© 2000 American Heart Association, Inc.
Cellular Biology |
Effects of the Renin-Angiotensin System on the Current Ito in Epicardial and Endocardial Ventricular Myocytes From the Canine Heart
From the Departments of Physiology and Biophysics (H.Y., J.G., H.W., I.S.C.) and Neurobiology and Behavior (D.M.) and Institute of Molecular Cardiology (H.Y., J.G., H.W., R.W., D.M., M.R.R., I.S.C.), State University of New York at Stony Brook; Department of Pharmacology, Pediatrics and Medicine (S.S., M.R.R.), Columbia University, College of Physicians and Surgeons, New York, NY; and Department of Biological Science (R.W.), University of Tulsa, Tulsa, Okla.
Correspondence to Dr Ira S. Cohen, Institute of Molecular Cardiology, 8661 SUNY, Stony Brook, NY 11794-8661. E-mail icohen{at}physiology.pnb.sunysb.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Abstract—The Ca2+-independent portion of transient outward K+ current (Ito) exhibits a transmural gradient in ventricle. To investigate control mechanisms for this gradient, we studied canine epicardial and endocardial ventricular myocytes with use of the whole-cell patch-clamp technique. Ito was larger in amplitude, had a more negative voltage threshold for activation, and had a more negative midpoint of inactivation in epicardium. Recovery from inactivation was >10-fold slower in endocardium. Incubation of epicardial myocytes with angiotensin II for 2 to 52 hours altered Ito to resemble unincubated endocardium and reduced the amplitude of the phase 1 notch of the action potential. In contrast, incubation of endocardial myocytes with losartan for 2 to 52 hours altered Ito to resemble unincubated epicardium and induced a phase 1 notch in the action potential. With RNase protection assays, we determined that incubations with angiotensin II or losartan did not alter mRNA levels for either Kv4.3 or Kv1.4; thus, a change in the
subunit for
Ito is unlikely to be responsible. To test
whether posttranslational modification produced the effects of
angiotensin II, we coexpressed Kv4.3 and the
angiotensin II type 1a receptor in Xenopus
oocytes. Incubation with angiotensin II increased the time
constant for recovery from inactivation of the expressed current by
2-fold with an incubation time constant of 3.7 hours. No effect on
activation or inactivation voltage dependence was observed. These
results demonstrate that the properties of
Ito in endocardium and epicardium are
plastic and likely under the tonic-differing influence of the
renin-angiotensin system.
Key Words: angiotensin • epicardium • endocardium • current
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Differences in the action potential duration of myocytes from the endocardium (ENDO) and the epicardium (EPI) of the canine heart contribute to the morphology and polarity of the T wave of the ECG.1 2 The ionic currents responsible for these differences are determinants of the T wave. One major difference between EPI and ENDO myocyte ion currents is in the Ca2+-independent transient outward current (referred to here as Ito). Previous investigations have demonstrated a lower density and slower recovery from inactivation in ENDO compared with in EPI.3 4 We recently identified the molecular basis of Ito in canine ventricle as a member of the Shaker family of K channels, Kv4.3.5
Among the potential modulators of the T wave is the renin-angiotensin system and its active hormone, angiotensin II (Ang II).6 Ang II has direct actions on cardiac membrane currents, increasing chloride current7 and decreasing Na+/K+ exchange current8 in rabbit ventricular myocytes. These actions occur through the Ang II type 1 (AT1) receptor, which is prevalent in cardiac tissues of many species.9 10 Not only is the AT1 receptor present in heart, but also an autocrine renin-angiotensin system is present in rat ventricular myocytes.11 12 13 This suggests that mammalian cardiac myocytes or nonmyocyte elements in mammalian hearts can produce this hormone, which modulates repolarizing currents.
In the present study, we first describe the properties of Ito in canine EPI and ENDO, outlining differences in both current density and gating properties. We then demonstrate that the differences between these 2 tissues are entirely plastic; that is, long-term exposure of EPI to Ang II or of ENDO to the AT1 receptor blocker losartan can convert properties of Ito of either region into those of the other, thereby providing a basis for an altered transmural gradient of repolarization in the ventricle and resultant Twave changes.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Cell Preparation
Adult dogs of either sex were euthanized with an injection of sodium pentobarbital. EPI and ENDO ventricular myocytes were dissociated according to the trituration method developed in our laboratory.14 Cells were stored in KB solution (which contained [in mmol/L] KCl 83, K2HPO4 30, MgSO4 5, Na-pyruvic acid 5, ß-OH butyric acid [Na-salt] 5, taurine 20, glucose 10, EGTA 0.5, HEPES 5, Na2ATP 5, and creatine 5, titrated to pH 7.2 with KOH)15 at room temperature for at least 1 hour before electrophysiological experiments. Cells were incubated in KB solution at room temperature the first day of experiments (2 to 5 hours) and then at 4°C for experimentation on days 2 and 3 (6 to 52 hours). Ang II and saralasin were purchased from Sigma Chemical Co, and losartan was kindly provided by Merck.
Measurement of Ito, Action Potentials,
and Data Analysis
Isolated cells were maintained at 32° to 35°C (±0.5°C in
each experiment).16 Ito and
action potentials were recorded with use of the whole-cell
patch-clamp technique. Ito was defined as
the difference between the peak value and the current level at the end
of a 300- or 400-ms pulse. The threshold was the most negative test
voltage that elicited an Ito of >10 pA.
The pipettes were filled with solution containing (in mmol/L) NaCl
6, K-aspartate 130, MgCl2 2,
CaCl2 5, EGTA 11, Na2ATP 2,
Na-GTP 0.1, Na-cAMP 0.2, and HEPES 10 (pH adjusted to 7.2 with KOH).
The external solution contained (in mmol/L) NaCl 137.7, NaOH 2.3,
MgCl2 1, glucose 10, HEPES 5, KCl 5.4,
CaCl2 1.8, MnCl2 2, and
CdCl2 0.2, pH 7.4. The liquid junction potential
of -11 mV between the electrode tip and the cell interior (cell
interior negative) was not corrected.17
Mn2+ and Cd2+ were used to
block Ca2+ currents, which can obscure
Ito activation.
RNase Protection Assays
ENDO and EPI myocytes were incubated for 24 hours either with or
without 2 µmol/L Ang II (EPI) or 2 µmol/L
losartan (ENDO). mRNA was isolated with the use of paramagnetic
poly(dT) beads (Dynal). RNA probes for Kv1.4 and Kv4.3 were prepared as
described previously.5 RNase protection assays were
performed and quantified as described previously.5
Heterologous Expression in Oocytes
Oocytes were prepared from Xenopus laevis as
previously described.5 Oocytes were injected with 50
nL Kv4.3 mRNA or an equimolar ratio of Kv4.3 and
AT1a mRNA. Injected oocytes were incubated at
18°C for 24 to 48 hours. In the study of Ang II treatment, oocytes
were then incubated in OR35 solution containing 4
µmol/L Ang II for 25 to 32 hours at 18°C before testing.
Oocytes were voltage-clamped with the use of a 2-microelectrode voltage clamp. The extracellular recording solution was OR2.5
Data are presented as mean±SEM. Statistical significance was tested with Student’s t tests. P<0.05 was considered statistically significant.
An expanded Materials and Methods section is available online at http://www.circresaha.org.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Gating Properties of Ito in ENDO Differ From Those in EPI
We began our investigation by characterizing Ito in both ENDO and EPI ventricular myocytes. We first examined the voltage dependence of activation. We held the cells at -65 mV and first briefly depolarized (5 ms) to -45 mV to inactivate INa and then depolarized to voltages from -40 to +50 mV in 10-mV increments for 300 ms. The average threshold for first observation of transient outward current (see Materials and Methods for definition) was -25±2 mV (n=24) in EPI myocytes and 4±3 mV (n=15) in ENDO myocytes. As previously reported,3 the amplitude of transient outward current is also larger in the EPI myocyte. The larger Ito was determined in the Table
by measuring the dependence of the transient
outward conductance on voltage, which increases almost 4-fold more
rapidly in EPI than in ENDO. Our results are reported normalized to
capacitance. The average capacitance was 125±26 pF (n=20) in ENDO
myocytes and 104±8 pF (n=26) in EPI myocytes.
|
We also examined the voltage dependence of inactivation of
Ito. We held the membrane at -65 mV and
used a 3-pulse protocol. We first depolarized for 5 ms to -45 mV to
inactivate INa and then used a
first (conditioning) pulse, which either depolarized or hyperpolarized
for 2 seconds to bring the membrane to a new starting value for
inactivation; with the second (test) pulse, we depolarized to +10 mV
for 400 ms (see Figure 1A).
Ito amplitude normalized to
Ito for the most negative conditioning
pulse is plotted against each conditioning voltage in Figure 1B, along with the fits of a Boltzmann 2-state model.
Ito exhibited a more positive midpoint of
inactivation in ENDO myocytes and a reduction in steepness of the
inactivation curve.
|
The time constant of inactivation of Ito
did not differ between ENDO and EPI. We then used a 2-pulse protocol to
investigate the kinetics of recovery from inactivation. The cycle
length was 8 seconds. The first depolarizing pulse of 300 ms in
duration was applied from the holding potential of -65 mV to the test
potential of +5 mV EPI, or +15 mV ENDO, to activate a
measurable Ito; then, a variable
interval at the holding potential was allowed for recovery from
inactivation, followed by a second identical test pulse. Data are
provided in Figures 1C
and 1E for EPI and ENDO myocytes,
respectively. Ito recovered from
inactivation at a much slower rate in ENDO than in EPI myocytes. This
difference in kinetics is quantified in Figures 1D and 1F. For
this example, recovery from inactivation of EPI
Ito is fit with a time constant of 30 ms,
whereas the recovery from inactivation for ENDO
Ito is fit by a constant of 950 ms. The
average results summarized in the Table suggest that
Ito in EPI is more dense, activates
more negatively, inactivates more negatively, and recovers
faster from inactivation than does the same current in ENDO.
Incubation of EPI Myocytes With Ang II Alters
Ito so That Its Gating Properties Resemble
Those Found in ENDO
Superfusion of EPI myocytes with 1 µmol/L Ang II for 5 to
20 minutes induced no change in the activation or density of
Ito (n=8). Recovery from inactivation was
also studied in 4 myocytes, where no change was observed. We then
studied the effects of chronic exposure of EPI myocytes to Ang II by
storing myocytes for a period of 2 to 52 hours in KB medium containing
0.5 to 2 µmol/L Ang II, after which
electrophysiological studies of
Ito were performed in the absence of Ang II
at 32° to 35°C. We also incubated EPI myocytes from the same
animals in the same storage solution and for the same time period but
without Ang II. These myocytes showed no significant difference from
the control values for EPI myocytes studied acutely. Figure 2A provides sample data from EPI myocytes
incubated in control solution or with Ang II for 24 hours (Figure 2B). Figure 2C clearly shows the current density is
reduced by Ang II and that the activation has been shifted to more
positive potentials (see Table).
|
We also examined the steady-state voltage dependence of inactivation
and the recovery from inactivation in the Ang II–incubated myocytes;
the results are presented in Figure 3. Steady-state inactivation is shifted
to more positive potentials, and the recovery from inactivation is
dramatically slowed by incubation with Ang II.
|
The Table shows a comparison of the properties of
Ito in Ang II–incubated EPI
ventricular myocytes with those from unincubated EPI and
ENDO. It is clear that the gating properties of
Ito and its density have been altered by
incubation with Ang II. Most of the properties of
Ito in EPI myocytes incubated with Ang II
now more closely resemble those of ENDO
Ito.
The effects of Ang II incubation on EPI Ito were prevented when the AT1 receptor blocker losartan (1 µmol/L) was included with Ang II in the incubate.
Incubation of ENDO Myocytes With the AT1
Receptor Blocker Losartan Alters
Ito Such That Its Properties Resemble Those
of EPI
Given the effects of incubation with Ang II on EPI myocytes and
the existence of an autocrine renin-angiotensin system, we
explored the possibility that blockade of the normal Ang II pathway via
the AT1 receptor might modulate
Ito in ENDO. We first acutely exposed ENDO
myocytes to losartan (1 µmol/L). No acute effects on
Ito activation or density (5 myocytes) or
recovery from inactivation (3 myocytes) were observed (data not
shown).
We next incubated ENDO myocytes for 2 to 52 hours with 1 to 2
µmol/L losartan in the same incubation solution as was used
for EPI myocytes. We also examined ENDO myocytes stored in the same
incubate without added losartan. We observed no change in the
properties of Ito from those of unincubated
ENDO myocytes. The effects of losartan on
Ito amplitude and the voltage dependence of
activation are presented in Figure 4. Ito is
increased and the voltage dependence of activation is shifted to more
negative potentials (see the Table), similar to control EPI.
|
We next examined the voltage dependence of inactivation and the time
course of recovery from inactivation in the losartan-incubated
ENDO myocytes. Figure 5 illustrates the
results. Steady-state inactivation shifts to more negative potentials,
and the time constant for recovery from inactivation becomes much
faster.
|
The Table compares properties of Ito
in ENDO myocytes incubated with losartan with unincubated ENDO
and EPI myocytes. Losartan incubation converts most properties
of Ito in ENDO myocytes to resemble those
of unincubated EPI myocytes.
Two additional control experiments were performed. In 1 experiment (n=10), EPI was incubated for 2 to 52 hours with losartan, and in the other (n=5), ENDO was incubated with Ang II for the same time period. No effect was observed of either incubation on Ito (data not shown).
Action Potential Notch Is Influenced by Ang II
Ito is responsible for phase 1 rapid
repolarization. Given the effects of Ang II and of losartan on
EPI and ENDO Ito, respectively, changes in
the action potential contour might be expected. We recorded action
potentials from 11 control EPI and 10 control ENDO myocytes as well as
from 5 EPI myocytes incubated for 24 hours with 1 µmol/L Ang II
and from 6 ENDO myocytes incubated for 24 hours with 1 µmol/L
losartan. Representative results are
illustrated in Figure 6. Control EPI
action potentials always demonstrated a notch, whereas control ENDO
action potentials did not (a difference noted previously by
others1 ). EPI myocyte incubation with Ang II resulted
in loss of the notch, whereas ENDO myocyte incubation with
losartan produced a notch. These changes are consistent
with the changes in Ito that we described
earlier.
|
mRNA levels for Kv4.3 and Kv1.4
The patch-clamp results revealed changes in
Ito induced by incubation with either Ang
II (EPI) or losartan (ENDO). However, they do not provide a
mechanism for the observed effects. One possibility is a change in the
molecular correlate of the current. We previously demonstrated that
Kv4.3 underlies Ito in the canine
ventricle. However, Kv1.4 is present in canine myocytes and
recovers from inactivation much more slowly. We therefore examined the
effects of incubation of EPI myocytes with 2 µmol/L Ang II for
24 hours and the effects of incubation of ENDO myocytes with 2
µmol/L losartan for the same period on the mRNA level for
these K+ channel subunits. The mRNA levels were
quantified from 3 samples with thee use of RNase protection assays. For
EPI, (EPI+Ang II)/EPI=1.00±0.07 for Kv4.3 and 0.98±0.09 for Kv1.4.
For ENDO, (ENDO+losartan)/ENDO=1.01±0.04 for Kv4.3 and
1.02±0.10 for Kv1.4. Neither incubation resulted in any change in mRNA
levels for either transcript.
Heterologous Expression of Kv4.3 With the AT1 Receptor
in X laevis Oocytes
If a change in the molecular correlate of
Ito does not occur, possibly the changes
could be induced by posttranslational modification of the existing
protein. To test this hypothesis, we heterologously expressed the
dominant molecular correlate of canine Ito,
Kv4.3, in X laevis oocytes along with the
AT1a receptor.
Figure 7 shows the results of our study
of the effects of incubation with 4 µmol/L Ang II for up to 32
hours on recovery from inactivation with the following protocol.
Membrane potential was depolarized to -20 mV for 600 to 900 ms from a
holding potential of -90 mV to completely inactivate Kv4.3
current. The recovery potential was -100 mV followed by test steps to
-20 mV at various intervals. The recovery kinetics were slower for the
treated oocyte (
=361 ms) compared with the control oocyte (=141
ms) (Figures 7A and 7B). The average 
2-fold slowing of the time
constant for recovery from inactivation is provided in Figure 7C
for all oocytes studied. Figure 7C also illustrates that this
effect is not observed in the absence of either Ang II or the
AT1a receptor. Figure 7D illustrates the
time course of the change in recovery from inactivation after
incubation with Ang II. The time constant is 3.7 hours.
|
Although an effect is observed on recovery from inactivation, there was no effect of incubation with Ang II on either the voltage dependence of inactivation or activation (data not shown).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In agreement with previous studies,3 4 we found a smaller density and a slower recovery from inactivation of Ito in ENDO than in EPI. We also observed a more positive threshold for Ito activation in ENDO. The smaller current density, more positive activation, and slower recovery from inactivation all contribute to the absence of a notch in the ENDO action potential during steady-state ventricular beating. One additional difference between these 2 tissue types is the voltage dependence of Ito inactivation, which is more positive in ENDO.
The critical findings in our study were that, first, Ang II converts many of the properties of EPI Ito to those normally seen in ENDO, and second, losartan converts many of the properties of ENDO Ito to those normally seen in EPI. Important to these observations is that neither exposure of ENDO to agonist nor exposure of EPI to antagonist had any effect and that exposure of EPI to agonist plus antagonist also had no effect. Moreover, none of the effects on EPI or ENDO were acute: incubation was required. Such incubation of EPI in Ang II (1) decreases the Ito current density, (2) shifts the threshold for Ito activation to more positive voltages, (3) shifts the voltage dependence of Ito inactivation to more positive voltages, and (4) slows Ito recovery from inactivation by >1 order of magnitude. Although the acute actions of Ang II on cardiac membrane currents in other species are mediated by activation of protein kinase C18 and may include mitogen-activated protein kinase in the signaling cascade,19 the signaling pathway that underlies the chronic action of Ang II on Ito remains to be determined.
Chronic incubation of ENDO with losartan induces (1) an increase in Ito density, (2) a more negative Ito activation, (3) a more negative voltage dependence of Ito inactivation, and (4) a dramatic speeding of Ito recovery from inactivation. The resultant ENDO Ito resembles that observed in normal EPI. This observation is all the more remarkable because it occurs in the absence of applied agonist. One plausible explanation is that tonic activation of the AT1 receptor of normal ENDO myocytes occurs both in vivo and in the incubate and that the source of this tonic activation is an autocrine renin-angiotensin system present in the canine ventricular myocytes or in nonmyocyte cells that remain in the incubate.
If an autocrine renin-angiotensin system contributes to modulation of the T wave, then ENDO is likely exposed to a larger tonic influence of Ang II than EPI. This supposition is based on the observation that the conversion of ENDO Ito to EPI Ito involves AT1 receptor blockade, whereas the converse action requires AT1 receptor activation. This raises the possibility that these 2 cell types are normally under a chronically differing influence of the renin-angiotensin system. An autocrine renin-angiotensin system has already been reported in rat ventricular myocytes.11 12 13 Either Ang II production, AT1 receptor density, or coupling of the AT1 receptor to its second messenger pathway might be more efficient in the ENDO, leading to a larger tonic effect. A higher activity of ACE in ENDO than in EPI has been reported in rat ventricle.20 Also, angiotensin mRNA is higher in ENDO than in EPI in human ventricle.21 Preliminary experiments with ACE inhibition in dogs have demonstrated alterations in the T wave vector.22
The changes we observed in EPI and ENDO Ito
could have been caused by at least 3 alternatives: (1) a change in the
molecular correlate of Ito, (2)
posttranslational modification of the channel protein, and (3) an
auxiliary (ß) subunit. We consider each in turn. (1) Regarding a
change in the molecular correlate of Ito,
in canine myocytes, Ito has been identified
as Kv4.3, although in control conditions, there also is some expression
of Kv1.4. Because Kv1.4 recovers from inactivation much more slowly
than Kv4.3, an isoform switch had to be given serious consideration.
Our RNase protection assays demonstrated no change in transcript level
for either channel with chronic incubation. Barring a dramatic
difference between message and protein level, a change in the
subunit of Ito is a remote possibility. (2)
Regarding posttransitional modification of the channel protein, our
results in X laevis oocytes demonstrated that after
incubation with Ang II, Kv4.3 exhibited a 2-fold slowing of recovery
from inactivation. However, no change in the voltage dependence of
activation or inactivation was observed. Possibly, the oocyte
environment cannot reproduce that of the ventricular
myocyte, and mammalian cells may allow for a more complete
reconstruction of the observed effects. (3) Regarding an auxiliary
(ß) subunit, it is known that ß subunits can alter the gating
properties of ion channels. In cardiac myocytes,
IKs is a heteromultimer of KCNQ1
and minK.23 KCNQ1 gates markedly more rapidly in the
absence of minK. Recently, a ß subunit has been identified for the
Kv4 family of ion channel subunits.24 The channel recovers
from inactivation more rapidly than in its absence. If this ß subunit
were to underlie our results, its density should be higher in EPI than
in ENDO, and this gradient should be altered by our long-term
incubations.
One area in which our observations are relevant is cardiac memory, in which ECG T wave changes are associated with an altered transmural gradient for repolarization6 and phenotypic expression is blocked by ACE inhibition or Ang II receptor blockade.22 Another setting in which our observations may play a role is myocardial hypertrophy, whether pathological (eg, hypertension) or physiological (eg, postnatal left ventricular hypertrophy). Nonetheless, the importance of our findings to the evolution of repolarization in the heart and the morphology of the T wave remains to be established.
|
Acknowledgments |
|---|
This work was supported by National Institutes of Health grants HL-20558, HL-53956, HL-28958, and NS-29755. Drs Wymore and Yu are supported by Scientist Development Awards of the American Heart Association. Dr Wang holds a postdoctoral fellowship from the American Heart Association, Northeast Affiliate.
Received February 4, 2000; accepted March 30, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Sicouri S, Antzelevitch C. A subpopulation of cells with unique electrophysiological properties in the deep subepicardium of the canine ventricle. Circ Res. 1991;68:1729–1741.
2.
Anyukhovsky EP, Sosunov EA, Rosen MR. Regional
differences in electrophysiologic properties of epicardium,
midmyocardium and endocardium: in vitro and in vivo
correlations. Circulation. 1996;94:1981–1988.
3.
Liu D-W, Gintant GA, Antzelevitch C. Ionic bases for
electrophysiological distinctions among
epicardial, midmyocardial, and endocardial myocytes from the free wall
of the canine left ventricle. Circ Res. 1993;72:671–687.
4.
Nabauer M, Beuckelmann DJ, Uberfuhr P, Steinbeck G.
Regional differences in current density and rate-dependent properties
of transient outward current in subepicardial and subendocardial
myocytes of human left ventricle. Circulation. 1996;93:168–177.
5.
Dixon JE, Shi W, Wang H-S, McDonald C, Yu H, Wymore
RS, Cohen IS, McKinnon D. Role of the Kv4.3 K+
channel in ventricular muscle: a molecular correlate for
the transient outward current. Circ Res. 1996;79:659–668.
6.
Rosen MR, Cohen IS, Danilo P Jr, Steinberg SF. The
heart remembers. Cardiovasc Res. 1998;40:469–482.
7.
Morita H, Kimura J, Endoh M.
Angiotensin II activation of a chloride current in rabbit
cardiac myocytes. J Physiol (Lond). 1995;483:119–130.
8.
Hool LC, Gray DF, Robinson BG, Rasmussen HH.
Angiotensin-converting enzyme inhibitors
regulate the Na+-K+ pump
via effects on angiotensin metabolism.
Am J Physiol. 1996;271:C172–C180.
9.
Tsuchiya K, Horie M, Watanuki M, Albrecht CA, Obayashi
K, Fujiwara H, Sasayama S. Functional compartmentalization of ATP is
involved in angiotensin II–mediated closure of cardiac
ATP-sensitive K+ channels.
Circulation. 1997;96:3129–3135.
10. Chorvatova A, Gallo-Payet N, Casanova C, Payet MD. Modulation of membrane potential and ionic currents by the AT1 and AT2 receptors of angiotensin II. Cell Signal. 1996;8:525–532.[Medline] [Order article via Infotrieve]
11.
Dostal DE, Rothblum KN, Chernin MI, Cooper GR, Baker
KM. Intracardiac detection of angiotensinogen and renin: a
localized renin-angiotensin system in neonatal rat heart.
Am J Physiol. 1992;263:C838–C850.
12. Sadoshima J-I, Xu Y, Slayter HS, Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell. 1993;75:977–984.[Medline] [Order article via Infotrieve]
13.
Zhang, X., Dostal, DE, Reiss K, Cheng W, Kajstura J, Li
P, Huang H, Sonnenblick EH, Meggs LG, Baker KM, Anversa P.
Identification and activation of autocrine
renin-angiotensin system in adult ventricular
myocytes. Am J Physiol. 1995;269:H1791–H1802.
14. Gintant GA, Datyner NB, Cohen IS. Gating of delayed rectification in acutely isolated canine cardiac Purkinje myocytes. Biophys J. 1985;48:1059–1064.[Medline] [Order article via Infotrieve]
15. Isenberg G, Klockner U. Calcium currents in bovine ventricular myocytes are fast and of large amplitude. Pflugers Arch. 1982;395:30–41.[Medline] [Order article via Infotrieve]
16. Datyner N, Gintant G, Cohen IS. Microprocessor controlled trituration device for dissociation of cardiac and other tissues. Pflugers Arch. 1985;403:105–108.[Medline] [Order article via Infotrieve]
17. Mathias RT, Cohen IS, Oliva C. Limitations of the whole cell patch clamp technique in the control of intracellular concentrations. Biophys J. 1990;58:759–770.[Medline] [Order article via Infotrieve]
18. Clement-Chomienne O, Walsh MP, Cole WC. Angiotensin II activation of protein kinase C decreases delayed rectifier K+ current in rabbit vascular myocytes. J Physiol (Lond). 1996;495:3:689–700.
19. Yamazaki T, Komuro I, Zou Y, Kudoh S, Mizuno T, Hiroi Y, Shiojima I, Takano H, Kinugawa K, Kohmoto O, Takahashi T, Yazaki Y. Protein kinase A and protein kinase C synergistically activate the Raf-1 kinase/mitogen-activated protein kinase cascade in neonatal rat cardiomyocytes. J Mol Cell Cardiol. 1997;29:2491–2501.[Medline] [Order article via Infotrieve]
20.
Yamada H, Fabris B, Allen AM, Jackson B, Johnston CI,
Mendelsohn FAO. Localization of angiotensin converting
enzyme in rat heart. Circ Res. 1991;68:141–149.
21. Kawaguchi H, Kitabatake A. Alterations of signal transduction system in heart failure. Jpn Heart J. 1997;38:317–332.[Medline] [Order article via Infotrieve]
22. Ricard P, Danilo P, Jr, Cohen IS, Burkhoff D, Rosen MR. A role for the renin angiotensin system in the evolution of cardiac memory. J Cardiovasc Electrophysiol. 1999;10:545–551.[Medline] [Order article via Infotrieve]
23. Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL, Keating MT. Coassembly of KvLQT1 and minK (IsK) proteins to form cardiac IKs potassium channel. Nature. 1996;384:80–83.[Medline] [Order article via Infotrieve]
24. Mattsson KI, Monaghan MM, Strassle BW, An WF, Bowlby MR, Trimmer JS, Buchwalder L, Rhodes KJ. Colocalization and coassociation of a novel family of neuronal calcium sensor homologs with Kv4-family K+ channels in mammalian brain. Soc Neurosci. 1999;25:983. Abstract.
This article has been cited by other articles:
 |
|
 |
|
  V. Valiunas, G. Kanaporis, L. Valiuniene, C. Gordon, H. Z. Wang, L. Li, R. B. Robinson, M. R. Rosen, I. S. Cohen, and P. R. Brink Coupling an HCN2-expressing cell to a myocyte creates a two-cell pacing unit J. Physiol., November 1, 2009; 587(21): 5211 - 5226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Xie, A. Garfinkel, J. N. Weiss, and Z. Qu Cardiac alternans induced by fibroblast-myocyte coupling: mechanistic insights from computational models Am J Physiol Heart Circ Physiol, August 1, 2009; 297(2): H775 - H784. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Michael, L. Xiao, X.-Y. Qi, D. Dobrev, and S. Nattel Remodelling of cardiac repolarization: how homeostatic responses can lead to arrhythmogenesis Cardiovasc Res, February 15, 2009; 81(3): 491 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. A. Potapova, S. V. Doronin, D. J. Kelly, A. B. Rosen, A. J. T. Schuldt, Z. Lu, P. V. Kochupura, R. B. Robinson, M. R. Rosen, P. R. Brink, et al. Enhanced recovery of mechanical function in the canine heart by seeding an extracellular matrix patch with mesenchymal stem cells committed to a cardiac lineage Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2257 - H2263. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Xiao, P. Coutu, L. R. Villeneuve, A. Tadevosyan, A. Maguy, S. Le Bouter, B. G. Allen, and S. Nattel Mechanisms Underlying Rate-Dependent Remodeling of Transient Outward Potassium Current in Canine Ventricular Myocytes Circ. Res., September 26, 2008; 103(7): 733 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Rivard, P. Paradis, M. Nemer, and C. Fiset Cardiac-specific overexpression of the human type 1 angiotensin II receptor causes delayed repolarization Cardiovasc Res, April 1, 2008; 78(1): 53 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Goette and U. Lendeckel Electrophysiological effects of angiotensin II. Part I: signal transduction and basic electrophysiological mechanisms Europace, February 1, 2008; 10(2): 238 - 241. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. S. Kasi, H. D. Xiao, L. L. Shang, S. Iravanian, J. Langberg, E. A. Witham, Z. Jiao, C. J. Gallego, K. E. Bernstein, and S. C. Dudley Jr. Cardiac-restricted angiotensin-converting enzyme overexpression causes conduction defects and connexin dysregulation Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H182 - H192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Saygili, O. R. Rana, E. Saygili, H. Reuter, K. Frank, R. H. G. Schwinger, J. Muller-Ehmsen, and C. Zobel Losartan prevents stretch-induced electrical remodeling in cultured atrial neonatal myocytes Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2898 - H2905. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Fiset and W. R. Giles Transmural Gradients of Repolarization and Excitation-Contraction Coupling in Mouse Ventricle Circ. Res., May 26, 2006; 98(10): 1237 - 1239. [Full Text] [PDF]
|
|
|
|
|
|
Y. Shimoni, D. Hunt, K. Chen, T. Emmett, and G. Kargacin Differential autocrine modulation of atrial and ventricular potassium currents and of oxidative stress in diabetic rats Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1879 - H1888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Rosen and I. S. Cohen Cardiac memory ... new insights into molecular mechanisms J. Physiol., January 15, 2006; 570(2): 209 - 218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Sun and H.-S. Wang Role of the transient outward current (Ito) in shaping canine ventricular action potential - a dynamic clamp study J. Physiol., April 15, 2005; 564(2): 411 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Szentadrassy, T. Banyasz, T. Biro, G. Szabo, B. I. Toth, J. Magyar, J. Lazar, A. Varro, L. Kovacs, and P. P. Nanasi Apico-basal inhomogeneity in distribution of ion channels in canine and human ventricular myocardium Cardiovasc Res, March 1, 2005; 65(4): 851 - 860. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. V. Doronin, I. A. Potapova, Z. Lu, and I. S. Cohen Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization J. Biol. Chem., November 12, 2004; 279(46): 48231 - 48237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. F. Tomaselli and D. P. Zipes What Causes Sudden Death in Heart Failure? Circ. Res., October 15, 2004; 95(8): 754 - 763. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Dun, S. Baba, T. Yagi, and P. A. Boyden Dynamic remodeling of K+ and Ca2+ currents in cells that survived in the epicardial border zone of canine healed infarcted heart Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1046 - H1054. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Potapova, A. Plotnikov, Z. Lu, P. Danilo Jr, V. Valiunas, J. Qu, S. Doronin, J. Zuckerman, I. N. Shlapakova, J. Gao, et al. Human Mesenchymal Stem Cells as a Gene Delivery System to Create Cardiac Pacemakers Circ. Res., April 16, 2004; 94(7): 952 - 959. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Cerbai and A. Mugelli Angiotensin AT2 receptor: the younger sibling attracts attention Cardiovasc Res, April 1, 2004; 62(1): 7 - 8. [Full Text] [PDF]
|
|
|
|
|
|
R. Caballero, R. Gomez, I. Moreno, L. Nunez, T. Gonzalez, C. Arias, M. Guizy, C. Valenzuela, J. Tamargo, and E. Delpon Interaction of angiotensin II with the angiotensin type 2 receptor inhibits the cardiac transient outward potassium current Cardiovasc Res, April 1, 2004; 62(1): 86 - 95. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Valiunas, S. Doronin, L. Valiuniene, I. Potapova, J. Zuckerman, B. Walcott, R. B. Robinson, M. R. Rosen, P. R. Brink, and I. S. Cohen Human mesenchymal stem cells make cardiac connexins and form functional gap junctions J. Physiol., March 15, 2004; 555(3): 617 - 626. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shimoni, M. Chuang, E. D. Abel, and David. L. Severson Gender-dependent attenuation of cardiac potassium currents in type 2 diabetic db/db mice J. Physiol., March 1, 2004; 555(2): 345 - 354. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Rosen, O. Binah, and S. Marom Cardiac Memory and Cortical Memory: Do Learning Patterns in Neural Networks Impact on Cardiac Arrhythmias? Circulation, October 14, 2003; 108(15): 1784 - 1789. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. W. Patberg, A. N. Plotnikov, A. Quamina, R. Z. Gainullin, A. Rybin, P. Danilo Jr, L. S. Sun, and M. R. Rosen Cardiac Memory Is Associated With Decreased Levels of the Transcriptional Factor CREB Modulated by Angiotensin II and Calcium Circ. Res., September 5, 2003; 93(5): 472 - 478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. N. Plotnikov, H. Yu, J. C. Geller, R. Z. Gainullin, P. Chandra, K. W. Patberg, S. Friezema, P. Danilo Jr, I. S. Cohen, S. J. Feinmark, et al. Role of L-Type Calcium Channels in Pacing-Induced Short-Term and Long-Term Cardiac Memory in Canine Heart Circulation, June 10, 2003; 107(22): 2844 - 2849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-S. Wang and I. S Cohen Calcium channel heterogeneity in canine left ventricular myocytes J. Physiol., March 15, 2003; 547(3): 825 - 833. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Rosen The Electrocardiogram 100 Years Later: Electrical Insights Into Molecular Messages Circulation, October 22, 2002; 106(17): 2173 - 2179. [Full Text] [PDF]
|
|
|
|
|
|
Members of the Sicilian Gambit New Approaches to Antiarrhythmic Therapy, Part II: Emerging Therapeutic Applications of the Cell Biology of Cardiac Arrhythmias Circulation, December 11, 2001; 104(24): 2990 - 2994. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Members of the Sicilian Gambit New Approaches to Antiarrhythmic Therapy, Part I: Emerging Therapeutic Applications of the Cell Biology of Cardiac Arrhythmias Circulation, December 4, 2001; 104(23): 2865 - 2873. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Members of the Sicilian Gambit New approaches to antiarrhythmic therapy; emerging therapeutic applications of the cell biology of cardiac arrhythmias Eur. Heart J., December 1, 2001; 22(23): 2148 - 2163. [Abstract] [PDF]
|
|
|
|
|
|
Members of the Sicilian Gambit New approaches to antiarrhythmic therapy: emerging therapeutic applications of the cell biology of cardiac arrhythmias Cardiovasc Res, December 1, 2001; 52(3): 345 - 360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shimoni Inhibition of the formation or action of angiotensin II reverses attenuated K+ currents in type 1 and type 2 diabetes J. Physiol., November 15, 2001; 537(1): 83 - 92. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-P. Benitah, E. Perrier, A. M. Gomez, and G. Vassort Effects of aldosterone on transient outward K+ current density in rat ventricular myocytes J. Physiol., November 15, 2001; 537(1): 151 - 160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Rosati, Z. Pan, S. Lypen, H.-S. Wang, I. Cohen, J. E Dixon, and D. McKinnon Regulation of KChIP2 potassium channel {beta} subunit gene expression underlies the gradient of transient outward current in canine and human ventricle J. Physiol., May 15, 2001; 533(1): 119 - 125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K S Thorneloe, X F Liu, M P Walsh, and Y Shimoni Transmural differences in rat ventricular protein kinase C epsilon correlate with its functional regulation of a transient cardiac K+ current J. Physiol., May 15, 2001; 533(1): 145 - 154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nabauer Tuning Repolarization in the Heart : A Multitude of Potassium Channels and Regulatory Pathways Circ. Res., March 16, 2001; 88(5): 453 - 455. [Full Text] [PDF]
|
|
|
|
|
|
J. L. Greenstein, R. Wu, S. Po, G. F. Tomaselli, and R. L. Winslow Role of the Calcium-Independent Transient Outward Current Ito1 in Shaping Action Potential Morphology and Duration Circ. Res., November 24, 2000; 87(11): 1026 - 1033. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||