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Cardiovascular Research 1999 44(2):429-435; doi:10.1016/S0008-6363(99)00223-0
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

A role for a glibenclamide-sensitive, relatively ATP-insensitive K+ current in regulating membrane potential and current in rat aorta

Santosh K Mishra1 and Philip I Aaronson*

Department of Pharmacology, The Guy's, King's College and St. Thomas’ Hospitals’ Medical and Dental School, St. Thomas's Campus, Lambeth Palace Road, London SE1 7EH, UK

* Corresponding author. Tel.: +44-171-960-5654; fax: +44-171-928-7482 p.aaronson{at}umds.ac.uk

Received 20 May 1999; accepted 1 July 1999


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: ATP-sensitive K+ channels have been classified based on their inhibition by cytoplasmic ATP. Recent evidence in vascular smooth muscle has suggested that these channels show weak sensitivity to intracellular ATP. However, it is not known whether these channels regulate the resting K+ conductance in vascular smooth muscles. Therefore, the aim of the present investigation was to characterize this current in rat aorta myocytes and to examine whether it contributes to setting the membrane potential. Methods: The conventional and nystatin-permeablised whole cell patch clamp techniques were used to characterize the effect of glibenclamide on membrane potential and K+ current in enzymatically dispersed rat aorta myocytes. Results: The mean resting potential measured in current clamp mode using the permeabilized patch approach was –54±5 mV (n=8). Glibenclamide (10 µM) caused a reversible 24-mV depolarization in these cells. In symmetrical K+ (135 mM) solution an inward glibenclamide-sensitive (10 µM) current (–4.1±0.7 pA/pF; n=5), hereafter termed Iglib, was observed at a membrane potential of –80 mV when cells held at –60 mV were ramped from –80 to +80 mV. In the absence of any nucleotide in the pipette solution, Iglib measured by the conventional whole-cell method was –23.69±4.65 pA/pF (n=9). With 1 and 3 mM ATP in the pipette, the average current density was –25±6.3 pA/pF (n=8), and –9.4±2.7 pA/pF (n=9), respectively. In the absence of ATP, 1 mM GDP significantly (P<0.01) increased Iglib (–44.8±8.4 pA/pF; n=13). Inclusion of 1 mM ATP in the GDP-containing pipette solution had no significant effect on the current amplitude (–56.4±10.7 pA/pF; n=7). Iglib fell to –11.0±2.9 pA/pF (n=10) if 1 mM GDP and 3 mM ATP were present. In symmetrical K+, the Iglib observed in the presence of 1 mM ATP in the pipette was increased by more than two-fold in the presence of 10 µM levcromakalim. In PSS containing 5 mM K+, a significant glibenclamide-sensitive current was observed at –45 mV membrane potential when cells dialyzed with 1 mM ATP were ramped between –80 to 30 mV. Conclusion: These results demonstrate that Iglib channels in rat aorta myocytes differ from classical KATP channels, being relatively insensitive to intracellular ATP. Iglib therefore appears to have an important role in contributing to the maintenance of the resting potential in rat aortic smooth muscle.

KEYWORDS Ion channels; Smooth muscle


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
K+ channels are critical in maintaining the normal resting membrane potential in a variety of excitable cells. Although ATP-sensitive K+ (KATP) channels are thought to play little role in maintaining the membrane potential under basal conditions, there have been several reports that the KATP channel blocker glibenclamide caused membrane depolarization, either of intact blood vessels [1] or of cells dialyzed with solutions containing millimolar concentrations of ATP [2]. Although these depolarizations were small, this observation is puzzling because the KATP channel is believed to be closed at normal concentrations of intracellular ATP. More recently, however, Zhang and Bolton [3] reported the existence of a type of glibenclamide-sensitive K+ channel (termed the MK channel) which was quite insensitive to ATP in inside-out patch experiments in rat portal vein myocytes. It is not known if this channel is present in other blood vessels and to what extent it might contribute to the resting K+ conductance.

In this study, we have utilized the conventional and nystatin-permeabilized whole cell patch clamp techniques in order to explore the role of glibenclamide-sensitive K+ channels in setting the resting membrane potential in the rat aorta, a widely used vascular preparation.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
Adult male Wistar rats (250–300 g) were killed by cervical dislocation in accordance with UK Home Office regulations and with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). The thoracic aorta was removed into ice cold physiological saline solution (PSS), cleaned of fat and connective tissue, cut into small pieces and incubated at 37°C in low Ca2+ (15 µM) PSS for 15 min. Tissue was then transferred to the same solution containing 0.23 mg/ml of elastase type I (Sigma) for 20 min, followed by incubation in low Ca2+ PSS containing collagenase type I (1 mg/ml), collagenase type XI (1 mg/ml), papain (0.5 mg/ml) and dithiolthreitol (1.1 mM) for a further 20 min. Tissues were washed in enzyme-free low Ca2+ PSS, triturated to disperse cells, and then stored in low Ca2+ PSS at 4°C for use within 5–6 h. Whole-cell membrane currents were recorded using either nystatin-perforated mode [4] or standard patch clamp techniques as described elsewhere [5]. Membrane currents were typically recorded during voltage ‘ramps’, in which the pipette potential was increased linearly from –80 to +30 or +80 mM over a period of 1 s; ramps were imposed at 0.1 Hz. The membrane potential was determined using the perforated patch technique in the current clamp mode. PSS contained (mM) NaCl, 130; KCl, 5.0; MgCl2, 1.2; CaCl2,1.5; HEPES, 10; glucose,10. The pH was adjusted to 7.4 with NaOH. Low-Ca2+ PSS contained 15 µM Ca2+. Ca2+-free, high-K+ (135 mM) solution was made by replacing NaCl with an equimolar concentration of KCl and removing Ca2+ from the PSS. The pipette solution for perforated patch recording contained (mM): KCl, 110; MgCl2, 2.5; HEPES, 10, EGTA, 10; nystatin 250 µg/ml and the pH was adjusted to 7.2 by KOH. For whole-cell conventional recording of ion currents, ATP (magnesium salt, 0.1, 1.0 or 3.0 mM) or GDP (sodium salt, 1.0 mM) alone or in combination were included in the pipette solution. Values in the text are shown as means±S.E.M (n=sample size). The statistical significance of differences between values was assessed using Student's unpaired t-test, with P<0.05 taken to indicate significance.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
Fig. 1A illustrates that 10 µM glibenclamide caused a large depolarization of the resting membrane potential (Em) when this was measured in current clamp mode using the perforated patch approach. Following wash, the recovery of Em was delayed but complete. Fig. 1B shows the mean values of Em measured in aorta myocytes under control conditions and then after the effect of 10 µM glibenclamide had stabilized. Em was –54±5 mV (n=8) in PSS, and decreased significantly (P<0.01) to –30±7 mV in glibenclamide. Following removal of glibenclamide, Em recovered to –59±6 mV. These results provide direct evidence for the contribution of Iglib to the resting Em in rat aorta.


Figure 1
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  		Fig. 1 (A) Shows the reversible depolarizing effect of 10 µM glibenclamide in a rat aorta myocyte. The membrane potential was recorded in current clamp mode in PSS using nystatin-perforated patch technique. (B) Bars depict the mean membrane potential of the aortic myocytes in the absence or in the presence of 10 µM glibenclamide (n=8). ** Indicates a significant inhibition (P<0.01).

 
Currents were recorded using the nystatin technique in cells held at –60 mV. The voltage was ramped from –80 to 80 mV as shown in Fig. 2A. We measured Iglib at a potential of –80 mV in order to minimize the interference from other K+ currents. As shown in Fig. 2, there was a small inward current at –80 mV in PSS containing 5 mM K+. When the superfusing medium was changed to Ca2+-free high K+ (135 mM+2 mM TEA) PSS in order to shift the K+ Erev to 0 mV and suppress any Ca2+-activated K+ current, an inward current of about –50 pA could be observed. Glibenclamide (10 µM) profoundly inhibited this current, which then recovered completely following wash, after a delay similar to that observed for the membrane potential. Fig. 2B illustrates the time-course of changes in the whole-cell current at –80 mV during this procedure. The numbers correspond to the traces shown in Fig. 2A. The mean amplitude of Iglib was –42.1±10.4 pA (n=5).


Figure 2
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  		Fig. 2 Effect of 10 µM glibenclamide on the resting current of rat aortic myocytes recorded with nystatin-perforated patch technique. (A) Currents during 1-s voltage-ramps from –80 to 80 mV at 0.1 Hz in a cell held at –60 mV and superfused with 5 mM K+ PSS (1), followed by Ca++-free, high K+ (135 mM) PSS containing 2 mM TEA in the absence (2), and then in the presence of 10 µM glibenclamide (3). (B) Inhibition of the current at –80 mV by 10 µM glibenclamide and recovery following wash; numbers correspond to current traces shown in A.

 
Since these data suggested that Iglib channels in rat aorta were open in the resting state at physiological concentrations of intracellular nucleotides, we further examined their regulation by ATP and the nucleotide diphosphate (NDP) GDP, as the actions of this NDP have previously been widely characterized in vascular myocytes [3,6].

One important characteristic of Iglib, as previously described [7], is its sensitivity to block by intracellular ATP. However, the current tracings shown in Fig. 3A demonstrate that a large Iglib was also present when the cells were dialyzed with a solution containing 1 mM ATP (with no other nucleotide). The time-course of the whole-cell current recorded at –80 mV is illustrated in Fig. 3B. Glibenclamide 1 µM was as potent as 10 µM in blocking the Iglib (data not shown), although we routinely used the higher concentration because it caused a more rapid effect.


Figure 3
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  		Fig. 3 Conventional whole-cell recording of Iglib with either 1 mM ATP or 1 mM GDP in the pipette, using voltage ramps as described for Fig. 1A. (A) Current tracings in 5 mM K+ (1), 135 mM K+ (2) and 135 mM K+ containing 10 µM glibenclamide (3) with 1 mM ATP in the pipette. (B) Reversible inhibition by 10 µM glibenclamide of ion current measured at the ramp potential of –80 mV; numbers correspond to current traces shown in A. (C) With 1 mM GDP in the pipette the ion currents were recorded in 5 mM K+ PSS (1), and in 135 mM K+ in the absence (2) and the presence of 10 µM glibenclamide (3). (D) The time-course of ion current recorded at the voltage ramp of –80 mV in the same cell as shown in C and its block by 10 µM glibenclamide and the subsequent recovery from glibenclamide-block following wash.

 
Fig. 3C shows the current—voltage relationship of the whole-cell current recorded with 1 mM GDP (no ATP) in the pipette. The current tracings show that the large inward current which developed when [K]bath was raised to 135 mM K+ was almost abolished by 10 µM glibenclamide, thereby confirming that the current was mediated by glibenclamide-sensitive K+-channels. Fig. 3D depicts the reversible effect of glibenclamide on the whole-cell current at –80 mV. As described above, recovery from glibenclamide block was delayed.

Fig. 4 illustrates the effects on Iglib of varying the concentration of ATP in the presence and absence of GDP. Current amplitude is expressed as current density; cells had a mean cell capacitance of 13.0±0.3 pF (n=229). Current amplitude was measured about 2 min after the [K]bath was raised to 135 mM (approximately 5 min after establishment of whole cell recording), because in some cases progressive rundown subsequently occurred (see below).


Figure 4
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  		Fig. 4 Averages of peak current densities measured at a ramp potential of –80 mV in cells superfused with Ca2+-free, high K+ (135 mM) PSS containing 2 mM TEA with the pipette containing either no nucleotide or different concentrations of ATP and GDP. Conventional whole-cell ion currents were measured in response to voltage-ramps from –80 to 80 mV at 0.1 Hz over a period of 1 s. (a) Refers to significant (P<0.05) inhibition of Iglib by 3 mM ATP in the pipette compared to either no nucleotide or with 0.1 or 1 mM ATP in the pipette. (b) Represents significant (P<0.01) stimulation of Iglib with 1 mM GDP when compared with no nucleotide in the pipette. (c) Denotes significant (P<0.01) stimulation of Iglib by 1 mM GDP in the presence of 1 mM ATP compared to 1 mM ATP alone in the pipette. (d) Indicates significant inhibition (P<0.01) of Iglib by 3 mM ATP with 1 mM GDP in the pipette as compared to the current recorded with either 1 mM GDP alone or with 1 mM GDP plus 1 mM ATP in the pipette.

 
In the absence of any nucleotide in the pipette, the mean current density of Iglib was –23.7±4.7 pA/pF (n=9) and the current showed run-down. Inclusion of either 0.1 or 1 mM ATP in the pipette had no significant effect on the current amplitude. Iglib was, however, significantly reduced (P<0.05) when pipette [ATP] was increased to 3 mM.

With 1 mM GDP only in the pipette, Iglib was significantly (P<0.01) greater than that in the absence of nucleotide. The current recorded in the presence of 1 mM ATP and 1 mM GDP was not significantly different from that with 1 mM GDP, alone, but was larger than the current present with 1 mM ATP alone (P<0.05). The current amplitude in the presence of 1 mM GDP and 3 mM ATP was similar to that observed when the pipette solution contained only 3 mM ATP.

Iglib showed complete (99±5%; n=4) recovery from block by 10 µM glibenclamide when 1 mM ATP was present in the pipette solution. On the other hand, with no ATP in the pipette, recovery from glibenclamide was consistently poor (12±9%, n=5). Recovery from glibenclamide amounted to 64±5% (n=4) and 84±5% (n=5) when 1 mM GDP and 1 mM GDP+1 mM ATP, respectively, were present in the pipette solution. This variability presumably represented differences in underlying current rundown which had occurred during exposure to glibenclamide and the prolonged recovery period, since separate experiments where glibenclamide was only applied after many minutes showed that a progressive slow rundown occurred with no ATP present, but not in the presence of 1 mM ATP (not shown).

Fig. 5(A,B) demonstrates that Iglib was also observed in the presence of 1 mM ATP in the pipette in Ca2+-free PSS containing a normal concentration of K+ (5 mM). The current measured at –45 mV (in order to minimize contamination by delayed rectifier and Ca2+-activated K+ currents) was 20.0±2.6 and –2.3±1.6 pA (n=6) in the absence and subsequent presence of 1 µM glibenclamide. The inhibition by glibenclamide was almost completely reversible.


Figure 5
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  		Fig. 5 (A,B) Conventional whole-cell recording of Iglib in Ca2+-free 5 mM K+ PSS with 1 mM ATP in the pipette in a myocyte ramped from –80 to 30 mV for 1 s at every 10 s from a holding potential of –60 mV. (A) Effect of 1 µM glibenclamide on the control current and its recovery following wash out of glibenclamide. (B) Illustrates the glibenclamide-sensitive current which was derived from subtraction of the glibenclamide-resistant current from the control current depicted in Fig. 4A. Note the linearity of the Iglib between –80 to 30 mV. (C,D) Effect of 10 µM levcromakalim on Iglib in a myocyte bathed in 135 mM K+ containing 2 mM TEA. The cell was ramped from –80 to 80 mV for 1 s at every 10 s from a holding potential of –60 mV. (C) Depicts the current traces in 5 mM K+ PSS followed by Ca2+-free 135 mM K+ PSS containing 2 mM TEA in the presence and absence of 10 µM levcromakalim. Note the enhancement of the basal Iglib by levcromakalim and its subsequent block by 10 µM glibenclamide. (D) Shows the time-course of development of Iglib and its potentiation by levcromakalim and subsequent block following treatment with 10 µM glibenclamide.

 
Zhang and Bolton [3] demonstrated that while the MK-type KATP current was stimulated by levcromakalim, the LK-type KATP channels were insensitive to stimulation by levcromakalim. In our study we observed that 10 µM levcromakalim increased the Iglib by more than two fold when the whole-cell current was measured with 1 mM ATP in the pipette and the cells were ramped between –80 and 80 mV in symmetrical K+ solution (Fig. 5C,D).

A small delayed rectifier K+ current (Ikv) was observed, and activated with an apparent threshold of –30 mV when cells held at –60 mV were stepped to test potentials between –70 to 50 mV (300 ms at 0.1 Hz) in PSS containing 2 mM TEA. The pipette contained 5 mM ATP and the other constituents were the same as described earlier for the pipette solution for the conventional whole-cell recording. This current was insensitive to 10 µM glibenclamide at all potentials. For example, at +50 mV Ikv was 31±7 and 31±8 pA in the absence and subsequent presence of glibenclamide, respectively (n=4).


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
It is generally believed that ATP-sensitive K+ channels are normally closed because of the high concentration of intracellular ATP. Nevertheless, in both cultured [8] and freshly dispersed porcine coronary artery cells [9], there was evidence of some KATP channel opening under basal conditions. On the other hand, in cells isolated from rabbit mesenteric artery [10], rabbit portal vein [6] and rat mesenteric artery [11], there was no evidence of any resting current measured in perforated patch mode. These divergent observations suggest the existence of multiple types of glibenclamide-sensitive channels which have differential sensitivities to intracellular ATP, and which are unequally expressed in different blood vessels.

We report here a K+ current in rat aorta myocytes that was sensitive to glibenclamide but was quite insensitive to intracellular ATP. The activation of this current at physiological levels of intracellular nucleotides was evident from a significant resting current (sensitive to 10 µM glibenclamide), measured using the nystatin technique. The observation of a significant Iglib in non-dialyzed rat aorta cells indicates that this K+ current may play an important role in maintaining resting K+ conductance. This was further substantiated by the finding that glibenclamide caused a reversible 24 mV membrane depolarization from the resting level of about –55 mV. This observation in single cells is consistent with the membrane depolarizing action of glibenclamide in intact rat aorta [12]. A high concentration of glibenclamide (e.g. >100 µM) has been reported to inhibit delayed rectifier K+ currents in rabbit portal vein [16]. However, the lack of effect of 10 µM glibenclamide on the Ikv in rat aorta myocytes suggests that the membrane depolarizing action of this drug is due to selective inhibition of Iglib.

To determine whether the Iglib channels in rat aorta differed from classical KATP channels with respect to sensitivity to intracellular ATP, we used conventional whole-cell recording with various pipette concentrations of ATP. The amplitude of Iglib was similar when pipette [ATP] was raised from 0 to 1.0 mM, although the current then ran down progressively in the absence of nucleotide. When 3 mM ATP was used in the pipette, there was an approximately 60% diminution of Iglib. In comparison, Xu and Lee [13] observed that the IC50 of ATP on the glibenclamide-sensitive current was 350 µM in canine coronary artery smooth muscle cells

Iglib in rat aorta was stimulated by 1 mM GDP, which is consistent with the ability of this nucleotide to cause KATP channel activation in other vascular smooth muscle cells [6,11,14]. This stimulation was similar in both the absence of ATP, and in the presence of 1 mM ATP, but did not occur in the presence of 3 mM ATP.

Recently, Zhang and Bolton [3] described two types of ATP-sensitive K+ channels in rat portal vein myocytes, one blocked by micromolar concentrations of ATP (LK-type) and the other displaying sensitivity to ATP only above a concentration of 1 mM (MK-type). Our results indicate that Iglib in rat aorta has MK-like properties. Apparently, LK-type K+ current was absent in these cells because Iglib displayed no sensitivity to ATP below 1 mM. Further, the stimulation by levcromakalim of Iglib in rat aorta is consistent with the similar property of the MK-type channel. Zhang and Bolton [3] drew parallels between the single MK channel current and the whole cell KNDP current their laboratory had previously identified. However, the current in rat aorta differs in two respects from KNDP. Firstly, Iglib was of similar amplitude in the presence and absence of 1 mM ATP, while Beech et al. [6] showed that the activation of KNDP channels by 1 mM GDP was inhibited by 60% in the presence of 1 mM ATP. Secondly, these authors did not report the occurrence of the KNDP current under basal conditions.

A glibenclamide-sensitive but ATP-insensitive K+ channel has recently been demonstrated in HEK293T cells cotransfected with SUR2B and Kir6.1 subunits [15]. As reviewed by these authors, Kir6.1 is ubiquitously expressed in rat tissues, including smooth muscles, while SUR2B is expressed in vascular smooth muscle cells. This channel appears therefore to resemble the MK channel, and has properties similar to those of Iglib in the rat aorta.

In conclusion, this work makes two novel and complementary observations. The first is that the membrane potential in rat aorta depends strongly on glibenclamide-sensitive K+ channels. The second observation, which is predicted by the first, is that Iglib in these cells is relatively insensitive to ATP, which at <1 mM is effective in blocking KATP channels in a variety of other tissues [7]. The steep inhibition of Iglib between ATP concentrations of 1 and 3 mM, which is especially prominent when GDP is present, suggests that in blood vessels where these channels are present, they might play a role, not only in maintaining the resting membrane potential under physiological conditions, but also of controlling vascular tone during metabolic stress associated with relatively small changes in intracellular nucleotides.

Time for primary review 20 days.


   Acknowledgements
 
We thank the Wellcome Trust for the Travelling Research Fellowship support to SKM.


   Notes
 
1 Present address: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar 243122, U.P., India. Back


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

  1. Nelson M.T., Huang Y., Brayden J.E., Hescheler J.K., Standen N.B. Arterial dilations in response to calcitonin gene-related peptide involve activation of K+ channels. Nature (1990) 344:770–773.[CrossRef][Medline]
  2. Clapp L.H., Gurney A.M. ATP-sensitive K+ channels regulate resting potential of pulmonary arterial smooth muscle cells. Am J Physiol (1992) 262:H916–H920.[Web of Science][Medline]
  3. Zhang H.L., Bolton T.B. Two types of ATP-sensitive potassium channels in rat portal vein smooth muscle cells. Br J Pharmacol (1996) 118:105–114.[Web of Science][Medline]
  4. Horn R., Marty A. Muscarinic activation of ionic currents measured by a new whole-cell recording method. J Gen Physiol (1988) 92:145–159.[Abstract/Free Full Text]
  5. Smirnov S.V., Robertson T.P., Ward J.P.T., Aaronson P.I. Chronic hypoxia is associated with reduced delayed rectifier K+ current in rat pulmonary artery muscle cells. Am J Physiol (1994) 266:H365–H370.[Web of Science][Medline]
  6. Beech D.J., Zhang H., Nakao K., Bolton T.B. K-channel activation by nucleotide diphosphates and its inhibition by glibenclamide in vascular smooth muscle cells. Br J Pharmacol (1993) 110:573–582.[Web of Science][Medline]
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  12. Bishop B.E., Doggrell S.A. The effects of racemic cromakalim, BRL38226 and levcromakalim on the membrane potential of the rat aorta and of BRL 38226 on the contractile activity of the rat aorta and portal vein. J Auton Pharmacol (1994) 14:99–108.[Web of Science][Medline]
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  14. Kajioka S., Kitamura K., Kuriyama K. Guanosine diphosphate activates an adenosine 5'-triphosphate-sensitive K+ channels in the rabbit portal vein. J Physiol (Lond) (1991) 444:397–418.[Abstract/Free Full Text]
  15. Yamada M., Isomoto S., Matsumoto S., et al. Sulphonylurea receptor 2nB and Kir6.1 form a sulphonylurea-sensitive but ATP-insensitive K+ channel. J Physiol (Lond) (1997) 499:715–720.[Abstract/Free Full Text]
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