Potassium currents in ventricular myocytes from genetically
diabetic rats
Katsuharu
Tsuchida and
Hiroshi
Watajima
Research Center, Taisho Pharmaceutical Company, Ohmiya, Saitama 330, Japan
 |
ABSTRACT |
Our previous study demonstrated the longer
duration of action potential in ventricular myocytes from genetically
diabetic WBN/Kob rats without change in calcium channel
density compared with age-matched controls [Tsuchida, K., H. Watajima, and S. Otamo. Am. J. Physiol. 267 (Heart Circ.
Physiol. 36): H2280-H2289, 1994]. In the
present study we examined the alteration of potassium currents, especially transient outward current, in ventricular myocytes of
genetically diabetic WBN/Kob rats. WBN/Kob rats gradually develop hyperglycemia with aging and show some similarity to
non-insulin-dependent diabetes mellitus models, which differ from the
insulin-dependent streptozotocin-treated rat model. The density of the
intracellular calcium ion-independent transient outward current
(Ito) from 17- to 19-mo diabetic rat myocytes was significantly smaller than that from
age-matched control rat myocytes. In addition, the density of
Ito from 17- to
19-mo rat myocytes was significantly less than that from 2-mo rat
myocytes, suggesting that aging-induced alteration of
Ito was
accelerated by the diabetic state. The steady-state inactivation curves
of Ito, the
recovery from Ito
inactivation, and the other outward currents were not significantly
altered between diabetic myocytes and age-matched control myocytes. In conclusion, the prolonged duration of action potential from genetically diabetic rat myocytes is mainly due to the depressed
Ito.
cardiomyocytes; transient outward current
 |
INTRODUCTION |
IT HAS LONG BEEN KNOWN that patients with diabetes
mellitus have increased risk of mortality from cardiac failure that
cannot simply be explained in terms of atherosclerosis, hyperlipidemia, or hypertension. Many studies have been performed to investigate the
cardiac function of diabetic animals, and a variety of mechanical, electrophysiological, and biochemical abnormalities have been identified in the myocardium of diabetic animal models (7). Chemical-induced diabetic models, especially the streptozotocin (STZ)-induced diabetic model, are frequently used as a model for insulin-dependent diabetes mellitus (IDDM) to investigate these abnormalities. With use of this animal model, contractile abnormalities have been reported (7), and this dysfunction has been related to
biochemical changes such as the altered distribution of myosin isozymes
(4); a decrease in uptake of Ca2+
into sarcoplasmic reticulum (6) and sarcolemma (9); decreased activity
of
Na+-K+-adenosinetriphosphatase
(14),
Na+-H+
exchange (15), and
Na+-Ca2+
exchange (16) in the sarcolemmal membrane; and
Ca2+ binding capacity (20).
Abnormalities of electrophysiological phenomena have also been
demonstrated in STZ-induced diabetic rats. Ventricular and atrial
action potentials were prolonged when the measurement was done for a
relatively longer term after STZ injection (1, 15). The L-type calcium
current was not altered from 6 days to 2 mo (12, 17) but was decreased
from 5 to 7 mo (28), whereas the transient outward potassium current was decreased significantly from 6 days to 7 mo after STZ injection (12, 17, 24, 28). Our previous study using genetically diabetic rats
(WBN/Kob) demonstrated that the ventricular action potential duration
is prolonged (25). STZ-treated rats closely resemble the IDDM model,
except in a special case (23), whereas WBN/Kob rats show some
similarities with the non-insulin-dependent diabetes mellitus (NIDDM)
model. That is, male WBN/Kob rats have been reported to develop
hyperglycemia, glycosuria, polyuria, and glucose tolerance from ~9 mo
of age, with a gradual and moderate decrease in serum insulin levels
(19). The rats survive without the administration of insulin, in
contrast to Bio-Breeding rats, a genetic model of IDDM. The
pathological process progresses slowly in WBN/Kob rats. Much clinical
attention has been paid to NIDDM-induced cardiomyopathy (7, 23). We
have previously reported that the L-type
Ca2+ channel did not alter
significantly, although the response of the L-type
Ca2+ channel to
-adrenergic
stimulation decreased in WBN/Kob rats (25). In this study, we first
examined changes in the potassium currents, especially the transient
outward potassium current, in this strain of genetically diabetic rats.
 |
MATERIALS AND METHODS |
Animal model of diabetes.
A particular strain of Wistar-derived WBN rats has been maintained at
the Institute of Pathology, Bonn University (Bonn, Germany). Several of
these animals were brought to Japan by Dr. O. Kobori in 1976 and became
known as WBN/Kob rats. A colony of these rats is currently being
maintained at the Shizuoka Laboratory Animal Center (Shizuoka, Japan).
Male WBN/Kob rats of 17 to 19 mo of age and age-matched Wistar rats
(purchased from the Shizuoka Laboratory Animal Center) were used. The
main clinical sign of diabetes, glucosuria, was evidently detected at
~14 mo of age, after a marked glucose intolerance at 12 mo.
Thereafter, some animals developed hyperlipidemia and gradual
emaciation (19, 26). After purchase at 6 mo and until they were used in
the experiment, all rats were maintained at the Taisho Pharmaceutical
Animal Laboratory and were fed standard rat chow.
Cell preparation.
Single ventricular cells were isolated according to the methods
previously reported (25). Briefly, the rat was anesthetized with
pentobarbital sodium (50 mg/kg ip), and the heart was rapidly excised
and attached to a Langendorff perfusion apparatus. The heart was then
retrogradely perfused for 2-3 min with nominally calcium-free
Krebs-Henseleit solution equilibrated with 95%
O2-5% CO2 at 36°C. The
Krebs-Henseleit solution contained (in mM) 130 NaCl, 4.8 KCl, 1.2 MgSO4, 1.1 NaH2PO4,
25 NaHCO3, and 12.5 glucose. Enzymatic digestion was achieved by recirculating the perfusion apparatus with the calcium-free Krebs-Henseleit solution containing 40-170 U/ml collagenase (Yakult, Tokyo, Japan). The perfusion pressure was maintained at ~80 mmHg. Enzymatic perfusion was stopped after 15-30 min. The heart was then washed with Kraftbrühe
(KB) solution containing (in mM) 70 L-glutamic acid, 5 KCl, 20 taurine, 5 KH2PO4,
11 glucose, 5 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), and 0.5 ethylene glycol-bis (
-aminoethyl
ether)-N,N,N',N'-tetraacetic acid (EGTA) free acid. The ventricle was separated from the whole heart
and minced into small pieces. Cells were filtered and stored in KB
solution at 4°C before being used in the electrophysiological experiment. After storage for 3-6 h in KB solution, the cells were
taken into the experimental chamber, which was perfused with Ca2+-containing Tyrode solution
when the electrophysiological experiment was performed.
Electrophysiological recording.
Some cells were transferred to a recording chamber (0.3 ml vol) placed
on the stage of an inverted microscope (Diaphot TMD, Nikon, Tokyo,
Japan), and the chamber was perfused at a constant rate of 1-2
ml/min. Membrane currents were recorded using the whole cell
patch-clamp method described by Hamill et al. (8) by use of a
patch-clamp amplifier (CEZ-2300, Nihon Kohden) connected to pClamp
software program (Axon Instruments, Burlingame, CA) or an Atari Mega
ST4-operated EPC-9 patch-clamp system (Heka, Lambrecht, Germany). Patch
pipettes (2-4 M
) were fabricated using a puller (PP-83,
Narishige, Tokyo) and were heat polished (MF-83, Narishige). To record
transient outward current
(Ito), we
filled the pipettes with solution containing (in mM) 140 KCl, 2 MgCl2, 1 CaCl2, 10 HEPES, 11 EGTA, and 5 Na2ATP (pH ajusted to 7.2 with KOH). The extracellular mediums were standard Tyrode solution containing Co2+, to eliminate a
calcium ion current
(ICa), or a
Na+-free
Co2+-containing solution to
eliminate the tetrodotoxin (TTX)-sensitive Na+ current, the
Na+-activated
K+ current, and
ICa. The
composition of Na+-free solution
was (in mM) 135 choline chloride, 5.4 KCl, 1 MgCl2, 1.8 CaCl2, 10 HEPES, 10 glucose, and 3 CoCl2 (pH 7.4 with KOH). In some
experiments, 4-aminopyridine (4-AP; Sigma Chemical, St. Louis, MO) was
used to block
Ito, and TTX
(Sankyo, Tokyo, Japan) was used to block sodium ion current
(INa).

View larger version (38K):
[in this window]
[in a new window]
|
Fig. 1.
Representative outward currents recorded in single ventricular myocytes
isolated from diabetic (17-19 mo) and age-matched control rat
heart and in young adult (2 mo) normal rat ventricular myocytes.
Currents were elicited by applying a 300-ms depolarizing step in 10-mV
increments to +70 mV from a holding potential of 70 mV every 5 s. Effects of 5 mM 4-aminopyridine (4-AP) on the current elicited by a
test pulse to +70 mV from 70 mV are also represented. Six
families of current tracings are from different myocytes. Total cell
capacitances (pF) are as follows:
right (R) 170, left (L) 132 in 17- to 19-mo control
rats; R 153, L 186 in 17- to 19-mo diabetic rats; R 117, L 144 in 2-mo
rats.
|
|
Concerning the determination of cell membrane capacitance, the
procedure described below was used. Just after the patch was broken,
pulses with a duration of 50 ms, from
60 to
62 mV, were applied to the cell. The exponential components of the decaying current
were determined. Two time constants were obtained corresponding to the
electrode and membrane capacitance. The time constant of the electrode
was <0.02 ms, and the time constant of the membrane capacitance was
just under 2 ms. After the electrode capacitance was compensated for,
the capacitance of the membrane was calculated according to the
equation
where
Cm is the membrane capacitance,
Tc is the time
constant of the membrane capacitance,
Io is the maximum
capacitance current value,
Em is the
amplitude of the voltage step, and I is the steady-state current. The series resistance
(Rs) was
calulated as
which
ranged from ~4 to 10 M
. In some cases, membrane capacitance and
series resistance were determined electronically. Then membrane
capacitance was compensated for, and series resistance was reduced
maximally for the voltage-clamp experiments to examine the membrane
currents.
Data analysis.
Statistical significance was determined with the Student's
t-test for unpaired data or with the
repeated-measures analysis of variance test for multiple comparison. A
value of P < 0.05 was considered
significant.
 |
RESULTS AND DISCUSSION |
Plasma glucose level and clinical state.
Plasma glucose levels were 558 ± 16 (SE) mg/dl with 17- to 19-mo
WBN/Kob rats (n = 34), whereas plasma
glucose levels of age-matched control Wistar rats were within the range
of ~110-140 mg/dl. Almost all WBN/Kob rats showed glucosuria and
ruffled hair including transient alopecia and seemed sluggish at
17-19 mo.
Effects of genetic diabetes on
Ito.
Outward currents were recorded after blocking
ICa with 3 mM
Co2+ or
INa with
30-50 mM TTX, or changing extracellular NaCl with choline chloride and the intracellular
Ca2+-activated current with 11 mM
EGTA added in the pipettes. From a holding potential of
70 mV,
depolarizing pulses in 10-mV increments were applied from
60 mV
up to +70 mV. Ito
was elicited by depolarizing pulses more positive than
20 mV in
both normal and diabetic ventricular myocytes. Application of 5 mM 4-AP
suppressed Ito,
and the 4-AP-insensitive component of the outward current remained.
Figure 1 shows typical currents obtained from diabetic
(17-19 mo), age-matched control (17-19 mo), and young (2-mo)
rat ventricular myocytes.
Ito consists of
4-AP-sensitive and -insensitive components. The 4-AP-insensitive
Ito is reported
to be activated by increased intracellular calcium concentration
([Ca2+]i).
Because we used a pipette solution containing a relatively high
concentration of EGTA (11 mM), the
[Ca2+]i-dependent
activation of Ito
could be ruled out, thereby leaving only one component of
Ito, namely, the
4-AP-sensitive component shown in Fig. 1. Hereafter, we will refer only
to this component of
Ito. The
amplitude of Ito
was expressed as the difference in current between the peak current
amplitude and the terminal component of the current at the end of
depolarizing test pulses of 300-ms duration. The amplitude of
Ito is shown in
Fig. 2A.
The current density of the difference in current between peak and
300-ms terminal currents was significantly less in diabetic ventricular
myocytes than in the age-matched control myocytes. Apkon and Nerbonne
(2) described a slowly activating and inactivating
K+ current
(IK in their
terminology) in rat ventricular myocytes, which was sensitive to
external tetraethylammonium but not to 4-AP. Thus the terminal
component at the end of 300-ms pulses is considered to consist of two
different currents. One is the residual component of the slowly
inactivating Ito
at the end of 300-ms pulses, and the other is the 4-AP-insensitive
outward current. To determine the total
Ito as the 4-AP
sensitive current, the difference in current between the absence and
the presence of 5 mM 4-AP was obtained and shown in the inset of Fig.
2A. The density of the 4-AP-sensitive
current was also significantly less in the diabetic ventricular
myocytes than in the age-matched control myocytes. The decrease of
Ito density in
the genetically diabetic WBN/Kob rats is consistent with findings
reported in STZ-treated diabetic rats (12, 17, 28). We used aged rats
of 17-19 mo as controls, because WBN/Kob rats gradually develop
hyperglycemia with aging. We examined the influence of aging on
Ito as well. Wei
et al. (29) demonstrated that the action potential duration in the
senescent (24-mo) rat ventricular myocytes was longer than that in the
young adult (7-mo) rat myocytes. Other authors have reported similar
changes of action potential duration (3). Walker et al. (27)
demonstrated that
Ito was depressed
more markedly in the cardiac cells of the aged (24- to 25-mo) rat than in those of young adult (2- to 3-mo) rats. The current density of
Ito from 17- to
19-mo rat myocytes was significantly less than that from 2-mo rat
myocytes (Fig. 2A). The decay
process of Ito seemed to be fitted with biexponential curves with fast and slow time
constants (
f and
s, respectively). Because the
pulse duration was too short to determine
s correctly, we have presented
only
f. At +70 mV,
f was 32.8 ± 2.9 ms
(n = 21) in 17- to 19-mo control, 32.3 ± 1.2 ms (n = 19) in 17- to 19-mo
diabetic, and 33.4 ± 1.5 ms (n = 14)
in 2-mo normal rats. All values were not significantly different.
Possible values of
s seemed
roughly ten times longer than those of
f. The terminal current
amplitude at the end of 300-ms pulses is shown in Fig.
2B. The terminal component was not
altered in WBN/Kob rat myocytes compared with that in the age-matched
control rat myocytes. Jourdon and Feuvray (12) and Wang et al. (28)
described the significant decrease in this time-independent outward
current in the STZ-treated rat myocytes. The present result is
different from their results. In addition, the current amplitude of the
terminal component was not altered between examinations of 17- to 19-mo
rats and 2-mo rat myocytes (Fig.
2B).

View larger version (19K):
[in this window]
[in a new window]
|
Fig. 2.
Current-voltage relationships of transient outward current
(Ito) and
terminal components of the outward current in ventricular myocytes from
diabetic (17-19 mo) and age-matched control rats, and from young
adult (2 mo) rats. Amplitude of
Ito was measured
as the difference in current amplitude between the peak current
amplitude and the terminal current amplitude at the end of 300-ms test
pulses. A:
Ito;
B: terminal current. , Diabetic
myocytes (n = 23); , age-matched
control myocytes (n = 22); , young
adult myocytes (n = 14).
Inset a: voltage-clamp protocol;
inset b: 4-AP-sensitive current induced by a
300-ms test pulse to +70 mV from 70 mV. Control,
n = 16; WBN/Kob,
n = 16. Values are means ± SE.
* P < 0.05 vs. age-matched
control (17-19 mo) for diabetic rat myocytes, and
+ P < 0.05 vs. young
adult (2 mo) rat for aged (17 - 19 mo) rat myocytes at
each membrane potential (Student's
t-test). A supplemental explanation:
repeated-measures analysis of variance test showed that current
(Ito)-voltage
relationships were significantly (P < 0.05) different between diabetic rats and age-matched control rats.
Current
(Ito)-voltage
relationships were also significantly
(P < 0.05) different between 2-mo
rats and 17- to 19-mo rats.
|
|
Modification of inactivation kinetics of
Ito.
In this series of experiments,
Ito was also
expressed as the change in current between the peak amplitude and the
terminal component of the current. The steady-state inactivation
kinetics of Ito
were compared between the diabetic myocytes and the age-matched control
myocytes. A test pulse to +70 mV (duration 300 ms) was preceded by 1-s
conditioning prepulses to various potentials (from
80 mV to 0 mV). The relative amplitude of
Ito (normalized
by taking the value at
80 mV as unity) was plotted against
conditioning potentials, and the data were fitted by the following
Boltzmann distribution function with a least squares method
where
I/Imax
is the relative amplitude of
Ito,
Vm is the
conditioning voltage,
V0.5 is the
voltage of half-inactivation, and k is
the slope factor. The values of
V0.5 and
k were
43.9 ± 2.1 and 7.7 ± 0.54 mV for age-matched control myocytes, and
47.3 ± 3.1 and
6.9 ± 0.38 mV for diabetic myocytes, respectively (Fig.
3). The value of
V0.5 was not
altered significantly between the two groups. The value of
k was not significantly different between the two groups, either. Furthermore, the values of
V0.5 and
k were
51.6 ± 2.9 and 6.6 ± 0.65 mV for 2-mo rat myocytes. The
V0.5 value in
2-mo rat myocytes shifted several mV negatively, and significantly,
compared with 17- to 19-mo normal rat myocytes, without any change in
k.

View larger version (22K):
[in this window]
[in a new window]
|
Fig. 3.
Steady-state inactivation curves of
Ito in diabetic
(17-19 mo) and age-matched controls and young adult (2 mo) rat
myocytes.
I/Imax,
relative amplitude of
Ito. ,
Diabetic (n = 18) myocytes; ,
controls (n = 16); , young adult
myocytes (n = 10). Values are
means ± SE. Inset:
voltage-clamp protocol.
|
|
The time course of recovery from inactivation of
Ito was also
compared between the diabetic and age-matched control rat myocytes by
use of a double-pulse method. Double pulses to +70 mV from a holding
potential of
70 mV (each pulse duration 300 ms) were applied
every 10 s, while the interpulse interval was increased from 10 ms to 1 s. The relative amplitude of
Ito induced by
the second pulse vs. the
Ito amplitude
induced by the first pulse was plotted against the interpulse interval.
Recovery from its inactivation was not different between diabetic
myocytes and age-matched control rat myocytes, as shown in Fig.
4. In addition, the recovery of
Ito was not
altered in normal 17- to 19-mo rat myocytes compared with 2-mo rat
myocytes. The previous studies showed that the kinetics of steady-state
inactivation and recovery kinetics from inactivation were not altered
in STZ-treated rats with short treatment periods of 1.5-2 mo (12)
but were slowed in long-term (5- to 7-mo) STZ-treated rats (28). It
seems that the kinetic changes of
Ito may occur in
the severely diseased myocardium with long-term STZ-induced diabetes.

View larger version (12K):
[in this window]
[in a new window]
|
Fig. 4.
Time course of recovery from inactivation of
Ito in
ventricular myocytes from diabetic (n = 18), age-matched (17-19 mo) controls
(n = 17), and young adult (2 mo) myocytes (n = 12). Double pulses
(each duration 300 ms) from 70 mV to +70 mV were applied at
varying interpulse intervals (from 10 ms to 1 s) every 10 s. ,
Diabetic myocytes; , age-matched control myocytes; , young adult
myocytes. Values are means ± SE.
Inset: voltage-clamp protocol.
|
|
Effects of diabetes on inward rectifying current.
The current amplitudes, elicited by hyper- and depolarizing steps from
70 mV to up to
10 to about
110 mV, were not
different between diabetic rat myocytes and age-matched
control rat myocytes (Fig. 5). Furthermore,
the terminal component of the outward current elicited by depolarizing
test pulses up to ~0 mV from a holding potential of
70 mV was
not altered in diabetic rat myocytes compared with age-matched control
myocytes (Fig. 2B). These results
suggest that the inward rectifying potassium current
(IK1) was not
altered in the diabetic state. No alteration in the
IK1 has also been demonstrated by other authors in STZ-treated diabetic rats (12, 17,
20), whereas reduced
IK1 was reported
in other diseased cardiac myocytes (13).

View larger version (20K):
[in this window]
[in a new window]
|
Fig. 5.
Inward rectifying potassium current density in ventricular myocytes
from diabetic and age-matched (17-19 mo) control and young adult
(2 mo) rats. Steady-state inward current measured at end of 1-s
duration of hyperpolarizing test pulses at 10 mV increased voltage
steps from a holding potential of 70 mV to 10 up to
110 mV. , Diabetic (n = 15);
, age-matched (17-19 mo) control
(n = 13); , young adult (2 mo)
(n = 10) myocytes. Values are means ± SE. Inset: voltage-clamp
protocol.
|
|
Summary of results and significance of the decrease in
Ito.
The present study has, first of all, demonstrated that the current
density of Ito in
ventricular myocytes isolated from genetically diabetic rats sharing
the characteristics with NIDDM was significantly less than that from
17- to 19-mo-old matched control rats. The current density of
Ito from aged
(17- to 19-mo) rats was significantly less than that from young adult
(2-mo) rats. Thus the
Ito density was
reduced by aging, and the reduction was further accelerated by a
diabetic state.
Ito is considered
to be one of the most important repolarizing currents in rat myocytes
(11). The present study indicates that the lower
Ito density, but
not kinetic changes of the
Ito, may be
responsible for the longer duration of action potential in WBN/Kob
rats, as already shown in our previous study (25). Shimoni et al. (24)
demonstrated that the diabetic state exerted differential effects on
the Ito in
epicardial and endocardial myocytes from the left ventricle of
short-term (6- to 7-day) STZ-treated rats. Such regional differences
were not a focus of the present study but may be important in
understanding the pathophysiology of the diabetic heart more
thoroughly. We previously demonstrated that the L-type
Ca2+ current was not altered in
19-mo WBN/Kob rat ventricular myocytes in vitro under the condition of
the inhibition of the potassium current by use of the whole-cell
patch-clamp technique (25). However, the in situ ventricular myocytes
exist in circumstances without any artificial restriction of the
potassium current. The action potential duration of rat ventricular
cells is short enough to allow maximum
Ca2+ influx from extracellular
medium, so that the lengthening of the action potential duration due to
the inhibition of
Ito may lead to
increased Ca2+ influx and
subsequent enhancement of Ca2+
release from intracellular stores, resulting in some compensatory effects on the decreased contractile force of diabetic myocardium (10,
21). Our previous study (25) indicated that WBN/Kob rats demonstrated
decreased contractile force in situ. Thus the compensation resulting
from lengthening the action potential duration was not considered to be
sufficient for many reasons (see the introductory section of this
paper) other than the decreased
ICa being
responsible for the decreased contractile force in WBN/Kob rats.
Recently, Xu et al. (30) demonstrated that the decreased
Ito density may
be caused by the decrease in cellular glucose metabolism in ventricular
myocytes of short-term (14 days to 1 mo) STZ-treated rats (30). Such
biochemical changes may be involved in downregulating Ito in genetic
NIDDM myocytes. The lower density of the
Ito observed in
the diabetic ventricular myocytes may result from a decrease in the
number of channels. Concerning a molecular basis of the decreased
Ito in diabetic
myocytes, because Dixon et al. (5) demonstrated that both the
ventricular potassium (Kv) 4.2 and Kv
4.3 channels were likely to contribute to the
Ito in rat heart, the alteration of the expression of these genes may account for the
altered Ito
density in WBN/Kob rats. The molecular alterations in the channel
proteins remain to be elucidated as an interesting problem.
 |
FOOTNOTES |
Address for reprint requests: K. Tsuchida, Research Center, Taisho
Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Ohmiya, Saitama 330, Japan.
Received 25 February 1997; accepted in final form 4 June 1997.
 |
REFERENCES |
1.
Aomine, M.,
S. Nobe,
and
M. Arita.
Increased susceptibility to hypoxia of prolonged action potential duration in ventricular papillary muscles from diabetic rats.
Diabetes
39:
1485-1489,
1990[Abstract].
2.
Apkon, M.,
and
J. M. Nerbonne.
Characterization of two distinct depolarization-activated K+ currents in isolated adult rat ventricular myocytes.
J. Gen. Physiol.
97:
973-1010,
1991[Abstract].
3.
Capasso, J. M.,
A. Malhotra,
R. M. Remily,
J. Scheuer,
and
E. H. Sonnenblick.
Effects of age on mechanical and electrical performance of rat myocardium.
Am. J. Physiol.
245 (Heart Circ. Physiol. 14):
H72-H81,
1983[Medline].
4.
Dillmann, W. H.
Diabetes mellitus induces changes in cardiac myosin in the rat.
Diabetes
29:
579-582,
1980[Medline].
5.
Dixon, J. E.,
W. Shi,
H.-S. Wang,
C. MacDonald,
H. Yu,
R. S. Wymore,
I. S. Cohen,
and
D. McKinnon.
Role of the Kv 4.3 K+ channel in ventricular muscle: a molecular correlate for the transient outward current.
Circ. Res.
79:
659-668,
1996[Abstract/Free Full Text].
6.
Fein, F. S.,
I. B. Kornstein,
J. E. Strobeck,
J. M. Capasso,
and
E. H. Sonnenblick.
Altered myocardial mechanics in diabetic rats.
Circ. Res.
47:
922-933,
1980[Abstract].
7.
Gøtzsche, O.
Myocardial cell dysfunction in diabetics mellitus. A review of clinical and experimental studies.
Diabetes
35:
1158-1162,
1986[Abstract].
8.
Hamill, O. P.,
A. Marty,
E. Neher,
B. Sakmann,
and
F. J. Sigworth.
Improved patch-clamp technique for high-resolution current recording from cells and cell-free membrane patches.
Pflügers Arch.
391:
85-100,
1981[Medline].
9.
Heyliger, C. E.,
A. Prakash,
and
J. H. McNeill.
Alterations in cardiac sarcolemmal Ca2+ pump activity during diabetes mellitus.
Am. J. Physiol.
252 (Heart Circ. Physiol. 21):
H540-H544,
1987[Abstract/Free Full Text].
10.
Isenberg, G.,
U. Klockner,
D. Mascher,
and
U. Ravens.
Changes in contractility and membrane currents as studied with a single patch-electrode whole-cell clamp technique.
In: Electrophysiology of Single Cardiac Cells, edited by D. Noble,
and T. Powell. London: Academic, 1987, p. 26-67.
11.
Josephson, I. R.,
J. Sanchez-Chapula,
and
A. M. Brown.
Early outward current in rat single ventricular cells.
Circ. Res.
54:
157-162,
1984[Abstract].
12.
Jourdon, P.,
and
D. Feuvray.
Calcium and potassium currents in ventricular myocytes isolated from diabetic rats.
J. Physiol. Lond.
470:
411-429,
1993[Abstract].
13.
Kääb, S.,
B. Nuss,
N. Chiamvimonvat,
B. O'Rourke,
P. H. Pak,
D. A. Kass,
E. Marban,
and
G. F. Tomaselli.
Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure.
Circ. Res.
78:
262-273,
1996[Abstract/Free Full Text].
14.
Ku, D. D.,
and
B. M. Sellers.
Effects of streptozotocin diabetes and insulin treatment on myocardial sodium pump and contractility of the rat heart.
J. Pharmacol. Exp. Ther.
222:
395-400,
1982[Medline].
15.
Lagadic-Gossmann, D.,
J. M. Chesnais,
and
D. Feuvray.
Intracellular pH regulation in papillary muscle cells from streptozotocin diabetic rats: an ion sensitive microelectrode study.
Pflügers Arch.
412:
613-617,
1988[Medline].
16.
Legaye, F.,
P. Biegelman,
E. Deroubaix,
and
E. Coraboeuf.
Effect of 3,5,3'-triiodothyronine treatment on cardiac action potential of streptozotocin-induced diabetic rat.
Life Sci.
42:
2269-2274,
1988[Medline].
17.
Magyar, J.,
Z. Rusznak,
P. Szentesi,
G. Szucs,
and
L. Kovacs.
Action potentials and potassium currents in rat ventricular muscle during experimental diabetes.
J. Mol. Cell. Cardiol.
24:
841-853,
1992[Medline].
18.
Makino, N.,
K. S. Dhalla,
V. Elimban,
and
N. S. Dhalla.
Sarcolemmal Ca2+ transport in streptozotocin-induced diabetic cardiomyopathy in rats.
Am. J. Physiol.
253 (Endocrinol. Metab. 16):
E202-E207,
1987[Abstract/Free Full Text].
19.
Nakama, K.,
K. Shichinohe,
K. Kobayashi,
K. Naito,
O. Uchida,
K. Yasuhara,
and
M. Tobe.
Spontaneous diabetes-like syndrome in WBN/Kob rats.
Acta Diabet. Lat.
22:
335-342,
1985[Medline].
20.
Nobe, S.,
M. Aomine,
M. Arita,
S. Ito,
and
R. Takaki.
Chronic diabetes mellitus prolongs action potential duration of rat ventricular muscles: circumstantial evidence for impaired Ca2+ channel.
Cardiovasc. Res.
24:
381-389,
1990[Medline].
21.
Noda, N.,
H. Hayashi,
H. Miyata,
S. Suzuki,
A. Kobayashi,
and
N. Yamazaki.
Cytosolic Ca2+ concentration and pH of rat myocytes during metabolic inhibition.
J. Mol. Cell. Cardiol.
24:
435-445,
1992[Medline].
22.
Pierce, G. N.,
J. B. Kutryk,
and
N. S. Dhalla.
Alterations in Ca2+ binding by and composition of the cardiac sarcolemmal membrane in chronic diabetes.
Proc. Natl. Acad. Sci. USA
80:
5412-5416,
1983[Abstract].
23.
Schaffer, S. W.,
B. H. Tan,
and
G. L. Wilson.
Development of a cardiomyopathy in a model of noninsulin-dependent diabetes.
Am. J. Physiol.
248 (Heart Circ. Physiol. 17):
H179-H185,
1985[Medline].
24.
Shimoni, Y.,
D. Severson,
and
W. Giles.
Thyroid status and diabetes modulate regional differences in potassium currents in rat ventricle.
J. Physiol. Lond.
488:
673-688,
1995[Abstract].
25.
Tsuchida, K.,
H. Watajima,
and
S. Otomo.
Calcium current in rat diabetic ventricular myocytes.
Am. J. Physiol.
267 (Heart Circ. Physiol. 36):
H2280-H2289,
1994[Abstract/Free Full Text].
26.
Tsuchitani, M.,
T. Saegusa,
I. Narama,
T. Nishikawa,
and
T. Gonda.
A new diabetic strain of rat (WBN/Kob).
Lab. Anim.
19:
200-207,
1985[Medline].
27.
Walker, K. E.,
E. G. Lakatta,
and
S. R. Houser.
Age associated changes in membrane currents in rat ventricular myocytes.
Cardiovasc. Res.
27:
1968-1977,
1993[Medline].
28.
Wang, D. W.,
T. Kiyosue,
S. Shigematsu,
and
M. Arita.
Abnormalities of K+ and Ca2+ currents in ventricular myocytes from rats with chronic diabetes.
Am. J. Physiol.
269 (Heart Circ. Physiol. 38):
H1288-H1296,
1995[Abstract/Free Full Text].
29.
Wei, J. Y.,
H. A. Spurgeon,
and
E. G. Lakatta.
Excitation-contraction in rat myocardium: alterations with adult aging.
Am. J. Physiol.
246 (Heart Circ. Physiol. 15):
H784-H791,
1984[Medline].
30.
Xu, Z.,
K. P. Patel,
and
G. J. Rozanski.
Metabolic basis of decreased transient outward K+ current in ventricular myocytes from diabetic rats.
Am. J. Physiol.
271 (Heart Circ. Physiol. 40):
H2190-H2196,
1996[Abstract/Free Full Text].
AJP Endocrinol Metab 273(4):E695-E700
0193-1849/97 $5.00
Copyright © 1997 the American Physiological Society