Voltage-gated sodium channels contribute to action potentials and spontaneous contractility in isolated human lymphatic vessels
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Voltage-gated sodium channels contribute to action potentials and spontaneous contractility in isolated human lymphatic vessels. / Telinius, Niklas; Majgaard, Jens; Kim, Sukhan; Katballe, Niels; Pahle, Einar; Nielsen, Jørn; Hjortdal, Vibeke; Aalkjaer, Christian; Boedtkjer, Donna Briggs.
In: The Journal of Physiology, Vol. 593, No. 14, 15.07.2015, p. 3109-22.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Voltage-gated sodium channels contribute to action potentials and spontaneous contractility in isolated human lymphatic vessels
AU - Telinius, Niklas
AU - Majgaard, Jens
AU - Kim, Sukhan
AU - Katballe, Niels
AU - Pahle, Einar
AU - Nielsen, Jørn
AU - Hjortdal, Vibeke
AU - Aalkjaer, Christian
AU - Boedtkjer, Donna Briggs
N1 - © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.
PY - 2015/7/15
Y1 - 2015/7/15
N2 - Voltage-gated sodium channels (VGSC) play a key role for initiating action potentials (AP) in excitable cells. VGSC in human lymphatic vessels have not been investigated. In the present study, we report the electrical activity and APs of small human lymphatic collecting vessels, as well as mRNA expression and function of VGSC in small and large human lymphatic vessels. The VGSC blocker TTX inhibited spontaneous contractions in six of 10 spontaneously active vessels, whereas ranolazine, which has a narrower VGSC blocking profile, had no influence on spontaneous activity. TTX did not affect noradrenaline-induced contractions. The VGSC opener veratridine induced contractions in a concentration-dependent manner (0.1-30 μm) eliciting a stable tonic contraction and membrane depolarization to -18 ± 0.6 mV. Veratridine-induced depolarizations and contractions were reversed ∼80% by TTX, and were dependent on Ca(2+) influx via L-type calcium channels and the sodium-calcium exchanger in reverse mode. Molecular analysis determined NaV 1.3 to be the predominantly expressed VGSC isoform. Electrophysiology of mesenteric lymphatics determined the resting membrane potential to be -45 ± 1.7 mV. Spontaneous APs were preceded by a slow depolarization of 5.3 ± 0.6 mV after which a spike was elicited that almost completely repolarized before immediately depolarizing again to plateau. Vessels transiently hyperpolarized prior to returning to the resting membrane potential. TTX application blocked APs. We have shown that VGSC are necessary for initiating and maintaining APs and spontaneous contractions in human lymphatic vessels and our data suggest the main contribution from comes NaV 1.3. We have also shown that activation of these channels augments the contractile activity of the vessels.
AB - Voltage-gated sodium channels (VGSC) play a key role for initiating action potentials (AP) in excitable cells. VGSC in human lymphatic vessels have not been investigated. In the present study, we report the electrical activity and APs of small human lymphatic collecting vessels, as well as mRNA expression and function of VGSC in small and large human lymphatic vessels. The VGSC blocker TTX inhibited spontaneous contractions in six of 10 spontaneously active vessels, whereas ranolazine, which has a narrower VGSC blocking profile, had no influence on spontaneous activity. TTX did not affect noradrenaline-induced contractions. The VGSC opener veratridine induced contractions in a concentration-dependent manner (0.1-30 μm) eliciting a stable tonic contraction and membrane depolarization to -18 ± 0.6 mV. Veratridine-induced depolarizations and contractions were reversed ∼80% by TTX, and were dependent on Ca(2+) influx via L-type calcium channels and the sodium-calcium exchanger in reverse mode. Molecular analysis determined NaV 1.3 to be the predominantly expressed VGSC isoform. Electrophysiology of mesenteric lymphatics determined the resting membrane potential to be -45 ± 1.7 mV. Spontaneous APs were preceded by a slow depolarization of 5.3 ± 0.6 mV after which a spike was elicited that almost completely repolarized before immediately depolarizing again to plateau. Vessels transiently hyperpolarized prior to returning to the resting membrane potential. TTX application blocked APs. We have shown that VGSC are necessary for initiating and maintaining APs and spontaneous contractions in human lymphatic vessels and our data suggest the main contribution from comes NaV 1.3. We have also shown that activation of these channels augments the contractile activity of the vessels.
KW - Action Potentials
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Female
KW - Humans
KW - Lymphatic Vessels/drug effects
KW - Male
KW - Middle Aged
KW - Muscle Contraction
KW - NAV1.3 Voltage-Gated Sodium Channel/genetics
KW - Sodium Channel Blockers/pharmacology
KW - Sodium Channels/genetics
U2 - 10.1113/JP270166
DO - 10.1113/JP270166
M3 - Journal article
C2 - 25969124
VL - 593
SP - 3109
EP - 3122
JO - The Journal of Physiology
JF - The Journal of Physiology
SN - 0022-3751
IS - 14
ER -
ID: 246781031