The contribution of K⁺ channels to human thoracic duct contractility

Abstract

Telinius N, Kim S, Pilegaard H, Pahle E, Nielsen J, Hjortdal V, Aalkjaer C, Boedtkjer DB. The contribution of K ϩ channels to human thoracic duct contractility. Am J Physiol Heart Circ Physiol 307: H33-H43, 2014. First published April 28, 2014 doi:10.1152/ajpheart.00921.2013In smooth muscle cells, K ϩ permeability is high, and this highly influences the resting membrane potential. Lymph propulsion is dependent on phasic contractions generated by smooth muscle cells of lymphatic vessels, and it is likely that K ϩ channels play a critical role in regulating contractility in this tissue. The aim of this study was to investigate the contribution of distinct K ϩ channels to human lymphatic vessel contractility. Thoracic ducts were harvested from 43 patients and mounted in a wire myograph for isometric force measurements or membrane potential recordings with an intracellular microelectrode. Using K ϩ channel blockers and activators, we demonstrate a functional contribution to human lymphatic vessel contractility from all the major classes of K ϩ channels [ATP-sensitive K ϩ (KATP), Ca 2ϩ -activated K ϩ , inward rectifier K ϩ , and voltage-dependent K ϩ channels], and this was confirmed at the mRNA level. Contraction amplitude, frequency, and baseline tension were altered depending on which channel was blocked or activated. Microelectrode impalements of lymphatic vessels determined an average resting membrane potential of Ϫ43.1 Ϯ 3.7 mV. We observed that membrane potential changes of Ͻ5 mV could have large functional effects with contraction frequencies increasing threefold. In general, KATP channels appeared to be constitutively open since incubation with glibenclamide increased contraction frequency in spontaneously active vessels and depolarized and initiated contractions in previously quiescent vessels. The largest change in membrane voltage was observed with the KATP opener pinacidil, which caused 24 Ϯ 3 mV hyperpolarization. We conclude that K ϩ channels are important modulators of human lymphatic contractility. lymphatic vessels; membrane potential; potassium channels; thoracic duct; human LYMPHATIC COLLECTING VESSELS have an intrinsic capacity to generate phasic contractions that enable lymph to be pumped away from tissue and eventually back to the venous circulation. The intrinsic contractile activity of lymphatic vessels is triggered by an underlying electrical activity in lymphatic smooth muscle cells (LSMCs) of the vessel wall. The electrical activity of LSMCs has been measured by various techniques in several animal species but has not yet been demonstrated in human lymphatic vessels. Animal LSMCs produce spontaneous depolarization and action potentials consisting of a rapid depolarization and repolarization of the LSMC membrane potential (V m ) without a plateau phase (30). Intracellular microelectrode impalements of bovine and guinea pig mesenteric collecting lymphatic vessels (70 -500 m in diameter) have shown that the resting membrane potential (RMP) of LSMCs averages around Ϫ60 mV (27-29, 32, 33), whe...

Adenosine Triphosphate-Sensitive Potassium Currents in Heart Disease and Cardioprotection

“…While the classical understanding was that fluid flow in the lymphatic system was passive, it is now clear that lymphatic vessels are lined by smooth muscle. Contractility of these vessels is clearly sensitive to K ATP activation 62 , with a pharmacological profile that is consistent with the major subunits expressed in lymphatic muscle being Kir6.1 and SUR2 63 .…”

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“…After the initial spike, there is a rapid repolarization with an undershoot (1062, 1111). The fast, initial repolarization may be due to an outward current caused by activation of K v channels (1061). L-type voltage-gated Ca 2+ channels, which open more slowly than the fast voltage-gated Na + channels, contribute to the plateau phase of cardiac action potentials, and are suspected to contribute to the depolarization and plateau phase in lymphatic smooth muscle (445, 1064).…”

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“…These functions act to regulate the excitability of smooth muscle cells. Voltage-gated K+ channels may regulate the frequency and the amplitude of the spontaneous smooth muscle contractions in lymphatic collectors and ducts (Telinius et al, 2014). Polymorphisms in KCNA1 have been linked to episodic ataxia and myokymia (D’Adamo et al, 2015).…”

“…Ion movement and cell excitability are essential components of the intrinsic pump mechanism, which facilitates lymph transport. Deficits in this pumping mechanism may compromise lymph flow (Telinius et al, 2014; von der Weid et al, 2012). …”

“…Telinius et al (2014) found that the major classes of K+ channels have a role in the regulation of spontaneous contractions in the thoracic duct in humans. Because of their role in establishing and re-establishing normal voltage differentials across the cell membrane, K+ channels play an important role in lymph pump activity and lymph transport.…”