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      Role of Voltage-Dependent and Ca 2+-Activated K + Channels on the Regulation of Isometric Force in Porcine Coronary Artery


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          We investigated the role of K<sup>+</sup> channels in the regulation of vascular tone in de-endothelialized porcine coronary artery. Isometric force and intracellular Ca<sup>2+</sup> ([Ca<sup>2+</sup>]<sub>i</sub>) under resting conditions were increased by treatment with 4-aminopyridine (4-AP, 1 m M), an inhibitor of voltage-dependent K<sup>+</sup> (K<sub>v</sub>) channels, but not by tetraethylammonium chloride (TEA, 1 m M) or charybdotoxin (100 n M), both inhibitors of Ca<sup>2+</sup>-activated K<sup>+</sup> (K<sub>Ca</sub>) channels, or glibenclamide (10 μ M), an inhibitor of ATP-sensitive K<sup>+</sup> channels. Under stimulated conditions with 9,11-dideoxy-11α,9α-epoxymethano-prostaglandin F<sub>2α</sub> (U46619), 4-AP as well as TEA or charybdotoxin increased isometric force and [Ca<sup>2+</sup>]<sub>i</sub>, but not glibenclamide. 4-AP was the most potent in terms of depolarization of membrane potential compared with TEA or glibenclamide in the presence or absence of EGTA. In the presence of U46619, a high concentration of 4-AP (10 m M) caused a further contraction with oscillations. The force oscillations induced by 4-AP were inhibited by diltiazem (10 μ M), an inhibitor of voltage-dependent Ca<sup>2+</sup> channels, or TEA (1 m M), but not by glibenclamide (10 μ M). These force oscillations may be associated with the periodic activation of K<sub>Ca</sub> channels. These findings suggested that 4-AP-sensitive K<sub>v</sub> channels play an important role in the control of vascular tone in both resting and stimulated conditions. Moreover, under stimulated conditions, K<sub>Ca</sub> channels also have an important role in the regulation of vascular tone. Dysfunction of these channels induces abnormal vasoconstriction and may be implicated in vascular diseases such as hypertension and vasospasm.

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          The Influence of Sarcoplasmic Reticulum Ca2+ Concentration on Ca2+ Sparks and Spontaneous Transient Outward Currents in Single Smooth Muscle Cells

          Localized, transient elevations in cytosolic Ca2+, known as Ca2+ sparks, caused by Ca2+ release from sarcoplasmic reticulum, are thought to trigger the opening of large conductance Ca2+-activated potassium channels in the plasma membrane resulting in spontaneous transient outward currents (STOCs) in smooth muscle cells. But the precise relationships between Ca2+ concentration within the sarcoplasmic reticulum and a Ca2+ spark and that between a Ca2+ spark and a STOC are not well defined or fully understood. To address these problems, we have employed two approaches using single patch-clamped smooth muscle cells freshly dissociated from toad stomach: a high speed, wide-field imaging system to simultaneously record Ca2+ sparks and STOCs, and a method to simultaneously measure free global Ca2+ concentration in the sarcoplasmic reticulum ([Ca2+]SR) and in the cytosol ([Ca2+]CYTO) along with STOCs. At a holding potential of 0 mV, cells displayed Ca2+ sparks and STOCs. Ca2+ sparks were associated with STOCs; the onset of the sparks coincided with the upstroke of STOCs, and both had approximately the same decay time. The mean increase in [Ca2+]CYTO at the time and location of the spark peak was ∼100 nM above a resting concentration of ∼100 nM. The frequency and amplitude of spontaneous Ca2+ sparks recorded at −80 mV were unchanged for a period of 10 min after removal of extracellular Ca2+ (nominally Ca2+-free solution with 50 μM EGTA), indicating that Ca2+ influx is not necessary for Ca2+sparks. A brief pulse of caffeine (20 mM) elicited a rapid decrease in [Ca2+]SR in association with a surge in [Ca2+]CYTO and a fusion of STOCs, followed by a fast restoration of [Ca2+]CYTO and a gradual recovery of [Ca2+]SR and STOCs. The return of global [Ca2+]CYTO to rest was an order of magnitude faster than the refilling of the sarcoplasmic reticulum with Ca2+. After the global [Ca2+]CYTO was fully restored, recovery of STOC frequency and amplitude were correlated with the level of [Ca2+]SR, even though the time for refilling varied greatly. STOC frequency did not recover substantially until the [Ca2+]SR was restored to 60% or more of resting levels. At [Ca2+]SR levels above 80% of rest, there was a steep relationship between [Ca2+]SR and STOC frequency. In contrast, the relationship between [Ca2+]SR and STOC amplitude was linear. The relationship between [Ca2+]SR and the frequency and amplitude was the same for Ca2+ sparks as it was for STOCs. The results of this study suggest that the regulation of [Ca2+]SR might provide one mechanism whereby agents could govern Ca2+ sparks and STOCs. The relationship between Ca2+ sparks and STOCs also implies a close association between a sarcoplasmic reticulum Ca2+ release site and the Ca2+-activated potassium channels responsible for a STOC.
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            An essential 'set' of K+ channels conserved in flies, mice and humans.

            The molecular genetic approach to studying K+ channels has revealed that at least four subfamilies of voltage-gated K+ channels originally discovered in Drosophila are conserved in mice and humans. This conservation of the K+ channel subfamilies Shaker, Shal, Shab, and Shaw suggests that not only the broad outlines of membrane electrical properties but also many molecular details as well evolved in the parent species ancestral to both invertebrate and vertebrate life. Shaker, Shal, Shab, and Shaw K+ channels have similar structures, but appear to be independent channel systems: when co-expressed in Xenopus oocytes, all four function independently. These four K+ channel subfamilies may be part of an essential 'set' of excitable channels required by most nervous systems. The task now remaining is to understand the functions of each member of the set.
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              Structural elements involved in specific K+ channel functions.


                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                February 2000
                07 March 2000
                : 37
                : 1
                : 16-25
                Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
                25709 J Vasc Res 2000;37:16–25
                © 2000 S. Karger AG, Basel

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                Page count
                Figures: 7, References: 49, Pages: 10
                Research Paper

                General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                Smooth muscle,K+ channels,4-Aminopyridine,Patch clamp,Calcium, intracellular,Coronary artery, porcine


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