title: Human lymphatic vessel contractile activity is inhibited in vitro but not in vivo by the calcium channel blocker nifedipine.
abstract: Calcium channel blockers (CCB) are widely prescribed anti-hypertensive agents. The commonest side-effect, peripheral oedema, is attributed to a larger arterial than venous dilatation causing increased fluid filtration. Whether CCB treatment is detrimental to human lymphatic vessel function and thereby exacerbates oedema formation is unknown. We observed that spontaneous lymphatic contractions in isolated human vessels (thoracic duct and mesenteric lymphatics) maintained under isometric conditions were inhibited by therapeutic concentrations (nanomolar) of the CCB nifedipine while higher than therapeutic concentrations of verapamil (micromolar) were necessary to inhibit activity. Nifedipine also inhibited spontaneous action potentials measured by sharp microelectrodes. Furthermore, noradrenaline did not elicit normal increases in lymphatic vessel tone when maximal constriction was reduced to 29.4 ± 4.9% of control in the presence of 20 nmol l(-1) nifedipine. Transcripts for the L-type calcium channel gene CACNA1C were consistently detected from human thoracic duct samples examined and the CaV1.2 protein was localized by immunoreactivity to lymphatic smooth muscle cells. While human lymphatics ex vivo were highly sensitive to nifedipine, this was not apparent in vivo when nifedipine was compared to placebo in a randomized, double-blinded clinical trial: conversely, lymphatic vessel contraction frequency was increased and refill time was faster despite all subjects achieving target nifedipine plasma concentrations. We conclude that human lymphatic vessels are highly sensitive to nifedipine in vitro but that care must be taken when extrapolating in vitro observations of lymphatic vessel function to the clinical situation, as similar changes in lymphatic function were not evident in our clinical trial comparing nifedipine treatment to placebo.
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark Department of Cardiothoracic Surgery, Aarhus University Hospital, Aarhus, Denmark telinius@me.com.
authors.forename: Niklas
authors.initials: N
authors.lastname: Telinius
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark Department of Cardiothoracic Surgery, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Sheyanth
authors.initials: S
authors.lastname: Mohanakumar
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 Cardiothoracic Surgery, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Hans
authors.initials: H
authors.lastname: Pilegaard
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: International Congenital Cardiac Centre, Harley Street Clinic, London, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: de Leval
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Aalkjaer
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 Department of Cardiothoracic Surgery, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Donna Briggs
authors.initials: DB
authors.lastname: Boedtkjer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D018592:Cross-Over Studies; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008209:Lymphedema / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology*; D013897:Thoracic Duct / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D009543:Nifedipine