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J Vasc Surg. 2012 Jun;55(6):1716-25. doi: 10.1016/j.jvs.2011.10.124. Epub 2011 Dec 30.

Endothelium-dependent nitric oxide and hyperpolarization-mediated venous relaxation pathways in rat inferior vena cava.

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Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.



The vascular endothelium plays a major role in the control of arterial tone; however, its role in venous tissues is less clear. The purpose of this study was to determine the role of endothelium in the control of venous function and the relaxation pathways involved.


Circular segments of inferior vena cava (IVC) from male Sprague-Dawley rats were suspended between two wires and isometric contraction to phenylephrine (Phe; 10(-5)M) and 96 mM KCl was measured. Acetylcholine (Ach; 10(-10) to 10(-5)M) was added and the percentage of venous relaxation was measured. To determine the role of nitric oxide (NO) and prostacyclin (PGI(2)), vein relaxation was measured in the presence of the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME; 3 × 10(-4) M) and the cyclooxygenase inhibitor indomethacin (10(-5) M). To measure the role of hyperpolarization, vein relaxation was measured in the presence of K(+) channel activator cromakalim (10(-11) to 10(-6) M), and the nonselective K(+) channel blocker tetraethylammonium (TEA; 10(-3) M). To test for the contribution of a specific K(+) channel, the effects of K(+) channel blockers: glibenclamide (adenosine triphosphate [ATP]-sensitive K(ATP), 10(-5) M), 4-aminopyridine (4-AP; voltage-dependent K(v), 10(-3) M), apamin (small conductance Ca(2+)-dependent SK(Ca), 10(-7) M), and iberiotoxin (large conductance Ca(2+)-dependent BK(Ca), 10(-8) M) on Ach-induced relaxation were tested.


Ach caused concentration-dependent relaxation of Phe contraction (maximum 49.9 ± 4.9%). Removal of endothelium abolished Ach-induced relaxation. IVC treatment with L-NAME partially reduced Ach relaxation (32.8 ± 4.9%). In IVC treated with L-NAME plus indomethacin, significant Ach-induced relaxation (33.6 ± 3.2%) could still be observed, suggesting a role of endothelium-derived hyperpolarizing factor (EDHF). In IVC treated with L-NAME, indomethacin and TEA, Ach relaxation was abolished, supporting a role of EDHF. In veins stimulated with high KCl, Ach caused relaxation (maximum 59.5 ± 3.5%) that was abolished in the presence of L-NAME and indomethacin suggesting that any Ach-induced EDHF is blocked in the presence of high KCl depolarizing solution, which does not favor outward movement of K(+) ion and membrane hyperpolarization. Cromakalim, an activator of K(ATP), caused significant IVC relaxation when applied alone or on top of maximal Ach-induced relaxation, suggesting that the Ach response may not involve K(ATP). Ach-induced relaxation was not inhibited by glibenclamide, 4-AP, or apamin, suggesting little role of K(ATP), K(v) or SK(Ca), respectively. In contrast, iberiotoxin significantly inhibited Ach-induced relaxation, suggesting a role of BK(Ca).


Thus, endothelium-dependent venous relaxation plays a major role in the control of venous function. In addition to NO, an EDHF pathway involving BK(Ca) may play a role in endothelium-dependent venous relaxation.

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