Skip Navigation

Cardiovascular Research 1997 33(1):123-130; doi:10.1016/S0008-6363(96)00186-1
© 1997 by European Society of Cardiology
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Watanuki, M.
Right arrow Articles by Sasayama, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Watanuki, M.
Right arrow Articles by Sasayama, S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 1997, European Society of Cardiology

Endothelin-1 inhibition of cardiac ATP-sensitive K+ channels via pertussis-toxin-sensitive G-proteins

Masato Watanuki, Minoru Horie*, Kunihiko Tsuchiya, Kazuhiko Obayashi and Shigetake Sasayama

The Department of Cardiovascular Medicine, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-01, Japan

Received 8 February 1996; accepted 14 July 1996


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: Secretion of endothelin-1 (ET-1) and activation of cardiac ATP-sensitive K+ (KATP) channels are facilitated under myocardial metabolic stress. The aim of this study was to investigate the effects of ET-1 on KATP channels and to assess underlying mechanisms in ventricular myocytes. Methods: Single channel currents were measured with the voltage-clamp technique in cell-attached patches from enzymatically-isolated single guinea pig ventricular myocytes. In some experiments, the open-cell-attached mode was employed by permeating the membrane with streptolysin-O. Results: ET-1 concentration-dependently inhibited single KATP channel currents, which had been activated by metabolic poisoning, with an IC50 of 3.8 ± 0.7 pM. BQ-123, an ETA receptor-selective antagonist, reduced the effects of ET-1. ET-1 effects were largely abolished in the myocytes pre-incubated with pertussis toxin. In the open-cell-attached mode, where the intracellular ATP concentration ([ATP]) could be virtually controlled, the effects of ET-1 were abolished. Muscarinic receptor stimulation inhibited the channels in a similar manner to ET-1, whereas β-adrenoceptor stimulation accelerated channel activation. By analogy, ouabain also inhibited KATP channel activity under metabolic stress presumably because inhibition of the Na+/K+ pump spares subsarcolemmal ATP. ET-1 inhibited the KATP channels that had been reactivated in the continuous presence of ouabain. Conclusions: ET-1 reversibly inhibited KATP channels. This effect appears to be mediated by an increase in subsarcolemmal [ATP] which results from inhibition of adenylate cyclase activities through PTX-sensitive G-proteins coupled to ETA receptors.

KEYWORDS Endothelin-1; Carbachol; Ouabain; G-proteins; Isoproterenol; Potassium channel; ATP-sensitive; Guinea pig; ventricular myocytes


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Endothelin-1 (ET-1), a 21 amino acid hormone constitutively released from vascular and endocardial endothelial cells [1, 2], is increased under certain pathophysiological conditions such as coronary vasospasm, myocardial ischaemia and infarction [3–5]. Under these conditions, cardiac ATP-sensitive K+ (KATP) channels have been proposed to open, thereby resulting in shortening of the action potential and reduction in Ca2+ entry, and to play a key role in the natural mechanism of cardioprotection from ischaemia [6–8]. KATP channel activation has been shown to decrease the infarct size in animal models [9, 10]. We have previously reported that membranes prepared from the ventricular myocardium of guinea pigs contain a large number of ETA and ETB receptors [11, 12]. Antibodies for ET-1 were reported to reduce the infarct size [13], suggesting ET-1-dependent modulation of KATP channel activation. More recently, nanomolar concentrations of ET-1 have been shown to inhibit whole-cell KATP currents in ventricular myocytes [14, 15]. However, the precise mechanism(s) remains unknown.

In the present study, we find that submicromolar concentrations of ET-1 inhibit single KATP channel activities in guinea pig ventricular myocytes through ETA receptors via a PTX-sensitive G-protein. Since activation of this type of G-protein by ET-1 was demonstrated to suppress adenylate cyclase activity [12, 16, 17], the finding may be interpreted as the inhibition of KATP channels by an increase of subsarcolemmal [ATP] resulting from inhibition of the enzyme. A preliminary report has appeared in abstract form elsewhere [18].


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Cell isolation
Adult guinea pigs of either sex (250 ~ 400 g) were deeply anesthetized with sodium pentobarbital (40 ~ 50 mg/kg i.p.) and the heart was quickly dissected under artificial respiration. On a Langendorff apparatus, the heart was perfused with Tyrode's solution for ~ 5 min, followed by nominally Ca2+-free Tyrode's solution for ~ 3 min at 36°C. The composition of Tyrode's solution was (in mM) 143 NaCl, 0.3 NaH2PO4, 5.4 KCl, 0.5 MgCl2, 1.8 CaCl2 and 5 HEPES-NaOH (pH 7.4). The heart was then perfused with nominally Ca2+-free Tyrode's solution containing 0.4 mg/ml of collagenase (type I, Sigma, St. Louis, USA) for 20 min and then rinsed with a high K+, low Ca2+ KB solution [19]. The ventricle was dissected into small pieces in KB solution at room temperature. Single cells were obtained by filtration through a 105-µm mesh, centrifuged at 400 r.p.m. for 4 min, and were pre-incubated at 36°C for > 120 min in glucose-free KB solution containing 5.5 mM 2-deoxy-glucose to minimize ATP production by glycolysis.

2.2. Electrophysiological recordings and solutions
Single-channel recordings were conducted on quiescent rod-shaped myocytes with clear striations. After the cell-attached configuration was established, the external bath solution was changed to a metabolic stress/high K solution (in mM): 150 KCl, 1 NaCN, 0.5 EGTA and 5 HEPES-KOH (pH 7.4).

This solution virtually eliminated the transmembrane potential. Channel activities were recorded by a patch clamp amplifier (AXOPATCH, 200A, AXON Instruments, USA) and were directly displayed on a chart recorder (Nihonkoden, RJG-4122, Japan) with a simultaneous backup on a video tape via a pulse-coded modulation converter system (NF RP880, Japan) for later analysis. Borosilicate glass pipettes had a resistance of ~ 5 M{Omega} when filled with normal Tyrode's solution. The criteria used to identify KATP channels were unitary current amplitudes, characteristic current-voltage relationships and sensitivity to glibenclamide.

2.3. Reagents
ET-1 (Peptide Institute, Osaka, Japan) and BQ-123 (Banyu Pharmaceutical Co., Tokyo, Japan) were prepared as stock solutions by dissolving in 0.5% acetic acid and were further diluted with test solutions immediately prior to use. Ouabain hydrochloride (Nacalai Tesque, Kyoto, Japan) was dissolved in distilled water. Pertussis toxin (PTX; Seikagaku-kogyo, Tokyo, Japan) was dissolved in KB solution (50 µg/ml stock solution) and was further diluted with the myocyte suspension to a final concentration of 5 µg/ml. The incubation was carried out at 36°C for > 60 min. Streptolysin-O (Wellcome, Dartford, UK) was dissolved in the bathing solution at the final concentration of 0.02 U/ml immediately before every experiment and was used within 1 h after preparation. Glibenclamide (Hoechst, Frankfurt, Germany) was dissolved in dimethylsulphoxide (DMSO) to make stock solutions of 1 mM. H89 (Seikagaku-kogyou) was also dissolved in DMSO. DMSO alone (< 0.1%) had no action on the KATP channels. All experiments were carried out at 36°C. This investigation conformed with the Guide for the Care and Use of Laboratory Animals by the US National Institutes of Health (NIH publication No. 85–23, revised 1985).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Concentration-dependent inhibition of cardiac KATP channels by ET-1
Superfusion of myocytes pre-incubated with 2-deoxy-glucose with the metabolic-stress/high K+ medium (0 glucose, 1 mM CN–) activated outward single channel currents at the holding potential of 0 mV usually in 10 ~ 20 min (Fig. GR1). The unitary current amplitude-voltage relation for outward currents showed a slight inward rectification and a slope conductance of 26 ± 0.5 pS at 0 mV holding potential with a reversal potential of –81 ± 3 mV (n = 4). Glibenclamide (1 µM) reversibly inhibited the single channel currents (Fig. GR1 A). These single channel properties identify cardiac KATP channels.


Figure 1
View larger version (21K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. GR1 ET-1 inhibits ATP-sensitive K+ (KATP) channels. (A and B) Slow chart records of single-channel currents in the cell-attached mode as indicated by the inset in panel B. Arrows to the left of each chart indicate the zero current level. Horizontal bars above the chart indicate extracellular applications of agents as labelled. (C) ET-1 concentration-inhibition relation. Mean patch currents were measured before and after application of various concentrations of ET-1 (NP and NPc). Mean patch currents in ET-1 were normalized by the control (before drug), and are plotted as a function of ET-1 concentrations (pM). Data were expressed as mean±s.e.m. (numbers of observations). A smooth curve was obtained by fitting all the data to the Hill equation: %NP/NPc = 100/(1 +(IC50/[ET-1])n), where IC50 indicates the ET-1 concentration for half-maximal inhibition and n the Hill coefficient.

 
Exposure of the myocytes to ET-1 inhibited the single-channel current in a concentration-dependent manner (Fig. GR1 B).Fig. GR1 C summarizes the concentration-dependence of inhibitory effects of ET-1 on KATP currents obtained from the pooled data in 30 cells. The smooth curve represents the best fit to the Hill equation with an IC50 of 3.8 ± 0.7 pM (Hill coefficient of 2.1 ± 0.4).

3.2. ET-1 inhibition of KATP channels through ETA receptors
Fig. GR2 A depicts representative results of the experiment using BQ-123, an ETA-receptor-selective antagonist. In this experiment, ET-1 (1 nM, > 250 times higher than IC50;Fig. GR1 C) produced a prompt and reversible block of KATP channel activity. BQ-123 (30 nM) alone was without effect, but the action of ET-1 was largely prevented by the presence of the antagonist. A similar antagonism by BQ-123 was consistently observed in 5 other experiments. Thus, ETA receptors, one of the two distinct ET receptor subtypes, appear to be involved in ET-1 inhibition of KATP channels.


Figure 2
View larger version (27K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. GR2 ETA receptors and pertussis toxin-sensitive G proteins mediate ET-1 inhibition of the channel. (A) A chart record of single-channel currents at 0 mV holding potential. Horizontal bars indicate exposures to 30 nM BQ-123, 1 nM ET-1 and the beginning of cell rigor. (B) A chart record of single-channel currents from a myocyte pre-incubated with PTX as described in Section 2. Note that calibrations are different between A and B. (C) A chart record of single-channel currents. Horizontal bars indicate applications of 1 nM ET-1 and 100 µM H89.

 
3.3. Pertussis-toxin sensitive G-proteins mediate ET-1 inhibitory action
Endothelin receptors (both ETA and ETB) are members of G-protein-linked receptors that generally have 7 trans-membrane spanning regions [20, 21]. It was shown that some G-proteins coupling between endothelin receptors and adenylate cyclase are PTX-sensitive [11, 12, 16, 17, 22]. We therefore examined whether G-proteins involved in this ET-1-induced inhibition are also PTX-sensitive. As shown in Fig. GR2 B, ET-1 action was indeed PTX-sensitive, and the inhibitory action of ET-1 (20 pM) was consistently abolished by preincubation of the myocytes with PTX (5 µg/ml, > 60 min at 36°, n = 4).

3.4. Lack of inhibitory effects of ET-1 on KATP channels in membrane-permeated cells
Using PKA (protein kinase A)-dependent Cl– conductance as a measure, we reported more recently that ETA receptors negatively couple to adenylate cyclase via PTX-sensitive G-proteins in the same preparation [11, 12]. Since these G-proteins are known to negatively couple to the membrane adenylate cyclase, modulation of the enzyme and PKA system may be involved in ET-1-mediated inhibition of channel activity.

The PKA-dependent phosphorylation process appears, however, not to be the intracellular mechanism for the channel inhibition. As shown in Fig. GR2 C, ET-1 could reversibly suppress KATP channel activity even in the presence of H-89 (100 µM), a membrane-permeable potent PKA inhibitor (n = 3). The same concentration of H89 alone did not alter channel activity (data not shown).

Applying the whole-cell patch-clamp technique to adult cat ventricular cells, Schackow and Ten Eick [23] recently demonstrated that β-adrenergic stimulation accelerates KATP current activation by consuming subsarcolemmal ATP through the activation of adenylate cyclase activity (see also Fig. GR4 A). We therefore sought to test whether ET-1 inhibition reflects an increase of subsarcolemmal [ATP] by suppressing adenylate cyclase.


Figure 4
View larger version (30K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. GR4 KATP channels are modulated by activities of adenylate cyclase and Na+ /K+ ATPase. (A) A chart record of single-channel currents at 0 mV holding potential. Horizontal bars indicate the application of 20 nM isoproterenol (ISO). (B) Bars indicate exposure of the myocyte to 1 µM carbachol (CCh) and 100 pM ET-1. (C) Continuous two-chart records at 0 mV. Interruption of the record indicates a deletion of 3 min record. Horizontal bars indicate exposures of the myocyte to 100 µM ouabain and 100 pM ET-1. Calibrations for time and current amplitude are given to the right of the lower panel.

 
In the experiments of Fig. GR3, we adopted an open-cell-attached patch condition by permeating the cell membrane with streptolysin-O (the open-cell-attached mode) [24]. Brief incubation with streptolysin-O (0.002 U / ml, 30 {approx} 60 s) made tiny holes in the cell membrane, thereby allowing us to control subsarcolemmal [ATP] by simply changing extracellular [ATP]. In this recording condition, the control of subsarcolemmal [ATP] seemed fairly good, because raising external [ATP] from 0.5 to 5 mM reversibly closed the KATP channel (n = 4) and also because inhibition of glycolysis by 2-deoxyglucose did not affect the channel activity (n = 4), as represented in Fig. GR3 A. In this type of open-cell-attached mode, ET-1 was without effect even at 2 nM (Fig. GR3 B). A similar loss of ET-1 action was observed in 5 experiments. The most straightforward interpretation was therefore that ET-1 acts through the increase of subsarcolemmal [ATP], although washout of unknown intracellular factor(s) may abort the ET-1 action in an additional manner.


Figure 3
View larger version (23K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. GR3 Subsarcolemmal ATP mediates ET-1 inhibition of the channel. (A) A chart record of single-channel currents from a myocyte pretreated with streptolysin-O as described in Section 2. Horizontal bars indicate applications of 10 mM 2-deoxyglucose, 0.5 mM or 5 mM ATP. (B) Horizontal bars indicate applications of 2 nM ET-1, 0.5 mM or 5 mM ATP.

 
3.5. β-Adrenergic and muscarinic modulation of KATP channels
Single KATP channel activities induced by metabolic stress were also modulated by the autonomic transmitters, isoproterenol and carbachol, in an antagonistic manner (Fig. GR4 A,B). Isoproterenol (20 nM), β-adrenergic agonist, which activates adenylate cyclase via stimulatory G-proteins (Gs), facilitated KATP channel activity (Fig. GR4 A). Similar results were obtained in 4 other experiments. The finding agrees with that of Schackow and Ten Eick [23], indicating that ATP-dependent activation may also occur at the single-channel current level.

On the other hand, carbachol (1 µM), which suppresses the activity of adenylate cyclase in a PTX-sensitive manner, inhibited KATP channel activities (Fig. GR4 B, n = 5). The exposure of myocytes to ET-1 in the prolonged presence of carbachol produced additional inhibitory effects on KATP channel currents. In contrast, ET-1 was no longer effective on the channel that had been reopened in the presence of carbachol (10 µM) (data not shown). Since the suppression of adenylate cyclase results in an increase of [ATP] in the vicinity of the channel, this increase may in turn suppress KATP channel activities. ET-1 and carbachol appeared to share the same intracellular signal transduction pathway(s).

3.6. Inhibition of membrane Na+/K+ ATPase closes the KATP channel
Accordingly, it is likely that inhibition of Na+/K+ ATPase increases the subsarcolemmal [ATP] and thereby closes the channels. We therefore tested whether ouabain, a Na+/K+ ATPase inhibitor, inhibits metabolic-stress-induced KATP channel opening. In the experiment shown inFig. GR4 C, ouabain (100 µM) was also able to inhibit the KATP currents (n = 8). This finding was in good agreement with a previous report by Benndort et al. [25]. In the continued presence of ouabain, the KATP channel reactivated in {approx} 8 min, which ET-1 (100 pM) could inhibit repeatedly (Fig. GR4 C). Thus, it is concluded that Na+/K+ ATPase is not involved in ET-1 inhibition of the channel.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
4.1. The mechanism of ET-1-dependent inhibition of KATP channel activity
The present study demonstrates that ET-1 reversibly inhibits KATP channels activated under metabolic stress. This effect appears to be mediated by an increase in subsarcolemmal [ATP] which results from inhibition of adenylate cyclase activities through PTX-sensitive G-proteins coupled to ETA receptors. Both augmented secretion of ET-1 [1–5] and facilitation of KATP current activation[7, 8] occur under myocardial ischaemic stress. Concerning the inhibition of KATP channels by ET-1, there have been several reports on smooth muscle cells [26] and cardiac myocytes [14, 15]. However, these previous reports do not mention the mechanism underlying the inhibitory effects of ET-1. In the present study, we demonstrated a concentration-dependent inhibition of cardiac single KATP channels by ET-1 via ETA receptors through PTX-sensitive G-proteins.

Two major intracellular signal pathways have been demonstrated during endothelin receptor stimulation: (1) activation of phospholipase C (PLC) and resultant phosphoinositide hydrolysis, which may lead to the activation of protein kinase C (PKC) [16] and (2) inhibition of adenylate cyclase via inhibitory G-proteins (Gi), which are sensitive to PTX [11, 12, 16, 22]. During the ET-1-induced suppression of KATP channels, the former mechanism appeared not to be involved, firstly because this pathway was shown to be mediated by PTX-insensitive G-proteins [16], and secondly because, in whole-cell experiments by Kobayashi et al. [14] and some preliminary results from our laboratory, ET-1 also suppressed outward KATP currents induced by metabolic stress. In these experiments, the pipette solution contained 5 {approx} 10 mM EGTA, which chelated intracellular CA2+ quite tightly and prevented the activation of Ca-sensitive signal transduction including PLC and PKC.

The involvement of the latter mechanism (i.e., adenylate cyclase activity) has recently been demonstrated by Schackow and Ten Eick. Activation of whole-cell KATP currents was accelerated by β-adrenergic stimulation in adult feline ventricular myocytes [23]. A similar acceleration was also observed at the single-channel current level in our preparation (Fig. GR4 A). The mechanism underlying this stimulatory action on channel activation was considered to be the depletion of subsarcolemmal ATP by activation of adenylate cyclase via Gs. On the contrary, we found that carbachol, a muscarinic agonist, is negatively coupled to adenylate cyclase via Gi protein, and through this mechanism it closes KATP channels. Therefore, through the activity of adenylate cyclase, Gs and Gi appear to modulate the activity of KATP channels in a countervailing manner.

More recently, Benndorf et al. [25] demonstrated that digitalis-induced suppression of Na+/K+ ATPase reversibly inhibits ATP-sensitive K+ conductance induced by metabolic stress. In the present study, we also obtained a similar ouabain-induced inhibition of single KATP channels (Fig. GR4 C). Like Gi-mediated inhibition, ouabain-induced inhibition of KATP currents is attributable to a subsarcolemmal [ATP] rise due to the suppression of Na+/K+ ATPase, which is another consumer of ATP.

Fig. GR5 shows a diagram of the mechanism we propose for the ET-1-mediated modulation of KATP channels. Similarly to ouabain and carbachol, ET-1 appears to activate PTX-sensitive G-proteins, which in turn inhibit adenylate cyclase and minimize ATP consumption in the vicinity of the cell membranes. Ultimately, the increase in subsarcolemmal [ATP] closes KATP channels.


Figure 5
View larger version (12K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. GR5 Summary of blocking pathways of KATP channels. ATP in the box indicates ATP in the subsarcolemmal space (fuzzy space).

 
Dynamic concentration gradients, for intracellular substances such as Na+, Ca2+, and ATP, have been noted in the vicinity of cell membrane (fuzzy space, [27]). Uneven distribution of mitochondria and supplemental production by glycolysis are principal factors in determining a gradient for [ATP]. Using saponin-induced open-cell-attached patch-clamp techniques in cardiac myocytes, Weiss and Lamp [28, 29] reported that ATP derived from glycolysis rather than mitochondrial oxidative phosphorylation prevents KATP channel activation more effectively, suggesting that this phenomenon occurred because glycolytic enzymes are located in the vicinity of the channels. Therefore, in the fuzzy space, a dynamic [ATP] gradient is indeed present. This idea may favour our finding that modulation of membrane enzymes consuming ATP can in turn alter fuzzy space [ATP] and influence channel activity.

The open-cell-attached mode we employed allowed us to control fuzzy space [ATP] more efficiently than that of Weiss and Lamp [28, 29], because the inhibition of glycolysis by 2-deoxyglucose did not increase channel activity in our preparation (Fig. GR3 A). However, Weiss and Lamp applied saponin briefly to the end of myocyte to obtain the open-cell-attached mode and observed a marked increase of channel opening by the application of 2-deoxyglucose. It is therefore through this mechanism that ET-1 may modulate channel activity through the fuzzy space [ATP] change.

4.2. Clinical significance
Under ischaemic stress, ET-1 has been shown to increase myocardial injury [3, 11, 30, 31]. ET-1-induced inhibition of KATP channels shown in the present study may account for the latter observations. Indeed, the activation of KATP currents has been proposed to play a key role in the natural mechanism of cardioprotection from ischaemia since the opening of KATP channels is associated with shortening of action potential, reduction in Ca2+ entry and sparing of cytosolic ATP [3–5, 32, 33].

The concentration of ET-1 in human plasma has been reported to be 0.6 {approx} 2.5 pM [3, 11, 34, 35] and would increase under various pathological conditions, such as essential hypertension, renal failure, vasospastic angina and acute myocardial infarction [3, 11, 36]. Since ET-1 signal transduction pathways have been noted to be diverse and multiple in an endocrine, paracrine, and autocrine manner[1, 37], the regional level of ET-1 is possibly higher than that reported in the plasma especially under metabolic stress, suggesting that ET-1 could at least partially inhibit KATP channel activities. ETA receptor antagonists as well as inhibitors for endothelin-converting enzymes may therefore be a potential therapeutic modality to reduce myocardial injury in certain clinical settings.


   Acknowledgements
 
We would like to thank Prof. A. Noma, Department of Physiology, Kyoto University, for continuous encouragement and Dr. A.F. James, Department of Medicine, King's College London, for valuable discussion. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan.


   Notes
 
* Corresponding author. Division of Cardiac Electrophysiology, The Department of Cardiovascular Medicine, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-01, Japan. Tel. +81 75 751-3196; Fax +81 75 761-9716; E-mail: horie@kuhp.kyoto-u.ac.jp Back


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

  1. Masaki T, Yanagisawa Y, Goto K. Physiology and pharmacology of endothelins. Med Res Rev (1992) 12:391–421.[Web of Science][Medline]
  2. Haynes W.G, Webb D.J. The endothelin family of peptides: local hormones with diverse roles in health and disease. Clin Sci (1993) 84:485–500.[Web of Science][Medline]
  3. Miyauchi T, Yanagisawa M, Tomizawa T, et al. Increased plasma concentrations of endothelin-1 and big endothelin-1 in acute myocardial infarction. Lancet (1989) ii 8653:53–54.
  4. Yasuda M, Kohno M, Tahara A, et al. Circulating immunoreactive endothelin in ischemic heart disease. Am Heart J (1990) 119:801–806.[CrossRef][Web of Science][Medline]
  5. Tomoda H. Plasma endothelin-1 in acute myocardial infarction with heart failure. Am Heart J (1993) 125:667–672.[CrossRef][Web of Science][Medline]
  6. Noma A. ATP-regulated K+ channels in cardiac muscle. Nature (1983) 305:147–148.[CrossRef][Medline]
  7. Nichols C.G, Lederer W.J. Adenosine triphosphate-sensitive potassium channels in the cardiovascular system. Am J Physiol (1991) 261:H1675–H1686.[Web of Science][Medline]
  8. Benndorf K, Bollmann G, Friedrich M, Hirche H. Anoxia induces time-independent K+ current through KATP channels in isolated heart cells of the guinea-pig. J Physiol (1992) 454:339–357.[Abstract/Free Full Text]
  9. Gross G.J, Auchampach J.A. Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circ Res (1992) 70:223–233.[Abstract/Free Full Text]
  10. Grover G.J, Sleph P.G, Dzwonczyk S. Role of myocardial ATP-sensitive potassium channels in mediating preconditioning in the dog heart and their possible interaction with adenosine A1-receptors. Circulation (1992) 86:1310–1316.[Abstract/Free Full Text]
  11. James AF, Xie L-H, Fujitani Y, Hayashi S, Horie M. Inhibition of the cardiac protein kinase A-dependent chloride conductance by endothelin-1. Nature (1994) 370:297–300.[CrossRef][Medline]
  12. James AF, Xie L-H, Hayashi S, Fujitani T, Horie M. ETA receptors mediate inhibition of the cardiac PKA-dependent Cl– current via a pertussis toxin-sensitive mechanism. Heart Vessel (1995) 9(suppl):83–85.
  13. Watanabe T, Suzuki N, Shimamoto N, Fujino M, Imada A. Contribution of endogenous endothelin to the extension of myocardial infarct size in rats. Circ Res (1991) 69(2):370–377.[Abstract/Free Full Text]
  14. Satoh H. Endothelin-1 inhibition of the ATP-sensitive K+ channel in guinea-pig ventricular cardiomyocytes. Gen Pharmacol (1995) 26:1549–1552.[Web of Science][Medline]
  15. Kobayashi S, Nakaya H, Takizawa T, et al. Effects of endothelin-1 on ATP-sensitive K+ current in cardiac cells. J Cardiovasc Pharmacol (1996) 27:12–19.[CrossRef][Web of Science][Medline]
  16. Dandan R.H, Urasawa K, Brunton L.L. Endothelin inhibits adenylate cyclase and stimulates phosphoinositide hydrolysis in adult cardiac myocytes. J Biol Chem (1992) 267:10620–10624.[Abstract/Free Full Text]
  17. Ono K, Tsujimoto G, Sakamoto A, et al. Endothelin-A receptor mediates cardiac inhibition by regulating calcium and potassium currents. Nature (1994) 370:301–304.[CrossRef][Medline]
  18. Watanuki M, Yuzuki Y, Tsuchiya K, Obayashi K, Xie L-H, Horie M. Endothelin-1 inhibition of cardiac ATP-sensitive K+ channels. Circulation 1995;92(suppl):I-639(Abstract).
  19. Isenberg G, Klöckner U. Calcium tolerant ventricular myocytes prepared by preincubation in a ‘KB’ medium. Pflügers Arch (1982) 395:6–18.[CrossRef][Web of Science][Medline]
  20. Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature (1990) 348:730–732.[CrossRef][Medline]
  21. Sakurai T, Yanagisawa M, Takuwa Y, et al. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature (1990) 370:732–735.
  22. Vogelsang M, Brede-Sitz A, Zerkowski H.R, Brodde O.E. Endothelin ETA-receptors couple to inositol phosphate formation and inhibition of adenylate cyclase in human right atrium. J Cardiovasc Pharmacol (1994) 23:344–347.[Web of Science][Medline]
  23. Schackow T.E, Ten Eick R.E. Enhancement of ATP-sensitive potassium current in cat ventricular myocytes by β-adrenoreceptor stimulation. J Physiol (1994) 474(1):131–145.[Abstract/Free Full Text]
  24. Tsuura Y, Ishida H, Hayashi S, Sakamoto K, Horie M, Seino Y. Nitric oxide opens ATP-sensitive K+ channels through suppression of phosphofructokinase activity and inhibits glucose-induced insulin release in pancreatic β cells. J Gen Physiol (1994) 104:1079–1099.[Abstract/Free Full Text]
  25. Benndorf K, Priebe L, Friedrich M. Influence of Na/K pump action on KATP channel opening in isolated guinea pig heart cells under metabolic stress. Biophys J (1995) 68:A251.
  26. Miyoshi Y, Nakaya Y, Wakatsuki T, et al. Endothelin blocks ATP-sensitive K+ channels and depolarizes smooth muscle cells of porcine coronary artery. Circ Res (1992) 70:612–616.[Abstract/Free Full Text]
  27. Carmeliet E. A fuzzy subsarcolemmal space for intracellular Na+ in cardiac cells? Cardiovasc Res (1992) 26:433–442.[Web of Science][Medline]
  28. Weiss J.N, Lamp S.T. Glycolysis preferentially inhibits ATP-sensitive K+ channels in isolated guinea-pig myocytes. Science (1987) 238:67–69.[Abstract/Free Full Text]
  29. Weiss J.N, Lamp S.T. Cardiac ATP-sensitive K+ channels. J Gen Physiol (1989) 94:911–935.[Abstract/Free Full Text]
  30. Underwood D.C, Falotico R, Cheung W, Tobia A.J. Dissociation of coronary vasoconstrictor and arrhythmogenic property of endothelin in the dog. Circulation 1989;80(suppl):II-149(Abstract).
  31. Donckier J, Hanet C, Stoleru L, et al. Effects of endothelin-1 at pathologic concentrations on coronary perfusion and mechanical function of normal and postischemic myocardium. J Cardiovasc Pharmacol (1994) 23:212–219.[Web of Science][Medline]
  32. Cole W.C, McPherson C.D, Sontag D. ATP-sensitive K+ channels protect the myocardium against ischemia/reperfusion damage. Circ Res (1991) 69:571–581.[Abstract/Free Full Text]
  33. Grover G.J, McCullough J.R, D'Alongo A.J, Sargent C.A, Atwal K.S. Cardioprotective profile of the cardiac-selective ATP-sensitive potassium channel opener BMS-180448. J Cardiovasc Pharmacol (1995) 25:40–50.[Web of Science][Medline]
  34. Suzuki N, Matsumoto H, Kitada C, Masaki T, Fujino M. A sensitive sandwich-enzyme immunoassay for human endothelin. J Immunol Method (1989) 118:245–250.[CrossRef][Web of Science][Medline]
  35. Ando K, Hirata Y, Schichiri M, Emori T, Marumo F. Presence of immunoreactive endothelin in human plasma. FEBS Lett (1989) 245:164–166.[CrossRef][Web of Science][Medline]
  36. Grover G.J, Sleph P.G, Fox M, Trippodo N.C. Role of endothelin-1 and big endothelin-1 in modulating coronary vascular tone, contractile function and severity of ischemia in rat heart. J Pharmacol Exp Ther (1992) 263:1074–1082.[Abstract/Free Full Text]
  37. Resink T.J, Hahn A.W, Scott-Bruden T, Powell J, Weber E, Buhler FR. Inducible endothelin mRNA expression and peptide secretion in cultured human vascular smooth muscle cells. Biochem Biophys Res Commun (1990) 168:1303–1310.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Watanuki, M.
Right arrow Articles by Sasayama, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Watanuki, M.
Right arrow Articles by Sasayama, S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?