Spontaneous and α-adrenoceptor-induced contractility in human collecting lymphatic vessels require chloride

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Human lymphatic vessels are myogenically active and respond to sympathetic stimulation: the role of various cations in this behavior has recently been investigated but whether the anion chloride (Cl-) is essential is unclear. With ethical approval and informed consent, human thoracic duct (TD) and mesenteric lymphatic vessels (MLV) were obtained from surgical patients. Spontaneous or norepinephrine-induced isometric force production from isolated vessels was measured by wire-myography; the transmembrane Cl--gradient and Cl- channels were investigated by substitution of extracellular Cl- with the impermeant anion aspartate and inhibition of Cl- transport and channels with the clinical diuretics furosemide and bendroflumethiazide, as well as DIDS and NPPB. The molecular expression of calcium-activated chloride channels was investigated by RT-PCR and proteins localized using immunoreactivity. Spontaneous and norepinephrine-induced contractility in human lymphatic vessels was highly abrogated after Cl- substitution with aspartate. 100‒300µM DIDS or NPPB inhibited spontaneous contractile behavior. Norepinephrine-stimulated tone was furthermore markedly abrogated by 200µM DIDS. Furosemide lowered spontaneous constrictions only whereas bendroflumethiazide had non-specific inhibitory effects. Consistent expression of TMEM16A (ANO1) was found in both TD and MLV and immunoreactivity with different antibodies localized TMEM16A to lymphatic smooth muscle cells and interstitial cells. The significant change in contractile function observed with inhibitors and anion substitution suggests that Cl- movement over the plasma membrane of lymphatic myocytes is integral for spontaneous and α-adrenoceptor-evoked contractility in human collecting lymphatic vessels. Consistent detection and localization of TMEM16A to myocytes suggests that this channel could play a major functional role.

OriginalsprogEngelsk
TidsskriftA J P: Heart and Circulatory Physiology (Online)
Vol/bind315
Nummer2
Sider (fra-til)H389-H401
Antal sider13
ISSN1522-1539
DOI
StatusUdgivet - 2018

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