The current study characterizes the mechanical properties of the human thoracic duct and demonstrates a role for adrenoceptors, thromboxane, and endothelin receptors in human lymph vessel function. With ethical permission and informed consent, portions of the thoracic duct (2-5 cm) were resected and retrieved at T7-T9 during esophageal and cardia cancer surgery. Ring segments (2 mm long) were mounted in a myograph for isometric tension (N/m) measurement. The diameter-tension relationship was established using ducts from 10 individuals. Peak active tension of 6.24 Ϯ 0.75 N/m was observed with a corresponding passive tension of 3.11 Ϯ 0.67 N/m and average internal diameter of 2.21 mm. The equivalent active and passive transmural pressures by LaPlace's law were 47.3 Ϯ 4.7 and 20.6 Ϯ 3.2 mmHg, respectively. Subsequently, pharmacology was performed on rings from 15 ducts that were normalized by stretching them until an equivalent pressure of 21 mmHg was calculable from the wall tension. At low concentrations, norepinephrine, endothelin-1, and the thromboxane-A2 analog U-46619 evoked phasic contractions (analogous to lymphatic pumping), whereas at higher contractions they induced tonic activity (maximum tension values of 4.46 Ϯ 0.63, 5.90 Ϯ 1.4, and 6.78 Ϯ 1.4 N/m, respectively). Spontaneous activity was observed in 44% of ducts while 51% of all the segments produced phasic contractions after agonist application. Acetylcholine and bradykinin relaxed norepinephrine preconstrictions by ϳ20% and ϳ40%, respectively. These results demonstrate that the human thoracic duct can develop wall tensions that permit contractility to be maintained across a wide range of transmural pressures and that isolated ducts contract in response to important vasoactive agents. lymphatic system; lymph pump; lymphangion; lymphatic smooth muscle THE EXCESS FLUID AND PROTEIN of the interstitial spaces in almost all tissues of the body are collected and removed by the lymphatic system. The lymphatic capillaries converge into larger collecting lymphatics, and, ultimately, these terminate into large transport vessels, which return lymph to the blood circulation. The lymphatic system lacks a central pump to drive the transport of lymph. Instead, it is generally accepted that the lymphatic smooth muscle cells (LSMCs) in the collecting and transporting lymphatic vessel wall are responsible for propelling lymph forward by intrinsic contractions. The lymphatic vessels responsible for pumping are comprised of multiple contractile segments separated by unidirectional valves to prevent backflow, termed a lymphangion, and each lymphangion performs much like a cardiac ventricle to provide unidirectional pumping. The contractile part of the lymphatic vasculature can thus be likened to a system of ventricles in series (27). The thoracic duct is the largest lymphatic vessel in the human body. Under normal conditions (i.e., in healthy individuals), it is a low-flow system that drains up to 1 ml/min to the venous circulation (30,44). The volume and flow of lymph a...

Background: The Fontan procedure has revolutionized the treatment of univentricular hearts. However, it is associated with severe complications such as protein-losing enteropathy, plastic bronchitis, and peripheral edema that may involve the lymphatic circulation. We aimed to assess lymphatic function and morphology in patients with a univentricular circulation. Methods: The functional state of lymphatic vessels in the lower extremities of patients with a Fontan circulation (n=10) was investigated using the novel technique near-infrared fluorescence imaging and compared with an age-, sex-, and weight-matched control group of healthy volunteers (n=10). The lymphatic morphology was described using T2-weighted magnetic resonance imaging, and microvascular permeability was estimated by strain gauge plethysmography. Results: The Fontan patients had 17% lower lymphatic pumping pressure (50±3.1 mm Hg) compared with controls (60±2.8 mm Hg; P =0.0341) and a 62% higher contraction frequency (0.8±0.1 min −1 ) compared with the healthy controls (0.5±0.1 min −1 ; P =0.0432). Velocity by which the lymph is moved and refill time after manual emptying of the lymphatic vessels showed no differences between the 2 groups. The thoracic duct was elongated 10% ( P =0.0409) and with an abnormal course in the Fontan patients compared with normal. No difference in microvascular permeability was found between the 2 groups. Conclusions: Patients with a Fontan circulation have an impaired lymphatic pumping capacity and morphologically changed thoracic duct. Our results indicate a challenged lymphatic vasculature in the Fontan circulation and may play a role in the pathogenesis of the complications that are seen in Fontan patients. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03379805.

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...