Positive chronotropic action of HCN channel antagonism in human collecting lymphatic vessels
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Positive chronotropic action of HCN channel antagonism in human collecting lymphatic vessels. / Majgaard, Jens; Skov, Frederik G.; Kim, Sukhan; Hjortdal, Vibeke Elisabeth; Boedtkjer, Donna M.B.
I: Physiological Reports, Bind 10, Nr. 16, e15401, 2022.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Positive chronotropic action of HCN channel antagonism in human collecting lymphatic vessels
AU - Majgaard, Jens
AU - Skov, Frederik G.
AU - Kim, Sukhan
AU - Hjortdal, Vibeke Elisabeth
AU - Boedtkjer, Donna M.B.
N1 - Publisher Copyright: © 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.
PY - 2022
Y1 - 2022
N2 - Spontaneous action potentials precede phasic contractile activity in human collecting lymphatic vessels. In this study, we investigated the expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in human collecting lymphatics and by pharmacological inhibition ex vivo tested their potential role in controlling contractile function. Spontaneous and agonist-evoked tension changes of isolated thoracic duct and mesenteric lymphatic vessels—obtained from surgical patients with informed consent—were investigated by isometric myography, and ivabradine, ZD7288 or cesium were used to inhibit HCN. Analysis of HCN isoforms by RT-PCR and immunofluorescence revealed HCN2 to be the predominantly expressed mRNA isoform in human thoracic duct and mesenteric lymphatic vessels and HCN2-immunoreactivity confirmed protein expression in both vessel types. However, in functional experiments ex vivo the HCN inhibitors ivabradine, ZD7288, and cesium failed to lower contraction frequency: conversely, all three antagonists induced a positive chronotropic effect with concurrent negative inotropic action, though these effects first occurred at concentrations regarded as supramaximal for HCN inhibition. Based on these results, we conclude that human collecting vessels express HCN channel proteins but under the ex vivo experimental conditions described here HCN channels have little involvement in regulating contraction frequency in human collecting lymphatic vessels. Furthermore, HCN antagonists can produce concentration-dependent positive chronotropic and negative inotropic effects, which are apparently unrelated to HCN antagonism.
AB - Spontaneous action potentials precede phasic contractile activity in human collecting lymphatic vessels. In this study, we investigated the expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in human collecting lymphatics and by pharmacological inhibition ex vivo tested their potential role in controlling contractile function. Spontaneous and agonist-evoked tension changes of isolated thoracic duct and mesenteric lymphatic vessels—obtained from surgical patients with informed consent—were investigated by isometric myography, and ivabradine, ZD7288 or cesium were used to inhibit HCN. Analysis of HCN isoforms by RT-PCR and immunofluorescence revealed HCN2 to be the predominantly expressed mRNA isoform in human thoracic duct and mesenteric lymphatic vessels and HCN2-immunoreactivity confirmed protein expression in both vessel types. However, in functional experiments ex vivo the HCN inhibitors ivabradine, ZD7288, and cesium failed to lower contraction frequency: conversely, all three antagonists induced a positive chronotropic effect with concurrent negative inotropic action, though these effects first occurred at concentrations regarded as supramaximal for HCN inhibition. Based on these results, we conclude that human collecting vessels express HCN channel proteins but under the ex vivo experimental conditions described here HCN channels have little involvement in regulating contraction frequency in human collecting lymphatic vessels. Furthermore, HCN antagonists can produce concentration-dependent positive chronotropic and negative inotropic effects, which are apparently unrelated to HCN antagonism.
KW - HCN2
KW - histamine
KW - ivabradine
KW - lymph vessel
KW - lymphatic smooth muscle
U2 - 10.14814/phy2.15401
DO - 10.14814/phy2.15401
M3 - Journal article
C2 - 35980021
AN - SCOPUS:85136030942
VL - 10
JO - Physiological Reports
JF - Physiological Reports
SN - 2051-817X
IS - 16
M1 - e15401
ER -
ID: 327074294