Requirement for Functional BK Channels in Maintaining Oscillation in Venomotor Tone Revealed by Species Differences in Expression of the β1 Accessory Subunits

Abstract

We determined the possible role of large-conductance Ca2+-activated K+ (BK) channels in regulation of venous tone in small capacitance veins and blood pressure. In rat mesenteric venous smooth muscle cells (MV SMC), BK channel α- and β1-subunits were co-expressed, unitary BK currents were detected, and single channel currents were sensitive to voltage and [Ca2+]i. Rat MV SMCs displayed Ca2+ sparks and iberiotoxin (IBTX)-sensitive spontaneous transient outward currents (STOCs). Under resting conditions in vitro, rat MV exhibited nifedipine-sensitive spontaneous oscillatory constrictions. Blockade of BK channels by paxilline and Ca2+ sparks by ryanodine constricted rat MV. Nifedipine caused venodilation and blocked paxilline-, KCl (20 mM) and BayK 8644-induced contraction. Acute inhibition of BK channels with IBTX in vivo increased blood pressure and reduced venous capacitance, measured as an increase in mean circulatory filling pressure in conscious rats. BK channel α-subunits and L-type Ca2+ channel α1-C subunits are expressed in murine MV. However, these channels are not functional as murine MV lacked nifedipine-sensitive basal tone and rhythmic constrictions. Murine MV were also insensitive to paxilline, ryanodine, KCl and BayK8644, consistent with our previous studies showing that murine MV do not have BK β1-subunits. These data show that not only there are species-dependent properties in ion channel control of venomotor tone, but also that BK channels are required for rhythmic oscillations in venous tone.

Ryanodine receptors are uncoupled from contraction in rat vena cava

“…Ca 2+ sparks have also been identified in mesenteric vein, and inhibition of these sparks causes contraction [32]. This suggests that functional RyR are present and coupled to contraction in other tissues from the venous circulation.…”

Impaired propulsive motility in the distal but not proximal colon of BK channel β1‐subunit knockout mice

“…Mice were euthanized using isoflurane anesthesia followed by cervical dislocation. We have used BK channel β1‐subunit KO mice in a number of previously published studies of smooth muscle function in vitro and in vivo 11,18,19 …”

“…We have used BK channel b1-subunit KO mice in a number of previously published studies of smooth muscle function in vitro and in vivo. 11,18,19 In vitro studies Cholinergic reactivity of small intestinal and colonic longitudinal muscle The small intestine and colon of WT and b1-subunit KO mice were dissected into proximal and distal segments. Each segment (1 cm) was suspended in individual jacketed tissue baths (25 mL volume) filled with warmed (37°C), oxygenated (95% O 2 , 5% CO 2 ) Krebs buffer solution of the following composition (millimolar): 117 NaCl, 4.7 KCl, 2.5 CaCl 2 , 1.2 MgCl 2 , 1.2 NaH 2 PO 4 , 25 NaHCO 3 , and 11 glucose.…”

“…8,9 b1-subunits contribute to regulation of smooth muscle tone in the trachea, blood vessels, and urinary bladder. [10][11][12][13] Ca 2+ -dependent activation of BK channels requires Ca 2+ influx through L-type Ca 2+ channels. 14 In smooth muscle cells, Ca 2+ activates ryanodine receptors (RyRs) on the smooth endoplasmic reticulum to cause Ca 2+ sparks.…”

Ca2+-Activated K+ Channels and the Regulation of the Uteroplacental Circulation

“…The importance of the BK Ca channel in the regulation of vascular function has been well demonstrated by pharmacological and genetic manipulations. The blockade of the BK Ca channel with iberiotoxin or tetraethylammonium (TEA) induces membrane depolarization, followed by an elevation of [Ca 2+ ] i , vasoconstriction, and elevated blood pressure [ 42 , 108 , 109 , 110 ]. Genetic ablation of the BK Ca channel α subunit leads to hypertension [ 111 ], suggesting an essential role of this channel in regulating blood pressure and controlling blood perfusion to organs.…”