Acetylcholine-induced K+ currents in smooth muscle cells of intact rat small arteries (original) (raw)
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British Journal of Pharmacology, 1991
1 Acetylcholine causes a concentration-dependent hyperpolarization of the rat small mesenteric artery (diameter at 100mmHg, 200-400,um). In the absence of tone the average potential change was from approximately -60 to -75mV. In the presence of tone induced by endothelin-1 (20nM), acetylcholine caused vasorelaxation in association with a marked hyperpolarization; from approximately -32 to -71mV. 2 A number of compounds known to antagonize the actions of cromakalim were tested for their ability to block responses to acetylcholine. Glibenclamide (0.1-3pM), phentolamine (10-100pM) and alinidine
Naunyn-Schmiedeberg's Archives of Pharmacology, 2008
This study was designed to determine whether putative openers of calcium-activated potassium channels of small and/or intermediate conductance (SK Ca and IK Ca ) induce vascular smooth muscle hyperpolarizations and to identify the underlying mechanisms. The membrane potential of guinea pig carotid artery smooth muscle cells was recorded with intracellular microelectrodes in the presence of N ω -nitro-L-arginine and indomethacin. Acetylcholine and NS-309 produced endothelium-dependent hyperpolarizations. The effects of acetylcholine were partially and significantly inhibited by apamin. The combinations of charybdotoxin plus apamin and TRAM-34 plus apamin markedly and significantly reduced these hyperpolarizations. 1-ethyl-2-benzimidazolinone (1-EBIO) induced hyperpolarizations that were unaffected by TRAM-34 but partially inhibited by charybdotoxin, apamin, TRAM-34 plus apamin, and charybdotoxin plus apamin. Riluzole produced only marginal hyperpolarizations. Therefore, in the guinea pig carotid artery, endothelium-dependent hyperpolarization to acetylcholine involves the activation of both SK Ca and IK Ca , with a predominant role for the former channel. 1-EBIO is a non-selective and weak opener of SK Ca , while riluzole is virtually ineffective. By contrast, NS-309 is a reasonably potent and selective opener of both SK Ca and IK Ca , and this compound mimics the endotheliumdependent hyperpolarizations to acetylcholine.
Clinical and Experimental Pharmacology and Physiology, 2004
1. The elusive nature of endothelium-derived hyperpolarizing factor (EDHF) has hampered detailed study of the ionic mechanisms that underlie the EDHF hyperpolarization and relaxation. Most studies have relied on a pharmacological approach in which interpretations of results can be confounded by limited specificity of action of the drugs used. Nevertheless, small-, intermediate-and large-conductance Ca 2+ -activated K + channels (SK Ca , IK Ca and BK Ca , respectively) have been implicated, with inward rectifier K + channels (K IR ) and Na + / K + -ATPase also suggested by some studies.
Hearing Research, 2002
Nitric oxide (NO) hyperpolarizes vascular smooth muscle cells and dilates blood vessels of various beds, but little is known on cochlear vasculatures. Using in vitro preparations of the spiral modiolar artery (SMA), intracellular electrical recording and labeling techniques, we found that the NO donor DPTA-NONOate (10 WM) caused a hyperpolarization of V9 mV in all the cells that had a low resting potential (RP) level near 340 mV. The hyperpolarization amplitude was concentration-dependent, with a 50% effect concentration (EC 50 ) of 1 WM. The responses occur in both smooth muscle and endothelial cells, neither of which was blocked by 18L-glycyrrhetinic acid. The induced hyperpolarization was completely blocked by glipizide, but not by charybdotoxin, apamin, barium, 4-aminopyridine or tetraethylammonium. The hyperpolarizing responses were imitated by pinacidil (EC 50 = 30 WM). The pinacidil-induced response was also blocked by glipizide but not by the other K þ channel blockers mentioned above. Both DPTA-NONOate and pinacidil had little membrane potential effect on cells that had a high RP level near 375 mV. However, when the high RP cells were depolarized to a level beyond 345 mV by barium, both DPTA-NONOate and pinacidil hyperpolarized these cells not differently from those that initially had a low RP. It is concluded that NO hyperpolarizes the SMA primarily by activating K ATP channels in both muscle and endothelial cells. ß 0378-5955 / 02 / $^see front matter ß 2002 Elsevier Science B.V. All rights reserved. PII: S 0 3 7 8 -5 9 5 5 ( 0 2 ) 0 0 4 9 7 -5
American Journal of Physiology-Heart and Circulatory Physiology, 2006
Ca+-activated K+-channels (KCa) regulate vasomotor tone via smooth muscle hyperpolarization and relaxation. The relative contribution of the endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation differs depending on vessel type and size. It is unknown whether these KCa channels are differentially distributed along the same vascular bed and hence have different roles in mediating the EDHF response. We therefore assessed the role of small- (SKCa), intermediate- (IKCa), and large-conductance (BKCa) channels in mediating acetylcholine-induced relaxations in both first- and fourth-order side branches of the rat superior mesenteric artery (MA1 and MA4, respectively). Two-millimeter segments of each MA were mounted in the wire myograph, incubated with Nω-nitro-l-arginine methyl ester (l-NAME, 100 μmol/l) and indomethacin (10 μmol/l), and precontracted with phenylephrine (10 μmol/l). Cumulative concentration-response curves to ACh (0.001–10 μmol/l) were performed in the abse...
British Journal of Pharmacology, 1999
1. We hypothesized that nitric oxide (NO) and the endothelium-dependent hyperpolarizing factor (EDHF) may dilate microvessels by different cellular mechanisms, namely Ca2+-desensitization versus decrease in intracellular free calcium. 2. Effects of acetylcholine (ACh) and the NO donors sodium nitroprusside (SNP, 0.1 - 10 micromol l(-1)) and S-Nitroso-N-acetyl-D, L-penicillamine (SNAP, 0.01 - 10 micromol l-1) on intracellular calcium ([Ca2+]i, fura 2) and vascular diameter (videomicroscopy) were studied in isolated resistance arteries from hamster gracilis muscle (194+/-12 microm) pretreated with indomethacin and norepinephrine. Membrane potential changes were determined using 1, 3-dibutylbarbituric acid trimethineoxonol (DiBAC4(3)). 3. ACh (0.1 and 1 micromol l-1)-induced dilations were associated with a [Ca2+]i decrease (by 13+/-3 and 32+/-4%) and hyperpolarization of vascular smooth muscle (VSM, by 12+/-1% at 1 micromol l-1 ACh). Nomega-nitro-L-arginine (L-NA, 30 micromol l(-1)) partially inhibited the dilation but did not affect VSM [Ca2+]i decreases or hyperpolarization. In contrast, the KCa channel inhibitors tetrabutylammonium (TBA, 1 mmol l(-1)) and charybdotoxin (ChTX, 1 micromol l(-1)) abolished the ACh-induced [Ca2+]i decrease and the hyperpolarization in VSM while a significant dilation remained (25 and 40%). This remaining dilation was abolished by L-NA. ChTX did not affect [Ca2+]i increase and hyperpolarization in endothelial cells. SNP- or SNAP-induced dilations were not associated with decreases in VSM [Ca2+]i or hyperpolarization although minor transient decreases in VSM [Ca2+]i were observed at high concentrations. 4. These data suggest that ACh-induced dilations in microvessels are predominantly mediated by a factor different from NO and PGI2, presumably EDHF. EDHF exerts dilation by activation of KCa channels and a subsequent decrease in VSM [Ca2+]i, NO dilates the microvessels in a calcium-independent manner.
British Journal of Pharmacology, 2001
In intact mesenteric arteries, increasing [K + ] o by 5 mM hyperpolarized both endothelial and smooth muscle cells. Subsequent exposure to 10 mM phenylephrine depolarized both cell types which were then repolarized by a 5 mM increase in [K + ] o . In endothelium-denuded vessels, increasing [K + ] o by 5 mM hyperpolarized the smooth muscle but K + had no eect after depolarization by 10 mM phenylephrine. On subsequent exposure to iberiotoxin plus 4-aminopyridine, the repolarizing action of 5 mM K + was restored. In endothelium-intact vessels exposed to phenylephrine, pretreatment with a gap junction inhibitor (gap 27) reduced K + -mediated smooth muscle repolarization without aecting the endothelial cell response. It is concluded that phenylephrine-induced eux of K + via smooth muscle K + channels produces a local increase in [K + ] o which impairs repolarization to added K + . Thus, studies involving vessels precontracted with agonists which increase [K + ] o maximize the role of gap junctions and minimize any contribution to the EDHF pathway from endothelium-derived K + .
The Journal of Physiology, 1988
1. The action of acetylcholine (ACh) on the hyperpolarization-activated ('pacemaker') current if was studied in single myocytes from the sino-atrial (SA) node region of the rabbit heart, where low doses of ACh slow spontaneous activity by prolonging the diastolic depolarization phase. 2. Besides activating an outward component at voltages positive to the K+ equilibrium potential (iK,ACh), ACh depressed the current if activated on hyperpolarization at concentrations in the range 0 03-1 /M. 3. The ACh-dependent if depression was dissected from modifications of iK,ACh by blocking iK,ACh with barium and was studied under conditions that minimized the interference of other current changes caused by ACh. 4. The study of if modification by ACh with three-pulse protocols and the measurement of fully activated I-V relations of if with and without ACh revealed that ACh acted on if by shifting the current activation range to more negative voltages, with no obvious alteration of the fully activated current amplitude. 5. The action of ACh on if was opposite to that caused by catecholamines. The presence of isoprenaline (IP) did not prevent ACh inhibition of if, nor did the presence of ACh prevent the if stimulation caused by IP. The effects of IP and ACh on if were additive. 6. The ACh-induced inhibition of if was reversed by addition of atropine and could be mimicked by muscarine, indicating that muscarinic receptors mediate it. The implications of these findings on the regulation of pacemaker activity by ACh is discussed.