JF - Hypertension

IS - 1

ER -