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 and purpose:The endothelium-derived hyperpolarizing factor (EDHF)-type relaxation in mesenteric small arteries from 21 week old Zucker lean (ZL) and Zucker diabetic fatty (ZDF) rats was investigated using (6,7-dichloro-1H-indole-2,3-dione 3-oxime) (NS309), a potent activator of small-conductance, calcium-activated potassium channel (SKCa) and intermediate-conductance, calcium-activated potassium channel (IKCa). Experimental approach: In the presence of inhibitors of cyclooxygenase and nitric oxide synthase [indomethacin and N w -nitro-L-arginine methyl ester (l-NAME), respectively], acetylcholine (ACh)-induced hyperpolarization and EDHF-type relaxation were investigated under isometric conditions in the wire myograph using 0.5 and 1 mM NS309 and/or selective blockers of SKCa and IKCa channels. Membrane potential was recorded with glass microelectrodes, and changes in the intracellular calcium concentration of endothelial cells were visualized by confocal microscopy. SKCa expression was assessed by Western blotting. Key results: In arteries from ZDF rats, ACh-induced relaxation and membrane hyperpolarization were attenuated and, compared with arteries from ZL rats, NS309 was less potent at causing relaxation. Incubation with 0.5 mM NS309 did not increase ACh-induced relaxation in arteries from ZDF rats significantly. However, 1 mM NS309 restored it (both in the absence and in the presence of indomethacin and l-NAME) without changing endothelial intracellular calcium concentration. The restored EDHF-type relaxation was more sensitive to diphenylmethyl]-1H-pyrazole) (1 mM) than to apamin. Expression of the SKCa channel was unaltered. Conclusions and implications:The attenuated EDHF-type relaxation in mesenteric small arteries from ZDF rats can be restored by NS309 without changes in the intracellular calcium concentration of endothelial cells. These results may have clinical implications for the treatment of endothelial dysfunction in overweight type 2 diabetic patients.

This study demonstrates the importance of bestrophins for synchronization of SMCs and strongly supports our hypothesis for generation of vasomotion.

Aim: Type 2 diabetes is associated with stroke and cardiac dysfunction. We therefore investigated isolated middle cerebral arteries and coronary septal arteries from the diabetic Goto-Kakizaki (GK) rat model of nonobese type 2 diabetes. Methods: Myogenic tone and agonist-induced responses were investigated under isobaric conditions with simultaneous recording of [Ca²⁺]_i. Rho-kinase and NO pathways were investigated using specific pharmacological tools. Results: Arteries from GK rats developed less tone at pressures from 20 to 100 mm Hg than arteries from control Wistar (CW) rats while [Ca²⁺]_i was similar. Blocking the Rho-kinase pathway decreased the pressure-induced development of tone and after blockade no difference in myogenic tone between arteries from GK and CW rats was seen. Cerebral arteries had similar tone to a maximal concentration of U46619 (GK: 35.5 ± 2% vs. CW: 31.6 ± 5%), while coronary arteries from GK rats developed less tone than arteries from CW rats (12 ± 3 vs. 26.1 ± 3%). Endothelium-dependent vasodilation to A23187 (cerebral) and to acetylcholine (coronary) was not different between arteries from GK and CW rats. Conclusion: Our data suggest that in resistance arteries from the brain and the heart of GK rats the myogenic tone is decreased due to impaired calcium sensitivity likely due to a defective Rho-kinase pathway.

No abstract