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

Abstract

Introduction 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. Methods Circular segments of inferior vena cava (IVC) from male Sprague-Dawley rats were suspended between two wires and isometric contraction to phenylephrine (Phe, 10−5M) and 96 mM KCl was measured. Acetylcholine (Ach, 10−10 to 10−5M) was added and the percentage venous relaxation was measured. To determine the role of nitric oxide (NO) and prostacyclin (PGI2), vein relaxation was measured in the presence of the NOS inhibitor L-NAME (3X10−4 M) and the COX 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 (ATP-sensitive KATP, 10−5M), 4-aminopyridine (4-AP, voltage-dependent Kv, 10−3M), apamin (small conductance Ca2+-dependent SKCa, 10−7M), and iberiotoxin (large conductance Ca2+-dependent BKCa, 10−8M), on Ach-induced relaxation were tested. Results Ach caused concentration-dependent relaxation of Phe contraction (max 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 (max 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, activator of KATP, caused significant IVC relaxation when applied alone or on top of maximal Ach-induced relaxation, suggesting that the Ach response may not involve KATP. Ach-induced relaxation was not inhibited by glibenclamide, 4-AP or apamin, suggesting little role of KATP, Kv or SKCa, respectively. In contrast, iberiotoxin significantly inhibited Ach-induced relaxation, suggesting a role of BKCa. Conclusions Thus endothelium-dependent venous relaxation plays a major role in the control of venous function. In addition to NO, an EDHF pathway involving BKCa may play a role in endothelium-dependent venous relaxation.

A de novo mutation in KCNN3 associated with autosomal dominant idiopathic non-cirrhotic portal hypertension

“…Cells lacking KCNN3 are less responsive to the vasodilator acetylcholine and shear stress on the vascular wall [7]. Little is known on the role of SK channels in venous vasoregulation [8].…”

Endothelium‐dependent relaxation mechanisms involve nitric oxide and prostanoids in the isolated bovine digital vein

“…Endothelium‐dependent relaxation caused by the activation of muscarinic receptors has been demonstrated not only in arteries but also in veins obtained from different species, including equine digital vein (Elliot et al., ), horse dorsal penile vein (Martínez et al., ), rabbit jugular vein (Itoh, Maekawa, & Shibayama, ), and rat inferior vena cava (Raffetto, Yu, Reslan, Xia, & Khalil, ). However, the venous endothelium produces and releases less amount of vasodilators than the arterial counterpart (Eguchi & Katusic, ).…”

“…Acetylcholine endothelium‐dependent relaxation can include an EDH component in some veins, such as the jugular and the superior cava vein (Itoh et al., ; Raffetto et al., ). Since, the L‐NAME/indomethacin combination abolished the endothelium‐dependent relaxation to acetylcholine, it is unlikely the presence of an EDH‐mediated relaxation component in the isolated bovine digital vein.…”

A Review of the Actions of Endogenous and Exogenous Vasoactive Substances during the Estrous Cycle and Pregnancy in Rats

“…In rats, Rees et al (1989) [114], found that blocking the formation of NO with the inhibitor L-NMMA resulted in an immediate rise in blood pressure and that the subsequent administration of the L-arginine substrate reversed this effect. NO also plays a role in the endothelium-dependent venous relaxation [115].…”