Human lymphatic vessel contractile activity is inhibited in vitro but not in vivo by the calcium channel blocker nifedipine
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Human lymphatic vessel contractile activity is inhibited in vitro but not in vivo by the calcium channel blocker nifedipine. / Telinius, Niklas; Mohanakumar, Sheyanth; Majgaard, Jens; Kim, Sukhan; Pilegaard, Hans; Pahle, Einar; Nielsen, Jørn; de Leval, Marc; Aalkjaer, Christian; Hjortdal, Vibeke; Boedtkjer, Donna Briggs.
In: The Journal of Physiology, Vol. 592, No. 21, 01.11.2014, p. 4697-714.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Human lymphatic vessel contractile activity is inhibited in vitro but not in vivo by the calcium channel blocker nifedipine
AU - Telinius, Niklas
AU - Mohanakumar, Sheyanth
AU - Majgaard, Jens
AU - Kim, Sukhan
AU - Pilegaard, Hans
AU - Pahle, Einar
AU - Nielsen, Jørn
AU - de Leval, Marc
AU - Aalkjaer, Christian
AU - Hjortdal, Vibeke
AU - Boedtkjer, Donna Briggs
N1 - © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.
PY - 2014/11/1
Y1 - 2014/11/1
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Calcium Channel Blockers/pharmacology
KW - Calcium Channels, L-Type/genetics
KW - Cross-Over Studies
KW - Gene Expression Regulation/drug effects
KW - Humans
KW - Lymphedema/chemically induced
KW - Male
KW - Membrane Potentials
KW - Middle Aged
KW - Muscle Contraction/drug effects
KW - Myocytes, Smooth Muscle/drug effects
KW - Nifedipine/pharmacology
KW - Thoracic Duct/cytology
KW - Tissue Culture Techniques
U2 - 10.1113/jphysiol.2014.276683
DO - 10.1113/jphysiol.2014.276683
M3 - Journal article
C2 - 25172950
VL - 592
SP - 4697
EP - 4714
JO - The Journal of Physiology
JF - The Journal of Physiology
SN - 0022-3751
IS - 21
ER -
ID: 246782913