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Department of Pharmacology, The University of Vermont, College of Medicine, Burlington, Vermont 05405
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Activation of ATP-sensitive potassium (KATP) channels can regulate smooth muscle function through membrane potential hyperpolarization. A critical issue in understanding the role of KATP channels is the relationship between channel activation and the effect on tissue function. Here, we explored this relationship in urinary bladder smooth muscle (UBSM) from the detrusor by activating KATP channels with the synthetic compounds N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide (ZD-6169) and levcromakalim. The effects of ZD-6169 and levcromakalim on KATP channel currents in isolated UBSM cells, on action potentials, and on related phasic contractions of isolated UBSM strips were examined. ZD-6169 and levcromakalim at 1.02 and 2.63 µM, respectively, caused half-maximal activation (K1/2) of KATP currents in single UBSM cells (see Heppner TJ, Bonev A, Li JH, Kau ST, and Nelson MT. Pharmacology 53: 170-179, 1996). In contrast, much lower concentrations (K1/2 = 47 nM for ZD-6169 and K1/2 = 38 nM for levcromakalim) caused inhibition of action potentials and phasic contractions of UBSM. The results suggest that activation of <1% of KATP channels is sufficient to inhibit significantly action potentials and the related phasic contractions.
ZD-6169; levcromakalim; incontinence; electrophysiology; guinea pig; potassium channel openers
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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URINARY BLADDER SMOOTH MUSCLE (UBSM) from the detrusor exhibits spontaneous action potentials (3, 8), which are thought to underlie the nature of spontaneous phasic contractions in this tissue. Excitability in UBSM and the subsequent contractions are dependent on Ca2+ influx through voltage-dependent Ca2+ channels (3, 17). The repolarization of the action potential depends in part on activation of iberiotoxin-sensitive, large-conductance, Ca2+-activated K+ (KCa) channels (8), and the afterhyperpolarization is caused by activation of apamin-sensitive, small-conductance KCa channels (4, 9, 14). Thus cell excitability, and therefore cytosolic Ca2+ concentration, can be decreased through the activation of K+ channels that act to hyperpolarize the membrane potential and decrease action potential frequency.
UBSM contains different types of K+ channels (3, 8, 15), including ATP-sensitive K+ (KATP) channels that can be activated by a variety of potassium channel openers (KCOs) (1, 5, 6, 12-14, 22, 25). In tonic smooth muscle, such as vascular smooth muscle, KCOs, including pinacidil, cromakalim, and levcromakalim activate KATP channels with one-half activation of the currents in the 1-3 µM range (20, 21). However, KCOs cause vasodilation at lower concentrations than are required for one-half activation of whole cell KATP currents. These compounds cause one-half relaxation of isolated vessels in the concentration range of 30-600 nM (20, 21, 26). This observation suggests that a small increase in KATP-channel conductance can have a large effect on the cell membrane potential and smooth muscle tone (18, 21). Unlike vascular smooth muscle, UBSM exhibits action potentials and phasic contractions. Therefore, we hypothesized that UBSM may be very sensitive to KCOs because small changes in KATP-channel conductance are likely to move the resting membrane potential away from the threshold of action potential activation, and thus have significant inhibitory effects on action potentials and related phasic contractions.
Trivedi et al. (24) and Howe et al. (11) described a new bladder-selective KCO, ZD-6169, the S-enantiomer of the racemic compound N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide, which opens KATP channels in guinea pig detrusor (7, 16) and hyperpolarizes the membrane potential through KATP channel activation (7, 16, 24). ZD-6169 and levcromakalim effectively inhibit K+-induced contractions of guinea pig bladder (5, 16). ZD-6169 is also highly effective at inhibiting spontaneous contractions of rat bladder in vivo (25). However, the effects of KCOs, and ZD-6169 in particular, have not been studied on UBSM action potentials and phasic contractions in physiological external K+ solution.
The goal of the present study was to determine the degree of KATP channel activation required to inhibit action potentials and related phasic contractions of UBSM using ZD-6169 and levcromakalim as KCOs. We found that ZD-6169 and levcromakalim at concentrations >10 nM inhibited action potentials and contractions. These findings suggest a direct action of ZD-6169 and levcromakalim on KATP channels in UBSM to decrease membrane excitability and contractility. The results support the idea that low levels of KATP-channel activation have substantial effects on UBSM excitability and contractility.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Tissue preparation and organ bath experiments (contractility studies). Guinea pigs (250-350 g) were euthanized by halothane overdose followed by exsanguination. This procedure was reviewed and approved by the Office of Animal Care Management at the University of Vermont. The entire urinary bladder was removed and placed in ice-cold physiological saline solution (PSS, see below for composition). The bladder was pinned to the bottom of a Petri dish containing nominally Ca2+-free dissection solution (see below).
Small strips (100- to 300-µm wide and 3- to 5-mm long) from the detrusor muscle were cut free from the bladder wall and transferred to a Petri dish containing dissection solution. Miniature aluminum clips were placed at each end of the muscle strip to allow mounting of the strip in a tissue bath. Individual strips were placed in thermostatically controlled (37°C) tissue baths (2 ml volume). One end of the strip was attached to a stationary metal hook while the other end was connected to a force-displacement transducer (model BG-10G; Kulite Semiconductor Products) for isometric tension recording. The force generation by the muscle strips was recorded on a computer-based data-acquisition system (Axotape, Axon Instruments, Foster City, CA) and a chart pen recorder. The strips were suspended under a 1-mN tension. There was a 60- to 90-min equilibration period. To ensure that the effects of ZD-6169 and levcromakalim are not caused by neurotransmitters released from autonomic nerves contained in the muscle strips, experiments were performed in a cocktail consisting of blockers for known neurotransmitter receptors in the UBSM: atropine (1 µM), muscarinic antagonist; phentolamine (1 µM),
-adrenergic
antagonist; propranolol (1 µM), 
-adrenergic antagonist; suramin
(10 µM), purinergic antagonist; and tetrodotoxin (1 µM), neuronal
Na+-channel blocker (see Ref. 10).
Measurements of membrane potential.
For intracellular recordings, several thin strips of UBSM were removed
from the serosal surface and pinned to the bottom of a recording
chamber. Oxygenated solution was superfused over the tissue (1 ml/min),
and the temperature was maintained at 37°C. To facilitate
intracellular recordings, tissue movement was reduced by increasing the
osmolarity of the superfusing PSS solution with the addition of 350 mM
sucrose (8, 12). Microelectrodes were pulled on a
Flaming/Brown gas puller (Sutter Instrument, Novato, CA) and had a
resistance of 40-50 M
when filled with 3 M KCl. The
transmembrane potential was measured using a Dagan 8500 intracellular amplifier (Dagan, Minneapolis, MN), and the electrical signals were
acquired using the Axotape program (Axon Instruments) and stored on
magnetic tape using a modified Sony 75ES DAT recorder.
Cell isolation and whole cell KATP current recordings. To dissociate UBSM cells, three or four tissue strips were placed in 1.5 ml of dissociation solution, which contained 1.0 mg/ml collagenase. The tissue was incubated at 37°C in a rotating water bath for 60 min. After the incubation, the digested tissue was washed several times in dissociation media. The digested tissue was then dispersed with gentle trituration. Several drops of the solution containing the dissociated cells were then placed in a recording chamber. Most cells were elongated and had a bright, shiny appearance when examined using phase-contrast microscopy.
Whole cell currents through KATP channels were measured using the conventional whole cell configuration of the patch clamp technique, as previously described (1, 2, 7, 16). The bathing solution contained (in mM) 82 NaCl, 60 KCl, 0.1 CaCl2, 1 MgCl2, 10 glucose, and 10 HEPES, pH 7.4. The pipette solution contained (in mM) 102 KCl, 1 CaCl2, (free Ca2+ 20 nM) 1 MgCl2, 10 EGTA, 10 HEPES, 38 KOH, 0.2 GTP, 0.1 ADP, and 0.1 ATP (free ATP = 0.0053), pH 7.2. Under these conditions and a holding potential of
70 mV, the KATP currents were inward (1, 2).
KATP currents were low-pass filtered at 2 Hz with an
eight-pole Bessel filter and digitized at 10 Hz. All experiments were
conducted at 22°C.
Solutions and drugs. PSS was made daily and contained (in mM) 119 NaCl, 4.7 KCl, 24 NaHCO3, 1.2 KH2PO4, 2.5 CaCl2, 1.2 MgSO4, and 11 glucose. The solution was aerated with 95% O2-5% CO2 to obtain pH 7.4. Dissection/dissociation solution contained (in mM) 80 monosodium glutamate, 55 NaCl, 6 KCl, 10 glucose, 10 HEPES, and 2 MgCl2, with pH adjusted to 7.3 with NaOH. ZD-6169 was obtained from AstraZeneca Pharmaceuticals. Atropine, phentolamine, propranolol, suramin, and tetrodotoxin were purchased from Sigma. ZD-6169 and levcromakalim were dissolved in dimethyl sulfoxide and further diluted in PSS. The maximum concentration of dimethyl sulfoxide in the tissue baths was 0.01%. ZD-6169 and levcromakalim were administered directly into the tissue baths as cumulative concentrations.
Statistics. Summary data are presented as means ± SE for n, the number of separate preparations, isolated from different animals. Isolated bladder strips contracted with irregular frequency and amplitude, therefore, a 5-min period of the contraction curve was used to assess contractility. Force integral was calculated by integrating the area under the force-time curve for a period of 5 min. Contractile frequencies, amplitudes, and force integrals are expressed relative to control (absence of pharmacological intervention) values. The last 5 min before drug application (for the control) and the period from the 10th to 15th min for each applied concentration of the drugs were taken as the analysis periods. Statistical analysis of drug effects and the difference between treatment groups were determined using ANOVA where Tukey-Kramer multiple comparisons test was used for multiple comparison. A P value <0.05 was considered significant. The percent KATP channel activation was calculated from the concentration-response curves.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Activation of KATP current by
KATP channel openers ZD-6169
and levcromakalim.
The effects of ZD-6169 and levcromakalim on the KATP
currents were investigated at a holding potential of 70 mV, and the intracellular calcium solution was buffered at 20 nM to minimize activation of voltage-dependent K+ channels and large
conductance Ca2+-activated K+ channels (see
Refs. 1, 2, 7). Figure
1 illustrates that ZD-6169 (10 µM) and
levcromakalim (10 µM) activate an inward KATP current,
which was reversed by the KATP-channel inhibitor
glibenclamide (10 µM). We previously demonstrated that ZD-6169 and
levcromakalim activate KATP currents in UBSM with a
one-half activation constant of 1.02 µM for ZD-6169 and 2.63 µM for
levcromakalim and a Hill coefficient of 1.46 for ZD-6169 and 1.62 for
levcromakalim, respectively (7).
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Inhibition of UBSM action potentials by low
concentrations of ZD-6169.
The average resting membrane potential recorded in intact bundles of
detrusor UBSM was 40.3 ± 2.4 mV, which is similar to previous
reports (8, 22). Most of the muscle preparations showed
spontaneous electrical activity, exhibited in the form of bursts of
action potentials (Fig. 2A).
ZD-6169, applied at a concentration of 100 nM, which causes ~3%
activation of KATP current (see Fig. 4 and
DISCUSSION), caused a small hyperpolarization and
inhibition of action potentials (n = 3; Fig.
2A). Washout of ZD-6169 resulted in a fast recovery of the
spontaneous action potentials to the control level (Fig.
2A). Small hyperpolarization and inhibition of action
potentials could be observed at a concentration of ZD-6169 as low as 10 nM (Fig. 2B), which corresponds to <0.2% activation of
KATP currents (see Fig. 4A and
DISCUSSION). Higher concentrations of ZD-6169 (
100 nM)
further hyperpolarized the membrane and inhibited the smooth muscle
action potentials (Fig. 2B). ZD-6169 at 10 µM caused ~6
mV hyperpolarization (7, 16). Levcromakalim also inhibited
action potentials (not illustrated).
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Inhibition of spontaneous phasic contractions by low concentrations of ZD-6169 and levcromakalim. In UBSM, a phasic contraction reflects an elevation of Ca2+ entry through voltage-dependent Ca2+ channels caused by a burst of action potentials (8, 10). The amplitude of a phasic contraction depends on the increase in Ca2+ entry caused by membrane depolarization during an action potential, whereas the duration of a phasic contraction depends on the duration of a burst of action potentials. The frequency of phasic contractions should reflect mechanisms that temporarily cause action potentials to cease, such as an increase in K+ conductance.
Activation of KATP channels by ZD-6169 and levcromakalim caused a concentration-dependent decrease in phasic contractions. The predominant effect of both ZD-6169 and levcromakalim was to decrease contraction frequency and muscle force integral, but not amplitude or duration (Fig. 3).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The activity of KATP channels in smooth muscle has been shown to be important in regulating membrane potential and muscle tone (21). Activation of KATP channels causes membrane potential hyperpolarization, thereby decreasing smooth muscle tone by reduction in steady-state Ca2+ influx through voltage-dependent Ca2+ channels (18). UBSM, unlike arterial smooth muscle, exhibits action potentials and phasic contractions. Theoretically, very small changes in K+ conductance should be able to decrease UBSM excitability by moving the membrane potential away from the action potential threshold (1). Therefore, we tested the hypothesis that a small degree of activation of KATP channels would inhibit action potentials and phasic contractions in UBSM.
Previously, ZD-6169 was found to be effective in inhibiting 15 mM K+-induced phasic contractions of detrusor in micromolar concentrations, with an IC50 of 1.6 µM (16, 25). Levcromakalim has also been reported to inhibit 20 mM K+-induced UBSM contractions with an IC50 of 0.86 µM (5). Therefore, under conditions of elevated K+ (15-20 mM), significant KATP channel activation is required to inhibit phasic contractions. This is not surprising because elevation of K+ to 15-20 mM would depolarize the membrane potential and affect the potassium equilibrium potential. In contrast, our results indicate that low percent activation of KATP channels by ZD-6169 and levcromakalim significantly inhibits action potentials and spontaneous phasic contractions of guinea pig UBSM in physiological external K+ concentration (Figs. 2 and 3).
A wide variety of synthetic compounds, including ZD-6169 and levcromakalim, activates KATP channels in smooth muscle (7, 19-21, 23). ZD-6169 and levcromakalim increased KATP currents with an apparent one-half activation constant of 1.02 and 2.63 µM, respectively, and Hill coefficient of 1.46 and 1.62, respectively (Fig. 4; see also Ref. 7). We observed statistically significant inhibition of phasic contractions at 30 nM ZD-6169 and levcromakalim (Fig. 3), which would correspond to activation of <1% of the KATP currents (Fig. 4). ZD-6169 at 300 nM caused complete inhibition of action potentials and phasic contractions (Figs. 2 and 3), corresponding to activation of <15% of the KATP currents (Fig. 4A). At the same concentration, levcromakalim also caused complete inhibition of spontaneous phasic contractions (Fig. 3) corresponding to activation of only ~3% of the KATP currents (Fig. 4B). The fraction of KATP channels that affects UBSM function is likely to be less than these values. The relationship between ZD-6169 and levcromakalim concentration and KATP currents was determined in single UBSM cells dialyzed with low intracellular ATP concentration (Fig. 4; see also Ref. 7). Elevating ATP concentration decreases KATP currents (1) and increases the one-half activation concentration of the KCOs (21). Furthermore, it is assumed that ZD-6169 and levcromakalim can increase single-channel open probability to one, which is unlikely (1). Therefore, under physiological conditions, activation of <1% of the KATP channels decreases UBSM excitability and phasic contractions. These results support the general concept that regulation of KATP channels is a potent mechanism to regulate UBSM function.
Perspectives
Urinary incontinence is associated with abnormal detrusor contractions and the involuntary leakage of urine. This urinary bladder dysfunction significantly impairs the lifestyle of millions of people. One type of urinary incontinence is known as unstable bladder or hyperactive bladder. The cause of unstable bladder is thought to lie within the UBSM. Current treatments for unstable bladder are not very effective and have unwanted side effects. In recent years, much effort has been devoted to increasing our understanding of ion channels, such as KATP channels, that are believed to play a significant role in regulating UBSM excitability. It is hoped that activation of these ion channels would decrease the excitability of UBSM and be useful in the treatment of unstable bladder. To develop ion channel therapeutics that are effective in controlling incontinence, the relationship between ion channel activation and functional effects must be clearly understood. In this study, we used a multifaceted approach to study the effects of KATP channel openers on single isolated UBSM cells and correlated these findings with functional studies. Together with previous findings (Refs. 1, 2, 7, 16), the present results point to a key role for KATP channels in the control of membrane potential, action potential generation, and related phasic contractions of UBSM. Our findings suggest that very low concentrations of KATP-channel openers are sufficient to inhibit UBSM contractions. Thus low-dose applications of KATP channel openers may cause minimal side effects and be an effective therapeutic for the treatment of certain types of urinary incontinence.| |
ACKNOWLEDGEMENTS |
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This work was supported by National Institute of Health Grant DK-53832 to M. T. Nelson. G. M. Herrera is a National Science Foundation Graduate Research Fellow.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. T. Nelson, Dept. of Pharmacology, Given Bldg., Univ. of Vermont, College of Medicine, Burlington, VT 05405 (E-mail: nelson{at}salus.med.uvm.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 2 November 2000; accepted in final form 11 January 2001.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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G. V. Petkov and M. T. Nelson Differential regulation of Ca2+-activated K+ channels by {beta}-adrenoceptors in guinea pig urinary bladder smooth muscle Am J Physiol Cell Physiol, June 1, 2005; 288(6): C1255 - C1263. [Abstract] [Full Text] [PDF]
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K.-E. Andersson and A. Arner Urinary Bladder Contraction and Relaxation: Physiology and Pathophysiology Physiol Rev, July 1, 2004; 84(3): 935 - 986. [Abstract] [Full Text] [PDF]
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K. S. Thorneloe and M. T. Nelson Properties of a tonically active, sodium-permeable current in mouse urinary bladder smooth muscle Am J Physiol Cell Physiol, June 1, 2004; 286(6): C1246 - C1257. [Abstract] [Full Text] [PDF]
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 G. M Herrera, M. J Pozo, P. Zvara, G. V Petkov, C. T Bond, J. P Adelman, and M. T Nelson Urinary bladder instability induced by selective suppression of the murine small conductance calcium-activated potassium (SK3) channel J. Physiol., September 15, 2003; 551(3): 893 - 903. [Abstract] [Full Text] [PDF]
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M. Gopalakrishnan, S. A. Buckner, K. L. Whiteaker, C.-C. Shieh, E. J. Molinari, I. Milicic, A. V. Daza, R. Davis-Taber, V. E. Scott, D. Sellers, et al. (-)-(9S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-Dioxide (A-278637): A Novel ATP-Sensitive Potassium Channel Opener Efficacious in Suppressing Urinary Bladder Contractions. I. In Vitro Characterization J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 379 - 386. [Abstract] [Full Text] [PDF]
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M. E. Brune, T. A. Fey, J. D. Brioni, J. P. Sullivan, M. Williams, W. A. Carroll, M. J. Coghlan, and M. Gopalakrishnan (-)-(9S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-Dioxide (A-278637): A Novel ATP-Sensitive Potassium Channel Opener Efficacious in Suppressing Urinary Bladder Contractions. II. In Vivo Characterization J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 387 - 394. [Abstract] [Full Text] [PDF]
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Current; 
, muscle force.
