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1 Main Line Health Heart Center, Wynnewood 19096; 2 Department of Pharmacology, Merck Research Laboratories, West Point 19486; and 3 Jefferson Medical College, Philadelphia, Pennsylvania 19107
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Excessive action potential (AP) prolongation and early afterdepolarizations (EAD) are triggers of malignant ventricular arrhythmias. A slowly activating delayed rectifier K+ current (IKs) is important for repolarization of ventricular AP. We examined the effects of IKs activation by a new benzodiazepine (L3) on the AP of control, dofetilide-treated, and hypertrophied rabbit ventricular myocytes. In both control and hypertrophied myocytes, L3 activated IKs via a negative shift in the voltage dependence of activation and a slowing of deactivation. L3 had no effect on L-type Ca2+ current or other cardiac K+ currents tested. L3 shortened AP of control, dofetilide-treated, and hypertrophied myocytes more at 0.5 than 2 Hz. Selective activation of IKs by L3 attenuates prolonged AP and eliminated EAD induced by rapidly activating delayed rectifier K+ current inhibition in control myocytes at 0.5 Hz and spontaneous EAD in hypertrophied myocytes at 0.2 Hz. Pharmacological activation of IKs is a promising new strategy to suppress arrhythmias resulting from excessive AP prolongation in patients with certain forms of long QT syndrome or cardiac hypertrophy and failure.
action potential; ion channel; early afterdepolarization; arrhythmia
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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CARDIAC HYPERTROPHY AND FAILURE cause >200,000 deaths annually in the United States. As many as 50% are sudden and due to the onset of polymorphic ventricular tachycardia (VT) or torsades de pointes associated with long QT syndrome (LQTS) (7). LQTS can be congenital or acquired. Congenital LQTS most commonly develops from mutations in genes encoding delayed rectifier K+ channels that cause functional decreases in repolarizing K+ currents (4, 12, 27). Acquired LQTS is associated with administration of certain antiarrhythmics, antihistamines, antibiotics, and other drugs (http://georgetowncert.org/qtdrugs_torsades.asp). Many of these agents can cause excessive action potential (AP) prolongation via inhibition of the rapidly activating delayed rectifier K+ current (IKr), resulting in a specific form of acquired LQTS (LQT2) (20). Heart failure may also be considered a commonly acquired form of LQTS (16). Functional downregulation of K+ currents is a recurring theme in hypertrophied and failing ventricular myocardium (26).
At the cellular level, excessive AP prolongation and unstable repolarization is consistently observed in ventricular myocytes from hypertrophied and failing hearts, animal models or patients with LQTS (2, 7, 31). Early afterdepolarizations (EAD) occur in the setting of prolonged AP due commonly to diminished K+ currents or in some cases to slowly or noninactivating components of Ca2+ or Na+ currents. EAD have been identified as the triggering mechanisms for polymorphic VT (2, 4, 35). Ventricular myocytes from hypertrophied and failing hearts are highly susceptible to EAD (3, 16, 17, 31). No effective or safe drugs are available for treatment of acquired LQT2 or ventricular arrhythmias associated with cardiac hypertrophy and failure.
We hypothesized that selective activation of the slowly activating delayed rectifier K+ current (IKs) could provide an effective antiarrhythmic action in certain forms of LQTS and heart failure. Recently, we (22) identified a new benzodiazepine (L3), a selective activator of IKs, which shortened AP of guinea pig ventricular myocytes. In this study of rabbits, we investigated whether L3-induced activation of IKs could abbreviate AP and suppress EAD resulting from IKr inhibition in acquired LQT2 or diminished IKs in left ventricular (LV) hypertrophy (LVH).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental animals. Male New Zealand White rabbits (1.4-2.0 kg) underwent unilateral nephrectomy and contralateral renovascular banding to produce LVH, as reported previously (19). Banded rabbits were studied 3 mo after surgery when documented LVH had developed. Data were collected from 15 control and 9 LVH rabbits.
Myocyte isolation. Single ventricular myocytes were isolated using a method described previously (19). After enzyme perfusion, a thin layer (<1.5 mm) of tissue was dissected from the epicardial (Epi) and endocardial (Endo) surface of the LV free wall (excluding the extreme apex and base) and myocytes were dispersed.
AP recording.
APs were recorded from Epi and Endo myocytes using standard
microelectrodes (25-40 M
) filled with 3 M KCl. Cells were
superfused with a solution containing (in mM) 137 NaCl, 5 KCl, 1 MgCl2, 2 CaCl2, 10 glucose, and 10 HEPES, pH
7.4, at 36 ± 0.3°C. AP were recorded at steady state using
various stimulus frequencies (0.2, 0.5 and 2 Hz). AP duration (APD) was
measured at 90% repolarization (APD90). Because of the
beat-to-beat variation of APD, especially at low frequencies,
APD90 was averaged from 10 consecutive APs.
Membrane current recording.
Membrane ionic currents were recorded at 36 ± 0.5°C using the
whole cell patch-clamp technique. The following five solutions were
used, composed of (in mM): 1) IKs and
IKr pipette: 119 K-gluconate, 15 KCl, 3.2 MgCl2, 5 HEPES, 5 EGTA, and 5 K2ATP, pH 7.2 (electrode resistance = 3-4 M); 2)
IKs bath: 132 NaCl, 2 KCl, 1.8 CaCl2, 1.2 MgCl2, 10 HEPES, 10 glucose, 1 µM
dofetilide, and 0.6 µM nisoldipine, pH 7.2; 3)
IKr bath: 132 NaCl, 5 KCl, 1.2 MgCl2, 10 HEPES, 10 glucose, 0.4 µM nisoldipine, and 0.1 µM L-768673, a specific IKs blocker
(32), pH 7.2; 4) L-type Ca2+
channel current (ICa,L) pipette: 151 CsOH, 10 L-aspartic acid, 20 taurine, 20 tetraethylammonium
chloride, 5 glucose, 10 EGTA, pH 7.5 with
H3PO4, 5 MgATP and 0.4 Na2GTP were
added before use, final pH 7.3 (electrode resistance 1-2 M);
and 5) ICa,L bath: 140 NaCl, 5 CsCl,
1 MgCl2, 2 CaCl2, 10 glucose, and 10 HEPES, pH
7.4. Series resistance was compensated electronically 70-80%. Liquid junction potential was compensated in the bath but not under
whole cell conditions.
40
mV to test potentials (Vt) of 20 to +60 mV in
20-mV increments (32). Isochronal activation curves for
IKs were determined from peak tail current
amplitudes during return to a Vh of 40 mV
after 5-s test pulses. Tail currents (I) were normalized to
the maximal tail current (Imax) obtained after a
step to Vt of +70 mV. A Boltzmann function,
I/Imax = 1/{1 + exp
[(V0.5 V)/k]},
where V0.5 is the half-maximal activation potential and k is the slope factor, was fit to the data.
Current-voltage (I-V) relations were plotted for
averaged data normalized to cell capacitance. A second-order
exponential function was fit to the deactivating tail current on return
to 40 mV after a 5-s test pulse to +30 mV to derive the time
constants of IKs deactivation.
IKr was induced by 500-ms pulses to
Vt of 10 mV from a Vh
of 50 mV. Six consecutive pulses were delivered at 0.2 Hz and the
current traces were averaged. IKr was quantified
as dofetilide-sensitive tail current. ICa,L was
recorded with 180-ms test pulses applied at a 5-s interpulse interval
from a Vh of 40 mV to
Vt of 30 to +50 mV in 10-mV increments.
Data analysis. Data are expressed as means ± SE. Statistical analyses were performed with the use of Prism version 2.0 software (GraphPad). A paired t-test was used to compare control and L3 treatment means. A two-way analysis of variance was used to compare means involving two different categorical variables. P < 0.05 was considered statistically significant.
Drugs. L3 was synthesized at Merck Research Laboratories (West Point, PA), as previously described (22). Dofetilide and nisoldipine were gifts from Pfizer and Bayer, respectively.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The effects of L3 on IKs in ventricular
myocytes of control rabbits are shown in Fig.
1. L3 throughout these studies was tested at its maximally effective concentration of 1 µM unless otherwise noted (22). Compared with control (Fig. 1A), L3
increased IKs amplitude and slowed deactivation
(Fig. 1B). L3 increased IKs significantly at all Vt (Fig. 1D). At
a Vt of +60 mV, L3 increased IKs density from 2.31 ± 0.35 to 3.05 ± 0.46 pA/pF (n = 10). Percent increases in
IKs declined with increasing membrane potential, 286 ± 20% at 20 mV versus 32 ± 2% at +60 mV
(n = 10, Fig. 1E). L3 shifted the midpoint
(V0.5) of the voltage dependence of
IKs activation by 17.6 mV (Fig.
1F). In control, deactivation of IKs
was best described by a second-order exponential function. L3 increased
the fast (
f) and slow (s) time constants
of IKs deactivation from 95 ± 7 to
116 ± 14 ms (n = 6, not significant) and from
279 ± 25 to 712 ± 127 ms (n = 6, P < 0.05), respectively.
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Figure 1C shows the ratio of IKs in
the presence of L3 to the control for a test pulse to +60 mV. During
the test pulse, L3 increased activating IKs by a
constant ratio of ~1.4 for the entire duration of the pulse,
analogous to the increase in current density measured at the end of the
pulse. On repolarization to 40 mV, the initial deactivating tail
current is increased to a degree similar to that during the pulse. More
importantly, however, because L3 slowed IKs
deactivation, the relative increase in IKs was
greater at later times in the deactivation process, such that at 1 s after repolarization, the relative current was increased by
~10-fold.
L3 had no effect on ICa,L at all
Vt. There was also no evidence for use-dependent
block of ICa,L during repetitive 500-ms pulses
from a Vh of 40 mV to a
Vt of +20 mV at 0.5 Hz (data not shown). L3
reduced IKr tail current slightly but not
significantly from 86 ± 9 to 82 ± 10 pA (n = 6), and had no significant effect on inward rectifier K+
current or transient outward K+ current (data not shown).
Thus, by all of these measures, L3 was a selective activator of
IKs.
L3 concentration dependently shortened AP in rabbit control ventricular
myocytes (Fig. 2). L3 (1 µM) decreased
APD90 at 0.5 and 2 Hz by 23 ± 2% and 17 ± 2%
in Epi and by 21 ± 2% and 14 ± 2% in Endo, respectively
(n = 8). Percent decreases in APD90 were similar between Epi and Endo myocytes, but were more pronounced at 0.5 than at 2 Hz.
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L3 attenuated AP prolongation and eliminated EAD induced by the
specific IKr blocker dofetilide in myocytes
isolated from control rabbits (Fig. 3).
At a stimulus frequency of 0.5 Hz, 0.1 µM dofetilide induced EAD in 4 of 11 Endo myocytes. L3 eliminated EAD in all four cells in the
continuous presence of 0.1 µM dofetilide (Fig. 3A). The
effects of L3 were reversible; e.g., EAD reappeared during washout of
L3 (data not shown). In the presence of 0.1 µM dofetilide, L3
decreased APD90 from 315 ± 41 to 245 ± 32 ms in
Epi myocytes and 627 ± 135 to 388 ± 70 ms in Endo myocytes at 0.5 Hz (n = 8). L3 effects on APD were frequency
dependent. L3 decreased APD90 by 15 ± 1% and 13 ± 1% at 2 Hz and by 24 ± 2% and 35 ± 3% at 0.5 Hz in
Epi and Endo, respectively (n = 8). AP prolonged by 0.1 µM dofetilide in myocytes from both Epi and Endo were shortened to a
lesser extent at 2 Hz than 0.5 Hz by L3. In the presence of dofetilide,
L3 decreased APD90 more in Endo (239 ± 69 ms) than
Epi myocytes (70 ± 11 ms) at 0.5 Hz (n = 8, P < 0.05).
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Three months after renal artery banding, rabbits developed LVH with
characteristic changes. LVH significantly increased the heart
weight-to-body weight ratio from 2.10 ± 0.04 (n = 15) to 2.53 ± 0.07 g/kg (n = 9, P < 0.05) and myocyte size, measured as cell membrane capacitance, from
158 ± 7 (n = 20) to 200 ± 12 pF
(n = 16, P < 0.05). Consistent with
our previous findings (32), IKs
density of rabbit LVH myocytes was significantly lower than that of
controls, 1.15 ± 0.21 versus 2.31 ± 0.35 pA/pF
(n = 10, P < 0.05). L3 had similar
effects on IKs of myocytes from both control and
LVH rabbits (Figs. 1D and 4A). At a
Vt of +60 mV, L3 increased
IKs density from 2.31 ± 0.35 to 3.05 ± 0.46 pA/pF and from 1.15 ± 0.21 to 1.51 ± 0.26 pA/pF,
respectively (n = 10). L3 increased
IKs by 264 ± 9% at 20 mV and 34 ± 4% at +60 mV in myocytes from LVH rabbits (n = 10, Fig. 4B). L3 shifted the
midpoint (V0.5) of the voltage dependence of
IKs activation in LVH rabbits by 19.0 mV (Fig.
4C).
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As observed previously (32), APD90 of Epi and
Endo ventricular myocytes in LVH rabbits was increased by 21% and 22%
at 2 Hz, respectively, compared with controls. At 0.5 Hz,
APD90 increased from 175 ± 15 to 212 ± 27 ms by
LVH in Epi and from 231 ± 18 to 296 ± 35 ms in Endo
myocytes, respectively (n 
11). Spontaneous EAD were
recorded in 3 of 13 myocytes from Endo of LVH rabbits at a stimulus
frequency of 0.2 Hz. L3 eliminated EAD in all three cells (Fig.
5A). In LVH myocytes, 1 µM
L3 decreased APD90 by 19 ± 2% and 13 ± 1% in
Epi and by 17 ± 2% and 13 ± 1% in Endo at 0.5 and 2 Hz,
respectively (n = 8). Percent decreases of
APD90 by L3 were similar between Epi and Endo at both 0.5 and 2 Hz. However, L3 decreased APD90 more at 0.5 Hz than
at 2 Hz.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study provides the first direct evidence that IKs activation can be useful in reversing excessive AP prolongation and suppressing arrhythmogenic EAD in certain forms of LQTS. We examined this utility in rabbit models of acquired LQTS using the selective activator of IKs, L3, described previously in detail (22). In a model of LQT2, IKr inhibition with dofetilide produced typical reverse frequency-dependent increases in APD and EAD (25). In a model of LVH induced by renovascular hypertension, APD were prolonged, spontaneous EAD occurred in 23% of Endo myocytes at 0.2 Hz, and IKs density was significantly reduced, consistent with our previous findings (32). These profiles of abnormal repolarization reflect deficiencies in two major repolarizing currents, IKr and IKs, respectively.
More importantly, in control, dofetilide-treated, and LVH myocytes, L3 shortened APD in a concentration-dependent manner and eliminated EAD in the latter two conditions. AP mapping across the LV free wall using arterially perfused wedge preparations shows that Endo has the longest and Epi the shortest APD in both control and LVH rabbits (33). Across the LV free wall, there is a gradual increase in APD from the Epi side to the Endo side. This differs from the canine left ventricle where the longest APD is recorded in subendocardium (M cells) (34). L3 decreased APD to a similar degree in Epi and Endo myocytes in both control and LVH (Fig. 2B and 5C), indicating that IKs activation by L3 in rabbits should not increase transmural dispersion of repolarization. In dofetilide-treated myocytes, L3 decreased APD more significantly in Endo than Epi at 0.5 Hz, due partly to elimination of EAD in Endo. Thus, in acquired LQT2 or abnormally prolonged repolarization due to IKr inhibition, IKs activation should actually decrease transmural dispersion of repolarization.
L3 decreased APD more at 0.5 Hz than 2 Hz in control, dofetilide-treated, and LVH myocytes. Because excessive AP prolongation, EAD, and torsades de pointes are associated with bradycardia, this characteristic of L3 could be particularly beneficial. Because of the complicated interaction of many time and voltage-dependent currents in controlling AP morphology, it is oversimplified to extrapolate changes in a single current to effects on APD. Nevertheless, the L3-induced slowing of deactivation may provide a basis for the greater shortening of APD observed at slower rates. Normally, due to its slow deactivation, IKs can accumulate more at higher frequencies and thereby contribute to the rate-dependent shortening of APD (11, 13, 24). L3 slows IKs deactivation and increases relative deactivating current more at later times or longer intervals (Fig. 1C). The larger relative increases in deactivating IKs at longer intervals may lead to greater than normal accumulation at the slower rates and explain the greater decreases in APD by L3 at 0.5 Hz than at 2 Hz. However, the mechanism underlying the frequency-dependent effects of L3 on APD still requires further study.
L3 concentration dependently activated IKs and
shortened APD in guinea pig ventricular myocytes (22). In
this study, L3 effects on rabbit IKs were
studied at a maximally effective concentration of 1 µM as determined
previously for the guinea pig. L3 increased IKs
in rabbit via a negative shift in the voltage-dependence of activation
and a slowing of deactivation. L3 shifted the
V0.5 of rabbit IKs
activation by 17.6 mV in control and by 19.0 mV in LVH, comparable
to the shift of 24 mV found previously for the guinea pig. This shift
accounts for the larger percent increases of IKs
at more negative Vt (Figs. 1E and
4B). Deactivation of IKs was best
described by a second-order exponential function. L3 increased both
f (22%) and s (155%) of deactivation of
rabbit IKs, consistent with the changes in the
guinea pig (70% and 190%, respectively).
Our experimental results indicate that L3 (up to 1 µM) is a selective activator of IKs in rabbit ventricular myocytes. L3 also slows deactivation of IKs. These selective actions on the gating of IKs are likely the predominant (if not only) mechanisms underlying the APD shortening and EAD elimination by L3. Both the negative shift in the voltage dependence of activation and the slowing of deactivation can increase the contribution of IKs to AP repolarization.
A reduction of repolarizing K+ currents in LQTS and hypertrophied hearts has been widely observed. Reductions in the density of the transient outward K+ current and the inward rectifier K+ current are commonly observed in cardiac hypertrophy and failure (26). Reductions in IKs and IKr, which play dominant roles in ventricular AP repolarization of many mammalian species including the rabbit (21), are also common. In cats, IKs density was decreased in right ventricular hypertrophy induced by pressure overload (14) and LVH was induced by aortic stenosis (10). In rabbits, LVH induced by renovascular hypertension significantly reduced IKs but not IKr density (32), whereas pacing-induced heart failure reduced both IKs and IKr (28). In dogs with chronic complete atrioventricular block, IKr density of midmyocardial cells was decreased in right ventricle and IKs density was decreased in both ventricles (30). In failing human hearts, IKs density was decreased by 60% (15). The reduction in the delayed rectifier K+ currents predisposes ventricular myocytes to potentially arrhythmogenic EAD (9, 17, 32). Computer models of the mammalian ventricular AP predict that reducing IKs induces EAD in the endocardial cells during normal cell-cell coupling (29).
Other studies aimed at treating arrhythmias resulting from excessive AP prolongation and LQTS have explored various strategies for augmenting repolarizing K+ currents. These include increasing IKr by elevating serum K+ concentrations (5, 6), administration of ATP-sensitive K+ channel openers (1, 8, 23), and overexpression of the human ether-á-go-go-related gene (18).
Study limitations. Because excessive APD prolongation and EAD are associated with bradycardia, the pacing rates used in this study are below the normal physiological rates in the rabbit. The rabbit models used in this study address only the downregulation of IKr amplitude (acquired LQT2) or IKs density (LVH). In patients with congenital LQTS, not only is current density affected, but also other properties of IKr or IKs channels may change. It is uncertain whether IKs activation will have antiarrhythmic effects in these patients. Use of IKs activators may not be void of adverse effects in some situations. Shortening APD by IKs activation may facilitate the development of reentrant arrhythmia under certain circumstances, particularly in myocardial ischemia and infarction. The effects of L3 on action potentials under ischemic conditions are unknown; however, we expect the APD shortening by IKs activation would be very modest and possibly overwhelmed by activation of the large conductance of the ATP-sensitive K+ channel current.
In conclusion, selective activation of IKs by pharmacological agents is a promising new strategy to suppress arrhythmias resulting from excessive AP prolongation in patients with certain forms of LQTS or cardiac hypertrophy and failure.| |
ACKNOWLEDGEMENTS |
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This study was supported in part by the Sharpe Foundation and the Fourjay Foundation.
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FOOTNOTES |
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Address for reprint requests and other correspondence: X. Xu, Main Line Health Heart Center, Suite 558, Medical Office Bldg. East, 100 Lancaster Ave., Wynnewood, PA 19096 (E-mail: xxujwang{at}aol.com).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
May 2, 2002;10.1152/ajpheart.00076.2002
Received 30 January 2002; accepted in final form 24 April 2002.
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TOP
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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