title: Voltage-gated sodium channels contribute to action potentials and spontaneous contractility in isolated human lymphatic vessels.
abstract: 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.
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|Department of Cardiothoracic Surgery, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Niklas
authors.initials: N
authors.lastname: Telinius
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Majgaard
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Sukhan
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Katballe
authors.affiliation: Department of Surgery, Viborg Hospital, Viborg, Denmark.
authors.forename: Einar
authors.initials: E
authors.lastname: Pahle
authors.affiliation: Department of Surgery, Viborg Hospital, Viborg, Denmark.
authors.forename: Jørn
authors.initials: J
authors.lastname: Nielsen
authors.affiliation: Department of Cardiothoracic Surgery, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Vibeke
authors.initials: V
authors.lastname: Hjortdal
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Aalkjaer
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|Department of Cardiothoracic Surgery, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Donna Briggs
authors.initials: DB
authors.lastname: Boedtkjer
mesh_terms: D000200:Action Potentials; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D042601:Lymphatic Vessels / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction; D062552:NAV1.3 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D062552:NAV1.3 Voltage-Gated Sodium Channel; C424715:SCN3A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels