© 2000 American Heart Association, Inc.
UltraRapid Communication |
Mechanism and Selectivity of the Effects of Halothane on Gap Junction Channel Function
From the Department of Physiology, University of Arizona, Tucson, Ariz.
Correspondence to Janis M. Burt, PhD, Department of Physiology, University of Arizona, AHSC, Room 4103, 1501 N Campbell Ave, Tucson, AZ 85724. E-mail jburt{at}u.arizona.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Abstract—Volatile anesthetics alter tissue excitability by decreasing the extent of gap junction–mediated cell-cell coupling and by altering the activity of the channels that underlie the action potential. In the present study, we demonstrate, using dual whole-cell voltage-clamp techniques, that coexpression of connexin (Cx) 40 and Cx43 rendered cells more sensitive to uncoupling by halothane than cells that express only Cx40 or only Cx43. The halothane-induced reduction in junctional conductance was caused by decreased channel mean open time and increased channel mean closed time. The magnitude of the effect of halothane on channel open time was least for Cx40-like channels and greatest for heteromeric channels. Thus, the data indicate that halothane gates gap junction channels to the closed state in a dose-dependent and connexin-specific manner. One consequence of the selectivity of halothane is that the profile of single-channel events observed in the presence of halothane may not be quantitatively representative of the population of channels contributing to macroscopic conductance in cells that express more than one connexin. In addition, in tissues that express multiple connexins, such as heart and blood vessels, the capacity of the gap junctions to transmit electrical and chemical signals in the presence of halothane could vary according to the pattern of connexin expression. The full text of this article is available at http://www.circresaha.org.
Key Words: gap junctions • connexins • volatile anesthetics • vascular smooth muscle • arrhythmia
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Gap junctions are specialized regions of cell-cell contact that contain tens to thousands of intercellular channels. These channels provide a pathway for intercellular exchange of ions and small solutes. The functional gap junction channel consists of two hemichannels (connexons), one contributed by each cell. When the connexons are identically comprised, the channel is homotypic; when they differ, the channel is heterotypic. Six connexin subunits comprise each connexon. When they are identical, the connexon is homomeric; when they are not, the connexon is heteromeric. The connexins form a gene family of at least 15 members.
The homomeric/homotypic channels formed by different connexins have distinct unitary conductances, gating properties, and permeability characteristics.1 Some connexins, including those in the heart and vasculature, are capable of forming functional heteromeric and heterotypic channels.2 3 4 5 Thus, in cells that coexpress two or more connexins, the connexin composition and consequently the conductances, gating, and permeability characteristics of the channels comprising the junction can be quite diverse.
Most cells and tissues express multiple connexins. This diversity of connexin expression suggests that the cell-specific distribution of gap junction channels may contribute to the tissue-specific regulation of intercellular communication. For example, in the heart, the number, size, and spatial distribution of gap junctions are important determinants of conduction velocity and anisotropy in different regions of the normal and diseased myocardium.6 7 8
The parameters that determine gap junction conductance
(gj) include channel number (N), unitary
conductance (
j), and open probability
(Po). In well-coupled cells, measurement of
j and Po is precluded
because of the large number of channels. Many investigators have
treated well-coupled cells with agents that reduce
gj to levels at which single-channel events can
be discerned. Agents commonly used for this purpose include heptanol,
octanol, acidosis (via CO2), and
halothane.9 10 11 12 It has generally been assumed, but not
rigorously tested, that the lipophilic agents in this list
nonselectively gate all gap junction channels and consequently that the
profile of unitary events observed in their presence is quantitatively
representative of the population of channels
present in the junction.
In the present study, we determine the effects of halothane on gap junction channel gating and evaluate whether these effects are nonselectively observed for all channels regardless of connexin composition. In particular, we address the dose dependence of the effect of halothane on gj for homomeric/homotypic connexin (Cx) 40 and Cx43 channels versus heteromeric Cx40-Cx43 channels. We demonstrate that cells coexpressing Cx40 and Cx43 were more easily uncoupled by halothane than cells that express only Cx40 or Cx43. Uncoupling involved an increase in channel mean closed time and a decrease in channel mean open time for a nearly 100-fold decrease in channel Po. The effects of halothane on the various channels expressed in A7r5 cells was, however, not uniform. Many of the heteromeric channels were more sensitive to these gating effects than homomeric/homotypic Cx43 or Cx40 channels. Cx40 channels were the least sensitive to halothane. These differences in sensitivity are discussed with respect to their possible implications for the effects of halothane on heart rhythmicity.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Cells and Culture Conditions
A7r5 cells, a rat embryonic aortic smooth muscle cell line, were obtained from the American Type Culture Collection (ATCC, Manassas, Va). These cells coexpress Cx40 and Cx43, which form heteromeric2 as well as heterotypic channels.4 Homomeric/homotypic Cx43 and Cx40 channels were studied in Rat-1 cells and N2A cells stably transfected with Cx40, respectively. All cells were cultured as described previously.2
Electrophysiology
Confluent A7r5, Rat-1, or N2A-Cx40 cells were trypsinized
(0.25% trypsin in
Ca2+-Mg2+–free PBS) and
replated at low density on glass coverslips. Thirty minutes to 5 hours
after plating, coverslips with attached cells were mounted in an
experimental chamber and the cells bathed at room temperature in a
solution containing (in mmol/L) NaCl 142.5, KCl 4,
MgCl2 1,
NaH2PO4 0.9, dextrose 5,
sodium pyruvate 2, HEPES 10, CsCl 15,
tetraethylammonium chloride 10, and
BaCl2 1. Patch-type microelectrodes (5 to 10
M
) were filled with a pipette solution containing (in mmol/L)
CsCl 67.8, potassium glutamate 67.8,
tetraethylammonium chloride 10,
CaCl2 0.5, MgCl2 3,
dextrose 5, HEPES 10, EGTA 10, Na2ATP 5, and
sodium creatine phosphate 6.7. Using dual whole-cell voltage-clamp
techniques as previously described, gj was
monitored until stable, and halothane (1, 2, or 4 mmol/L) was then
suffused over the cells.9 This protocol ensured that
observed changes in gj (and single-channel
events; see below) were induced by halothane, rather than a function of
changing series resistance or run-down. The range of 1 to 2 mmol/L
halothane corresponds to the 1% to 3% minimum alveolar
concentration used clinically.13
Single-channel data were obtained from poorly coupled cells (control conditions, no halothane) as well as from well-coupled cells treated with halothane to reduce gj and reveal single-channel events. No obvious changes in event-amplitude histograms occurred as a function of whole-cell clamp duration in any of the three cell types (data not shown), which further supports the absence of run-down in these cells. The A7r5 and Rat-1 cells assemble junctions very rapidly at 37°C. To obtain poorly coupled pairs, 30 minutes after plating (and incubation at 37°C), the cells were placed in a room-temperature incubator. Single-channel events observed immediately on removal from the incubator and several hours later were not different. Regardless of incubation conditions before the actual experiment, all electrophysiological experiments for all cell types were conducted at room temperature. Channel events were typically obtained with a transjunctional driving force of 40 mV. Data were monitored continuously by chart recorder and acquired in digitized format for subsequent analysis. Effective rise time of the equipment was 6.6 ms. Mean open and closed times were determined according to Ramanan et al.14 Open times for channels of specific amplitudes were obtained from cell pairs with only one channel of specific amplitude active and were measured by one of the investigators from the chart records. Precision of these measurements was ±3.125 pS for event amplitude and ±25 ms for event duration.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Halothane reversibly reduces gj between cells.9 15 We examined the dose-dependent effects of halothane on gj in cells that coexpress Cx40 and Cx43 (A7r5 cells) and compared the results to those obtained from cells that express only Cx43 (Rat-1 cells) or only Cx40 (N2A-Cx40 cells). Figure 1
shows the steady-state effects
of halothane on gj for these three cell types.
The initial gj for each cell type was not
different (Table 1). The data demonstrate
that A7r5 cells were the most sensitive and N2A-Cx40 cells the least
sensitive to uncoupling by halothane.
|
|
The time required to reach steady-state gj in
each cell type decreased as the halothane concentration increased.
These differences in time course are evident in Figure 2, which illustrates normalized
gj as a function of time (first 150 seconds) and
halothane concentration (1, 2, and 4 mmol/L), as well as in time
to steady state and 50% uncoupling, as presented in Table
1. These data provide further evidence supporting
high sensitivity of A7r5 cells to uncoupling by halothane.
|
, and 
indicate 1, 2, and 4 mmol/L halothane,
respectively. The gj at each time point was normalized to
the initial value for each cell pair, and mean±SEM of all cell pairs
at a given dose was plotted relative to time. Sample sizes are reported
in Table 1
To determine how halothane affected channel gating, we measured open
and closed times in the presence and absence of halothane in A7r5
cells. Single-channel records obtained from A7r5 cells in the
absence of halothane and during the early recovery period after
uncoupling by halothane application were acquired. In the absence of
halothane (Figure 3A), channels remained
open for long periods of time (>1 second; Table 2) whereas during recovery from
halothane-induced uncoupling (Figure 3B), channel open times
were quite brief (<0.2 seconds). Analysis of
Po in multiple single-channel records
comparable to those shown in Figure 3, with the use of software
developed by Ramanan et al,14 which makes no distinctions
between channels with different amplitudes, revealed that halothane
induced an approximate 10-fold decrease in mean open time and 20-fold
increase in mean closed time (Table 2). The net
effect of these changes was a 95% reduction in
Po.
|
|
In A7r5 cells, Cx40 and Cx43 form functional Cx40-Cx43 heteromeric
channels, some of which can be recognized by event amplitudes not
observed in cells that express only Cx43 or only Cx40.2 To
determine whether these heteromeric channels were more sensitive to the
effects of halothane than homomeric/homotypic Cx43 or Cx40 channels, we
compared single-channel event amplitudes observed in the presence
versus absence of halothane exposure. In the absence of halothane, a
diversity of channel amplitudes was observed in the A7r5 cells (Figure 3A). In the all-points histogram (displayed on the right), two
features characteristic of a mixed-channel population were evident: the
peak-to-peak separations did not correspond to actual event amplitudes,
and the peaks were broad. In the presence of halothane (Figure 3B), this diversity of channel amplitudes was absent, and the
all-points histogram revealed narrow peaks whose separations
corresponded to the observed event amplitudes. The event amplitude
observed most often in the early period of recovery from halothane was
140 pS, which is the amplitude most commonly observed for
homomeric/homotypic Cx40 channels.2 As recovery continued,
other channel amplitudes also occurred.16 An
amplitude-frequency histogram (Figure 4)
comparing single-channel events acquired in the presence versus absence
of halothane revealed that halothane significantly altered event
frequency.
|
To determine whether this altered amplitude-frequency histogram might
reflect nonuniform effects of halothane on the Po
of the various channel types evident in the histogram, we measured the
open times of these channels in the presence versus absence of
halothane. Figure 5 shows that open time
was significantly decreased by halothane for events of nearly all
amplitudes, providing qualitative confirmation of the result derived
from use of the analysis program of Ramanan et
al.14 However, events of different amplitudes were not
affected to the same extent (Figure 6A).
Interestingly, open times for channels whose amplitudes corresponded to
those observed for homomeric/homotypic Cx40 (165 pS) and Cx43 (90
pS)2 were somewhat longer in the presence versus absence
of halothane. However, these channel events were sufficiently
infrequent (Figure 4) that their contribution to cumulative open
time was quite small (Figure 6B). The prominence of the 140-pS
event in the halothane cumulative open time plot (Figure 6B, black bars) is consistent with the insensitivity of N2A-Cx40
cells to uncoupling by halothane, as illustrated in Figures 1 and 2, and consequent early recovery of this channel type during
halothane washout. Many, but certainly not all, of the channels whose
open durations were most severely affected by halothane (Figure 6A) correspond to channel amplitudes not typical of the
homomeric/homotypic setting. These events accounted for a large
percentage of the cumulative open time under control conditions but
significantly less so in the presence of halothane (Figure 6B).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Halothane, 2-bromo-2-chloro-1,1,1-trifluoroethane, is a volatile anesthetic agent that reversibly uncouples many cell types.9 13 15 In the present study, we demonstrated that coexpression of Cx40 and Cx43 rendered cells more sensitive to uncoupling by halothane than cells that express only one of these connexins. Uncoupling was the result of a significant decrease in Po caused by increased channel mean closed time and decreased mean open time. These effects on channel open time were not uniform for all channel amplitudes. Channel amplitudes common to the homomeric/homotypic setting (165 and 90 pS) were least affected. Indeed, at halothane concentrations where open times of heteromeric channels were greatly reduced, the open times of these Cx40- and Cx43-like channels were increased. However, the contribution to cumulative open time was small due to low frequency. The contribution to cumulative open time of the remaining channels, which are likely heteromeric in composition, was substantial, and the open times of many of these channel types were severely decreased by halothane. These data indicate that the dose-dependent differences in effect of halothane on gj reflected the connexin composition of the channels comprising the junction, with some heteromeric channels displaying a high degree of sensitivity. The data suggest that for cells expressing connexins capable of forming functional heteromers, the diversity of channel amplitudes observed in the presence of halothane may quantitatively underestimate the diversity of channel types present in the macroscopic junction. Possible implications of these data for conduction of impulses in the healthy and diseased heart are discussed.
Our data indicated that many of the heteromeric Cx40-Cx43 channels in
A7r5 cells were more sensitive to halothane-induced closure than
homomeric/homotypic Cx43 or Cx40 channels. Four lines of evidence
support this conclusion. First, the dose dependence of uncoupling
indicated greater sensitivity to halothane in the A7r5 versus Rat-1
(homomeric/homotypic Cx43) and N2A-Cx40 cells (homomeric/homotypic
Cx40). Second, the diversity of channel amplitudes observed in A7r5
cells in the presence versus absence of halothane was reduced. Third,
the open times of many channels whose amplitudes are not typical of
homomeric/homotypic Cx40 or Cx43 channels were reduced to a far greater
extent than the open times of channels common to this setting. Finally,
the channels most severely affected by halothane contribute 
50% of
cumulative open time in the absence of halothane. Reversibility of the
effect of halothane, the absence of change in macroscopic
gj under control conditions, and the
absence of differences in single-channel amplitude histograms as a
function of whole-cell clamp duration rule out any role of run-down in
the effects of halothane reported in the present study. Thus, our
results strongly suggest that many heteromeric Cx40-Cx43 channels are
more sensitive to halothane-induced closure than homomeric/homotypic
Cx43 or Cx40 channels.
Other investigators have examined chemical-dependent gating behavior of heteromeric channels and hemichannels. Bevans et al17 18 reported that reconstituted heteromeric Cx32-Cx26 hemichannels are more sensitive to gating by aminosulfonates and cyclic nucleotides than homomeric Cx32 hemichannels. Lee and Rhee19 found that Cx32-Cx26–coexpressing cells are more sensitive to pH-dependent uncoupling than cells that express only Cx26. Preliminary data recently presented by Gu et al20 suggest that heteromeric Cx40-Cx43 channels exhibited greater pH sensitivity than homomeric Cx40 or Cx43 channels. Thus, the available literature on heteromeric channels suggests that the chemical-dependent gating behavior of heteromeric channels (at least by pH and halothane) differs from that of either corresponding homomeric channel and is indeed not well predicted by the gating behavior of the corresponding homomeric channels. Interestingly, Wang and Peracchia21 found that the pH-dependent gating behavior of heteromeric channels composed of Cx32 and a C-terminal mutant form of Cx32 is dominated by the wild-type connexin. This observation might suggest that the alterations of chemical-dependent gating behavior observed for heteromeric channels composed of two connexin isoforms reflect subunit interactions in membrane spanning or extracellular domains.
Interestingly, heteromeric channels seem to be more resistant to voltage-dependent gating than their homomeric counterparts, which suggests that subunit interactions influence chemical- and voltage-dependent gating mechanisms very differently. Junctions composed of Cx37-Cx43 heteromeric channels5 displayed variable response to voltage, with the extremes of response outside the range predicted by either of the homomeric channels. Similarly, Cx40-Cx43 channels appear to be less sensitive to voltage-dependent gating than their homomeric/homotypic counterparts.2 The behavior of heteromeric hemichannels is also quite different from either homomeric hemichannels.22 These data suggest that heteromerization alters subunit interactions in a fashion that leads to enhanced Po through a broader range of voltages than occurs in the homomeric channel and hemichannel.
In studies of the function of gap junctions, many investigators have used halothane (and other lipophilic agents) to reduce coupling between cells to reveal single-channel events.9 13 15 The population of channel amplitudes observed in the presence of halothane has been assumed to be representative of all the channels present in the gap junction. The data in the present study indicate that this assumption is not warranted and could be misleading. Indeed, Moore and Burt16 observed a preponderance of 70-, 108-, and 140-pS channels in A7r5 cells in the presence of halothane and concluded, on the basis of these and other results, that Cx40 and Cx43 did not form heteromeric or heterotypic channels. The present study indicates that the conditions of the study presented by Moore and Burt favored visualization of the homomeric/homotypic channel forms. Thus, quantitative evaluation of the diversity of channels formed in a setting where heteromerization is possible cannot be achieved in the presence of halothane.
Clinically, halothane is arrhythmogenic in some settings23 24 whereas in others it abolishes arrhythmias.25 26 This dual effect of halothane could reflect differences in connexin expression in the arrhythmogenic versus antiarrhythmic settings. Most cells of the heart normally express more than one type of connexin. However, spatial and quantitative changes in connexin expression occur as a normal part of cardiac development,27 28 as well as in aging,29 ischemia-induced remodeling,29 30 and arrhythmia-induced remodeling.31 32 For example, sustained atrial fibrillation induces a permanent increase in Cx43 expression in the atrium.31 32 Such an increase could predispose the remodeled heart to arrhythmias. Similarly, infarction causes a redistribution of Cx43 in the infarction border zone30 32 and an increased susceptibility to ventricular tachycardia. Expression of other connexins was not examined in these studies; however, a change in the expression of only one connexin in a cell that expresses multiple connexins would be expected to significantly shift the connexin composition of the channel population.5 21 Because halothane affects homomeric and heteromeric gap junction channels with different sensitivities, expression-dependent effects of halothane on cardiac rhythmicity would be expected. Interestingly, if heteromeric channels are selectively closed in the presence of halothane, then the remaining channels would be predominantly homomeric channels. Homomeric channels are far more likely in the Cx40 knockout mouse and in the heterozygous Cx43+/- mouse, and both animals display an increased susceptibility to arrhythmias.33 34
In summary, our data demonstrate that halothane reduces gap junction channel Po in a dose-dependent and connexin-specific fashion. If comparable selectivity of effect were to occur in the heart, halothane could result in nonuniform changes in the conductive pathway that would predispose the healthy heart to arrhythmias but, as a consequence of altered connexin expression, oppose arrhythmogenesis in the diseased heart.
|
Acknowledgments |
|---|
This study was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (HL58732 and HL07249), the Arizona Disease Control Research Commission (1-217), and the Arizona Affiliate of the American Heart Association (AZGS-35-97).
Received May 8, 2000; accepted May 17, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-
Valiunas V, Bukauskas F, Weingart R. Conductances
and selective permeability of connexin43 gap junction channels examined
in neonatal rat heart cells. Circ Res. 1997;80:708–719.
[Abstract/Free Full Text] -
He DS, Jiang JX, Taffet S, Burt JM. Formation of
heteromeric gap junction channels by connexins 40 and 43 in vascular
smooth muscle cells. Proc Natl Acad Sci U S A. 1999;96:6495–6500.
[Abstract/Free Full Text] - Elenes S, Rubart M, Moreno AP. Junctional communication between isolated pairs of canine atrial cells is mediated by homogeneous and heterogeneous gap junction channels. J Cardiovasc Electrophysiol. 1999;10:990–1004.[Medline] [Order article via Infotrieve]
- Valiunas V, Weingart R, Brink PR. Formation of heterotypic gap junction channels by connexins 40 and 43. Circ Res. 2000;86:e42–e49.
- Brink PR, Cronin K, Banach K, Peterson E, Westphale EM, Seul KH, Ramanan SV, Beyer EC. Evidence for heteromeric gap junction channels formed from rat connexin43 and human connexin37. Am J Physiol. 1997;173:C1386–C1396.
-
Saffitz JE, Kanter HL, Green KG, Tolley TK, Beyer EC.
Tissue-specific determinants of anisotropic conduction velocity in
canine atrial and ventricular myocardium.
Circ Res. 1994;74:1065–1070.
[Abstract/Free Full Text] - Spach MS, Starmer CF. Altering the topology of gap junctions: a major therapeutic target for atrial fibrillation. Cardiovasc Res. 1995;30:337–344.[Medline] [Order article via Infotrieve]
- Spach MS, Dolber PC. The relation between discontinuous propagation in anisotropic cardiac muscle and the "vulnerable period" of reentry. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology and Arrhythmias. Orlando, FL: Grune & Stratton; 1985:241–252.
-
Burt JM, Spray DC. Volatile anesthetics block
intercellular communication between neonatal rat myocardial cells.
Circ Res. 1989;65:829–837.
[Abstract/Free Full Text] -
Burt JM, Massey KD, Minnich BN. Uncoupling of cardiac
cells by fatty acids: structure-activity relationships. Am J
Physiol. 1991;260:C439–C448.
[Abstract/Free Full Text] - Bastiaanse EML, Jongsma HJ, Van Der Laarse A, Takens-Kwak BR. Heptanol-induced decrease in cardiac gap junctional conductance is mediated by a decrease in the fluidity of membranous cholesterol-rich domains. J Membr Biol. 1993;136:135–145.[Medline] [Order article via Infotrieve]
- Morley GE, Ek-Vitorin JF, Taffet SM, Delmar M. Structure of connexin43 and its regulation by pHi. J Cardiovasc Electrophysiol. 1997;8:939–951.[Medline] [Order article via Infotrieve]
- Terrar DA, Jason GG, Victory BA. Isoflurane depresses membrane currents associated with contraction in myocytes isolated from guinea-pig ventricle. Anesthesiology. 1988;69:742–749.[Medline] [Order article via Infotrieve]
- Ramanan SV, Fan SF, Brink PR. Model invariant method for extracting single-channel mean open and closed times from heterogeneous multichannel records. J Neurosci Methods. 1992;42:91–103.[Medline] [Order article via Infotrieve]
- Peracchia C. Effects of the anesthetics heptanol, halothane and isoflurane on gap junction conductance in crayfish septate axons: a calcium- and hydrogen-independent phenomenon potentiated by caffeine and theophylline, and inhibited by 4-aminopyridine. J Membr Biol. 1991;121:67–78.[Medline] [Order article via Infotrieve]
-
Moore LK, Burt JM. Selective block of gap junction
channel expression with connexin-specific antisense
oligodeoxynucleotides. Am J Physiol. 1994;267:C1371–C1380.
[Abstract/Free Full Text] -
Bevans CG, Harris AL. Regulation of connexin channels
by pH. Direct action of the protonated form of taurine and other
aminosulfonates. J Biol Chem. 1999;274:3711–3719.
[Abstract/Free Full Text] -
Bevans CG, Harris AL. Direct high affinity modulation
of connexin channel activity by cyclic nucleotides.
J Biol Chem. 1999;274:3720–3725.
[Abstract/Free Full Text] - Lee MJ, Rhee SK. Heteromeric gap junction channels in rat hepatocytes in which the expression of connexin26 is induced. Mol Cells. 1998;8:295–300.[Medline] [Order article via Infotrieve]
- Gu H, Ek-Vitorin JF, Stergiopoulos K, Taffet SM, Delmar M. Co-expression of two connexins (Cx40 and Cx43) enhances pH sensitivity of gap junctions. Circulation. 1999;100:I-842. Abstract.
- Wang XG, Peracchia C. Chemical gating of heteromeric and heterotypic gap junction channels. J Membr Biol. 1998;162:169–176.[Medline] [Order article via Infotrieve]
-
Ebihara L, Xu X, Oberti C, Beyer EC, Berthoud VM.
Co-expression of lens fiber connexins modifies hemi-gap-junctional
channel behavior. Biophys J. 1999;76:198–206.
[Abstract/Free Full Text] - Zhang S, Todoroki S, Urechino H, Morooka H, Makita T, Shibata O. Role of potassium channels in halothane-epinephrine arrhythmias. Res Commun Mol Pathol Pharmacol. 1998;100:339–350.[Medline] [Order article via Infotrieve]
-
Campbell JHC, Campbell GR, Ross R.
Phenotype-dependent response of cultured aortic smooth muscle
to serum mitogens. J Cell Biol. 1981;89:379–383.
[Abstract/Free Full Text] - Novalija E, Hogan QH, Kulier AH, Turner LH, Bosnjak ZJ. Effects of desfurane, sevoflurane and halothane on post-infarction spontaneous dysrhythmias in dogs. Acta Anaesthesiol Scand. 1998;42:353–357.[Medline] [Order article via Infotrieve]
- Gallagher JD. The effects of halothane on abnormal automaticity in canine. Anesth Analg. 1998;86:488–492.[Abstract]
-
Delorme B, Dahl E, Jarry-Guichard T, Briand JP,
Willecke K, Gros D, Theveniau-Ruissy M. Expression pattern of connexin
gene products at the early developmental stages of the mouse
cardiovascular system. Circ Res. 1997;81:423–437.
[Abstract/Free Full Text] - Van Kempen MJ, Vermeulen JL, Moorman AF, Gros D, Paul DL, Lamers WH. Developmental changes of connexin40 and connexin43 mRNA distribution patterns in the rat heart. Cardiovasc Res. 1996;32:886–900.[Medline] [Order article via Infotrieve]
- Peters NS. New insights into myocardial arrhythmogenesis: distribution of gap-junctional coupling in normal, ischaemic and hypertrophied human hearts. Clin Sci (Colch). 1996;90:447–452.[Medline] [Order article via Infotrieve]
-
Peters NS, Coromilas J, Severs NJ, Wit AL. Disturbed
connexin43 gap junction distribution correlates with the location of
reentrant circuits in the epicardial border zone of healing canine
infarcts that cause ventricular tachycardia.
Circulation. 1997;95:988–996.
[Abstract/Free Full Text] - van der Velden HM, Van Kempen MJ, Wijffels MC, van Zijverden M, Groenewegen WA, Allessie MA, Jongsma HJ. Altered pattern of connexin40 distribution in persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol. 1998;9:596–607.[Medline] [Order article via Infotrieve]
-
Elvan A, Huang XD, Pressler ML, Zipes DP.
Radiofrequency catheter ablation of the atria eliminates pacing-induced
sustained atrial fibrillation and reduces connexin 43 in dogs.
Circulation. 1997;96:1675–1685.
[Abstract/Free Full Text] -
Hagendorff A, Schumacher B, Kirchhoff S, Luderitz B,
Willecke K. Conduction disturbances and increased atrial vulnerability
in connexin40-deficient mice analyzed by
transesophageal stimulation. Circulation. 1999;99:1508–1515.
[Abstract/Free Full Text] -
Thomas SA, Schuessler RB, Berul CI, Beardslee MA,
Beyer EC, Mendelsohn ME, Saffitz JE. Disparate effects of deficient
expression of connexin43 on atrial and ventricular
conduction: evidence for chamber-specific molecular determinants of
conduction. Circulation. 1998;97:686–691.
[Abstract/Free Full Text]
This article has been cited by other articles:
 |
|
 |
|
  J. S. Johansson Central nervous system electrical synapses as likely targets for intravenous general anesthetics. Anesth. Analg., June 1, 2006; 102(6): 1689 - 1691. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Garcia-Dorado, A. Rodriguez-Sinovas, and M. Ruiz-Meana Gap junction-mediated spread of cell injury and death during myocardial ischemia-reperfusion Cardiovasc Res, February 15, 2004; 61(3): 386 - 401. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Kanagaratnam, S. Rothery, P. Patel, N. J. Severs, and N. S. Peters Relative expression of immunolocalized connexins 40 and 43 correlates with human atrial conduction properties J. Am. Coll. Cardiol., January 2, 2002; 39(1): 116 - 123. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||