(Circulation. 2001;103:762.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Inhibition of the Na+/H+ Exchanger Delays the Development of Rapid Pacing–Induced Atrial Contractile Dysfunction
From the Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis.
Correspondence to Jeffrey E. Olgin, MD, Krannert Institute of Cardiology, Indiana University School of Medicine, 1111 W 10th St, Indianapolis, IN 46202. E-mail jolgin{at}iupui.edu
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Abstract |
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Background—Atrial mechanical stunning due to atrial fibrillation may persist after restoration of sinus rhythm. Although the mechanism of rapid rate–related contractile dysfunction remains unknown, ischemia, pH changes, and calcium overload have been postulated as potential mechanisms. We hypothesized that blockade of the Na+/H+ exchanger (NHE) would alter atrial contractile dysfunction from rapid rates.
Methods and Results—Twenty-three anesthetized dogs were studied and subjected to 5 hours of rapid right atrial pacing. Ten received an inhibitor of the NHE, 10 received saline, and 3 received nifedipine. All animals underwent placement of 2 sonomicrometers on the left atrium, transesophageal echocardiography, and invasive hemodynamic monitoring. All measurements were made in sinus rhythm. Except for baseline and postdrug measurements, reduction in left atrial fractional shortening was significantly less at all time points in the NHEI group than in the control and nifedipine groups (P=0.05). The percent change from baseline of left atrial function at all time intervals as assessed by left atrial appendage contraction velocity (LAACV) was significantly less in the NHEI group than in the control (P=0.05) group. LAACV was significantly preserved at all time intervals (except 300 minutes) in the NHEI group compared with the nifedipine group (P=0.05). The only significant difference in hemodynamics among the groups was between the control and the nifedipine groups at 30 minutes after drug (P=0.05).
Conclusions—Treatment with HOE642 significantly blunts the decline in left atrial mechanical function from rapid atrial rates compared with both control and nifedipine-treated groups.
Key Words: fibrillation • contractility • sodium • arrhythmias
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Introduction |
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Despite prompt restoration of sinus rhythm, even brief periods of atrial fibrillation (AF) can cause atrial contractile dysfunction,1 which can last for days and contribute to the risk of cardioembolic events after successful cardioversion to sinus rhythm.2 3 4 The mechanism for this AF-induced atrial contractile abnormality is currently unknown. Ischemia, changes in pH, and intracellular calcium overload have been hypothesized to be important factors for this mechanical "stunning."
Previous studies have demonstrated the efficacy of Na+/H+ exchanger (NHE) inhibitors (NHEIs) in the prevention of ischemia-induced stunning in the ventricle.5 6 7 We previously reported that electrical remodeling due to rapid rates in the atrium could be prevented with blockade of the NHE, suggesting a potential role for alterations in intracellular pH as one contributing factor.8 The purpose of this study was to test the hypothesis that selective blockade of the cardiac NHE-1 isoform with the specific NHE blocker (HOE642) would alter the rapid deterioration in atrial contractile function due to rapid rates imposed by AF.
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Methods |
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The experiments performed in this study were approved by the Institutional Animal Care and Use Committee of Indiana University and were in accordance with the Guide for Care and Use of Laboratory Animals published by the National Institutes of Health (NIH publication No. 86-23, revised 1985). Twenty-three adult mongrel dogs (21 to 29 kg) were anesthetized with a bolus dose of thiopental sodium (20 mg/kg IV), intubated, and placed on mechanical ventilation with a volume-cycled ventilator (Ohio Medical Products). Anesthesia was maintained with 1.0 to 2.0 vol% isoflurane. Introducer sheaths were inserted in the right femoral vein and the right femoral artery for venous access and for continuous blood pressure monitoring, respectively. The heart was exposed via left thoracotomy and suspended in a pericardial cradle. Two plunge electrodes were placed in the right atrial appendage for bipolar pacing.
A pair of sonomicrometer transducers (2.5 mm in diameter) (Triton Technology) were sewn into position on the medial and lateral aspects of the left atrium. The sonomicrometer signals were displayed on an oscilloscope, digitized, and recorded by PC-compatible computer for later analysis (WINDAQ/Pro software, DATAQ Instruments). Atrial contractile measurements were analyzed as described by Hoit et al.9 Minimum left atrial diameter (LAdmin) was taken at the end of atrial systole as reflected in the atrial pressure tracing and was correlated with the surface ECG. Maximum left atrial diameter (LAdmax) occurred at the time of mitral valve opening, corresponding to the time of the V wave of the atrial pressure tracing. An 8F introducer sheath was placed in the right internal jugular vein, through which a 7.5F fluid-filled triple-lumen flotation catheter was inserted to monitor intracardiac pressures (Baxter). A 5.0-MHz omniplane TEE probe (Hewlett Packard) was used for measurement of the peak systolic left atrial appendage contraction velocity (LAACV) (cm/s) by pulsed-wave Doppler analysis, as described by Tabata et al.2 The LAACV was measured with the sample volume 1 cm from the LAA orifice leading into the left atrial main chamber in a transverse view that included the left atrial main chamber and the LAA. The LAACV was the maximal systolic velocity recorded during a cardiac cycle. Baseline hemodynamic, LAACV, and atrial contractile measurements were recorded in sinus rhythm.
Ten dogs (NHEI group) received a maximally effective intravenous bolus dose of HOE642 (2 mg/kg) (Hoechst Marion Roussel), 10 dogs (control group) received an equivalent volume of saline, and 3 dogs received an intragastric suspension of rapid-onset nifedipine (1 mg/kg) (nifedipine group) with equivalent intravenous saline placebo. The dogs were observed for 30 minutes, and then repeat measurements of the previously mentioned parameters were performed. Rapid right atrial pacing was then initiated at 600 bpm with a pacing output of twice diastolic threshold. Data points were acquired in sinus rhythm, after temporary cessation of rapid atrial pacing, at 15-minute intervals for the first hour and then hourly for a total of 5 hours. Pacing was discontinued for no longer than 1 minute during acquisition of data and was immediately resumed after measurements were obtained.
Data were analyzed offline. A total of 10 sets of atrial contractile data (LAdmax and LAdmin, in millimeters) and peak systolic LAACVs were measured during sinus rhythm and averaged for each time interval. The percentage of left atrial fractional shortening (LAFS) was calculated as the mean (LAdmax-LAdmin/LAdmaxx100) at each time interval.
Statistical Analysis
Values are presented as mean±SD. Comparisons among
groups were made with ANOVA and a Fisher’s protected least significant
difference post hoc test. Probability values of
P=0.05 were considered
significant. Comparisons within each group at different time points
were made by ANOVA with repeated
measures.
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Results |
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Left Atrial Fractional Shortening
At baseline, there was no significant difference in LAFS among the 3 groups (control 23.0±5.5%, NHEI 24.3±5.3%, nifedipine 18.3±3.4%, P=0.200) (Figure 1
). After 15 minutes of pacing, LAFS decreased in the
control group 
31% from baseline values to 15.8±6.5%
(P=0.001)
(Figure 1). At 45 minutes, LAFS had decreased to 10.3±6.4%
(P=0.01). This trend continued
and reached a plateau at 180 minutes, where the LAFS value had
decreased 68% from baseline to 7.3±3.9%
(P<0.03). Further loss of LAFS
was not noted with continuation of pacing beyond 180 minutes. At 300
minutes of pacing, LAFS was 7.3±4.2%.
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0.05) of LAFS in NHEI group vs control and nifedipine groups. There are no significant differences between control and nifedipine groups.
In contrast to the control group, the NHEI group showed
significantly less decline in left atrial contractile function
(Figure 1
). By 15 minutes, LAFS had decreased only 13%
from baseline values to 21.0±4.5%
(P=0.05). At 45 minutes, LAFS
decreased to 19.1±4.4%
(P=0.001) compared with
control. The degree of decrement in LAFS was more gradual in the NHEI
group, such that LAFS at 180 minutes had decreased only 29% from
baseline to 17.2±5.2%
(P<0.0001). At the conclusion
of pacing, LAFS (15.3±5.3%) was still significantly preserved at 37%
from baseline (P=0.0009).
Significant differences in LAFS between the control group and the NHEI
group (P=0.05) were noted at
every time interval after the initiation of pacing.
The findings in the nifedipine group were very similar to
those of the control group
(Figure 1). After 15 minutes of pacing, LAFS decreased
39% from baseline values to 11.1±3.8%. At 15 minutes, this value
was significantly lower than that of the NHEI group
(P=0.01) but was not different
from controls. At 45 minutes, LAFS had decreased further to 7.4±3.0%.
This too was significantly lower than that in the NHEI group
(P=0.003) but not different
from controls. A progressive loss of atrial contractile function,
similar to that in the control group, was noted throughout the duration
of pacing. At the conclusion of 300 minutes of pacing, LAFS had
decreased 79% from baseline values to 3.9±1.3%, which was
significantly different from the NHEI group
(P=0.001).
LAFS was significantly lower in the nifedipine group at all time intervals after the initiation of pacing than in the NHEI group (P=0.05). LAFS in the nifedipine group was never significantly different from the control group (P>0.05) at any time interval after initiation of pacing.
Left Atrial Appendage Contraction
Velocity
At baseline, there was no significant difference in
LAACV among the 3 groups (control 56.1±21.0 cm/s, NHEI 48.5±11.2
cm/s, nifedipine 42.8±3.3 cm/s,
P=0.42)
(Figure 2). After 15 minutes of pacing, LAACV in the control
group decreased 21% from baseline values to 43.7±16.5 cm/s
(P=0.002)
(Figure 2). At 45 minutes, LAACV had decreased to 36.2±15.6
cm/s (P=0.001). This abrupt
downward trend continued and reached a plateau at 120 minutes, when the
LAACV value had decreased 49% from baseline values to 27.5±10.9
cm/s (P<0.0001 versus the NHEI
group). At 300 minutes, LAACV was 24.7±6.6 cm/s.
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In contrast to the control group, at 15 minutes of pacing,
the NHEI group displayed minimal reduction (6%) in LAACV from baseline
values to 45.1±9.8 cm/s
(P=0.01)
(Figure 2). The LAACV in the NHEI group (41.9±8.2 cm/s) was
significantly greater than that in controls at 45 minutes
(P=0.0004). The degree of
decrement in LAACV in the NHEI group was more gradual; at 180 minutes,
LAACV had decreased 19% from baseline to 37.9±6.3 cm/s
(P<0.0002 versus the control
group). At the conclusion of pacing, LAACV at 29.9±7.1 cm/s
(P=0.006) was still
significantly preserved at 36% from baseline compared with the control
group. Significant differences in LAACV between the control group and
the NHEI group (P=0.05) were
noted at every time interval after initiation of pacing.
The findings in the nifedipine group were very similar to
those of the control group. After 15 minutes of pacing, LAACV decreased
24% from baseline values to 32.5±5.6 cm/s. At 15 minutes, this
value was significantly lower than that of the NHEI group
(P=0.03)
(Figure 2). At 45 minutes, LAACV had decreased significantly
compared with the NHEI group to 25.7±3.9 cm/s
(P=0.003). This progressive
loss of contractile function was noted throughout the duration of the
pacing. At 300 minutes, LAACV had decreased 52%. Significant
differences in LAACV between the nifedipine and NHEI groups
(P=0.05) were noted at every
time interval after initiation of the pacing, except at 300 minutes
(P=0.08). LAACV was not
significantly different between the nifedipine and control groups at
any time interval.
Analyses of hemodynamic data are shown in
Figures 3 and 4. The mean arterial pressure (MAP) in the
nifedipine group at 30 minutes after drug was significantly lower than
in the control group (P=0.007).
Otherwise, no significant differences were noted in MAP or pulmonary
capillary wedge pressure (PCWP). There were no significant differences
in heart rate at any time among the 3
groups.
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Discussion |
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In this study, we demonstrated that the decline in atrial mechanical function after rapid atrial pacing in dogs, evaluated by pulsed-wave Doppler echocardiography and direct measurement of atrial contractile function, is blunted by selective blockade of the cardiac NHE-1 isoform. The degree of atrial mechanical dysfunction noted in the NHEI group was significantly blunted throughout the duration of pacing, showing only gradual decrement of atrial contractile function over time. In contrast to the NHEI group, we found that the control and nifedipine groups both exhibited significant abrupt losses of atrial contractile function ("stunning") immediately after the initiation of pacing. Atrial contractile function in these 2 groups continued to decrease significantly, compared with the NHEI group, with increasing duration of pacing. The only significant difference noted when hemodynamic data were analyzed was between the nifedipine and control groups at 30 minutes after drug.
One potential mechanism for atrial mechanical dysfunction or stunning may be intracellular acidosis, perhaps secondary to rapid rate–induced increases in oxygen consumption in the setting of an overall reduction in atrial flow reserve. Reduction of flow reserve coupled with increased metabolic demand could potentially lead to atrial ischemia. Whereas the NHE is relatively inactive at normal intracellular pH, it is primarily (but not absolutely) activated during intracellular acidosis.10 11 Activation of the cardiac NHE leads to an exchange of intracellular hydrogen ions for extracellular Na+ ions. The resulting influx of Na+ ions alters the reversal potential of the Na+/Ca2+ exchanger in a manner that inhibits Ca2+ efflux and/or enhances Ca2+ influx through this bidirectional mechanism, leading to a pathological increase in intracellular Ca2+. HOE642 is likely to afford a cardioprotective effect by inhibiting this sequence at an early stage through the limitation of Na+ influx. In fact, evidence suggests that HOE642 attenuates Ca2+ overload during ischemia and early reperfusion.12 Although an ischemic mechanism is plausible, preliminary data from our laboratory and from others suggest that oxidative metabolism is not altered (as measured by high-energy phosphates) during either short-term or long-term rapid atrial pacing.13 14 15 These studies did not directly measure intracellular pH, however, which is the primary mode by which the NHE is activated.
Another potential explanation for our findings may be that the NHE is activated earlier (without acidosis) by other mechanisms. Rapid atrial pacing may lead to sympathetic activation with release of neurotransmitters (eg, epinephrine, norepinephrine) and mechanical stimulation, which may trigger the discharge of vasoactive peptides (eg, atrial natriuretic peptide, angiotensin II). In addition to intracellular acidosis, it has been demonstrated that a number of other mediators can stimulate NHE activity or shift the pHi dependence of the NHE. Both norepinephrine and epinephrine have been shown to activate the NHE in cardiac cells.16 17 Jayachandran et al18 showed that sympathetic innervation and norepinephrine content are increased after rapid atrial pacing. ATP, endothelin, and angiotensin II also affect cardiac NHE activity.19 20 21 Thus, during high-rate pacing or a high-energy metabolic state, these may serve as adjunctive mechanisms resulting in NHE activation and ultimately lead to atrial contractile dysfunction.
The heart regulates pHi closely under normal physiological conditions. Studies of isolated ventricular myocytes have demonstrated that contractility is affected negatively by a decrease in pHi and somewhat positively by an increase in pHi.20 22 23 Rapid atrial rates during pacing may lead to enhanced cellular metabolism and activation of the neurohormonal milieu. These changes could potentially lead to a rise in H+, CO2, and HCO3- generation, in turn altering pHi and leading to early activation of the NHE. This may be another factor accounting for the preservation of atrial contractile function in the NHEI group.
Multiple studies have demonstrated the effectiveness of NHE inhibitors on ventricular contractile dysfunction during ischemia, infarction, and reperfusion.5 24 25 26 HOE42 has been shown to attenuate ventricular contractile dysfunction (stunning) and improve recovery of ventricular contractility during ischemia and after reperfusion.5 6 7 To date, few data exist regarding the effect of NHE inhibitors on the atrium, although Jayachandran et al8 showed that electrical remodeling due to rapid rates in the atrium could be prevented with blockade of the NHE, suggesting a potential role for alterations in pHi as a contributing factor.
Consistent with the findings in our control group, multiple studies have shown that even brief periods of AF in normal canine hearts result in marked atrial systolic dysfunction after a brief period of hypercontractility.3 13 We did not observe this brief hypercontractility, because our first time point was significantly longer than the 5 minutes used in a previous study.13 Blockade of L-type calcium channels with verapamil has been demonstrated to reduce the degree and duration of postfibrillation atrial contractile dysfunction.1 13 Furthermore, specific blockade of T-type Ca2+ channels with mibefradil has been demonstrated to attenuate atrial electrophysiological remodeling by atrial tachycardia,27 thus potentially contributing to inhibition of atrial stunning due to rapid atrial rates. Because verapamil has other cardiac pharmacological actions, such as sodium channel blockade,28 however, it remains unclear whether the blunting effect of verapamil is solely due to L-type Ca2+ channel blockade. We analyzed the efficacy of rapid-onset nifedipine because unlike verapamil, it is a pure L-type Ca2+ channel blocker at therapeutic levels.29 30 Studies performed in dogs showed that therapeutic levels of nifedipine could be rapidly achieved and maintained over a 6-hour period with this oral preparation at 1 mg/kg.31 32 In contrast to previous studies, our data reveal that specific blockade of the L-type Ca2+ channel with nifedipine did not blunt AF-induced atrial mechanical dysfunction.
The present study suggests that HOE642 may have some utility to attenuate atrial contractile dysfunction after cardioversion of even brief periods of AF. Because human AF is quite different from the animal model used in this study, further studies will be needed to evaluate the possible benefit of these findings in humans with AF. In addition, the influence of structural and degenerative atrial changes (observed even in patients with lone AF)33 34 35 on postcardioversion stunning is not known.
Limitations
Although HOE642 is a highly specific blocking agent of
the cardiac NHE, other pharmacological actions cannot be excluded.
Previous studies have shown a lack of effect of this drug on the
Na+ current as well as the
Na+/Ca2+
exchanger.36 In the present
study, HOE642 had no effect on atrial contractile function at baseline,
suggesting a lack of direct actions at baseline. Mathur and
Karmazyn37 showed that
HOE642 in combination with isoflurane produced an additive beneficial
effect on left ventricular function and led to preservation of ATP
levels. Although the effects of isoflurane on atrial contractile
function are unknown, no significant effect was noted during isoflurane
anesthesia at baseline, and the rate of isoflurane administration was
held constant in all groups during the study.
Although the oral route has been demonstrated to be an effective method of nifedipine administration, leading to rapid and sustained therapeutic drug levels31 32 adequate to achieve blockade of L-type Ca2+ channels, we cannot ensure that complete blockade of atrial L-type Ca2+ channels was achieved throughout the experiment. In addition, it is possible that increased autonomic tone may have prevented nifedipine-related changes and possibly have accounted for the lack of blunting of atrial contractile dysfunction noted in this group. This may potentially explain the lack of effectiveness of nifedipine in our study compared with that of verapamil in previous studies.13 Finally, although we evaluated the time course of deterioration of atrial contractile function from rapid rates, the length of the study precluded us from fully evaluating the recovery of contractile function after the cessation of rapid atrial pacing.
Conclusions
Loss of atrial mechanical function from prolonged rapid
atrial rates is blunted by blockade of the cardiac NHE. These
preliminary observations strongly suggest that the cardiac NHE may be a
factor in the pathophysiology of atrial contractile dysfunction after
acute episodes of AF. Further investigations will be necessary to fully
elucidate the mechanism and clinical implications of this
finding.
Received June 2, 2000; revision received August 10, 2000; accepted August 10, 2000.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Daoud EG, Marcovitz P, Knight BP, et al. Short-term effect of atrial fibrillation on atrial contractile function in humans. Circulation. 1999;99:3024–3027.
2. Tabata T, Oki T, Iuchi A, et al. Evaluation of left atrial appendage function by measurement of changes in flow velocity patterns after electrical cardioversion in patients with isolated atrial fibrillation. Am J Cardiol. 1997;79:615–620.[Medline] [Order article via Infotrieve]
3.
Louie EK, Liu D,
Reynertson SI, et al. "Stunning" of the left atrium after
spontaneous conversion of atrial fibrillation in sinus rhythm.
J Am Coll Cardiol. 1998;32:2081–2086.
4. Grimm RA, Stewart WJ, Maloney JD, et al. Impact of electrical cardioversion for atrial fibrillation on left atrial appendage function and spontaneous echo contrast: characterization by simultaneous transesophageal echocardiography. J Am Coll Cardiol. 1993;22:1359–1366.[Abstract]
5.
Shipolini AR,
Yokoyama H, Galinanes M, et al.
Na+/H+ exchanger
activity does not contribute to protection by ischemic preconditioning
in the isolated rat heart.
Circulation. 1997;96:3617–3625.
6.
Shimada Y, Hearse
DJ, Avkiran M. Impact of extracellular buffer composition on
cardioprotective efficacy of
Na+/H+ exchanger
inhibitors. Am J Physiol. 1996;270:H692–H700.
7. du Toit EF, Opie LH. Role for the Na+/H+ exchanger in reperfusion stunning in isolated perfused rat heart. J Cardiovasc Pharmacol. 1993;22:877–883.[Medline] [Order article via Infotrieve]
8.
Jayachandran JV,
Zipes DP, Weksler J, et al. Role of the
Na+/H+ exchanger
in short-term atrial electrophysiological remodeling.
Circulation. 2000;101:1861–1866.
9.
Hoit BD, Walsh RA.
Regional atrial distensibility. Am J
Physiol. 1992;262:H1356–H1360.
10. Lazdunski M, Frelin C, Vigne P. The sodium/hydrogen exchange system in cardiac cells: its biochemical and pharmacological properties and its role in regulating internal concentrations of sodium and internal pH. J Mol Cell Cardiol. 1985;17:1029–1042.[Medline] [Order article via Infotrieve]
11.
Wallert MA,
Frohlich O.
Na+-H+ exchange
in isolated myocytes from adult rat heart.
Am J Physiol. 1989;257:C207–213.
12.
Stromer H, de
Groot MC, Horn M, et al.
Na+/H+ exchange
inhibition with HOE642 improves postischemic recovery due to
attenuation of Ca2+ overload and prolonged
acidosis on reperfusion.
Circulation. 2000;101:2749–2755.
13.
Leistad E, Aksnes
G, Verburg E, et al. Atrial contractile dysfunction after short-term
atrial fibrillation is reduced by verapamil but increased by BAY K8644.
Circulation. 1996;93:1747–1754.
14.
Goette A,
Honeycutt C, Langberg JJ. Electrical remodeling in atrial fibrillation:
time course and mechanisms.
Circulation. 1996;94:2968–2974.
15. Ausma J, Coumans W, Duimel H, et al. Do high energy phosphates and mitochondrial enzyme activity change during prolonged atrial fibrillation? Circulation. 1999;100(suppl I):I–11. Abstract.
16. Iwakura K, Hori M, Watanabe Y, et al. Alpha 1-adrenoceptor stimulation increases intracellular pH and Ca2+ in cardiomyocytes through Na+/H+ and Na+/Ca2+ exchange [published erratum appears in Eur J Pharmacol. 1991;192:448]. Eur J Pharmacol. 1990;186:29–40.
17.
Lagadic-Gossmann
D, Vaughan-Jones RD, Buckler KJ. Adrenaline and extracellular ATP
switch between two modes of acid extrusion in the guinea-pig
ventricular myocyte. J Physiol
(Lond). 1992;458:385–407.
18.
Jayachandran JV,
Sih HJ, Winkle W, et al. Atrial fibrillation produced by prolonged
rapid atrial pacing is associated with heterogeneous changes in atrial
sympathetic innervation.
Circulation. 2000;101:1185–1191.
19.
Puceat M,
Clement-Chomienne O, Terzic A, et al. Alpha 1-adrenoceptor and
purinoceptor agonists modulate Na-H antiport in single cardiac cells.
Am J Physiol. 1993;264:H310–H319.
20.
Kramer BK, Smith
TW, Kelly RA. Endothelin and increased contractility in adult rat
ventricular myocytes: role of intracellular alkalosis induced by
activation of the protein kinase C-dependent
Na+-H+ exchanger.
Circ Res. 1991;68:269–279.
21. Ito N, Kagaya Y, Weinberg EO, et al. Endothelin and angiotensin II stimulation of Na+-H+ exchange is impaired in cardiac hypertrophy. J Clin Invest. 1997;99:125–135.[Medline] [Order article via Infotrieve]
22.
Bountra C,
Vaughan-Jones RD. Effect of intracellular and extracellular pH on
contraction in isolated, mammalian cardiac muscle.
J Physiol (Lond). 1989;418:163–187.
23.
Harrison SM,
Frampton JE, McCall E, et al. Contraction and intracellular
Ca2+, Na+, and
H+ during acidosis in rat ventricular
myocytes. Am J Physiol. 1992;262:C348–C357.
24. Rohmann S, Weygandt H, Minck KO. Preischaemic as well as postischaemic application of a Na+/H+ exchange inhibitor reduces infarct size in pigs. Cardiovasc Res. 1995;30:945–951.[Medline] [Order article via Infotrieve]
25. Klein HH, Bohle RM, Pich S, et al. Time delay of cell death by Na+/H+-exchange inhibition in regionally ischemic, reperfused porcine hearts. J Cardiovasc Pharmacol. 1997;30:235–240.[Medline] [Order article via Infotrieve]
26. Linz W, Albus U, Crause P, et al. Dose-dependent reduction of myocardial infarct mass in rabbits by the NHE-1 inhibitor cariporide (HOE 642). Clin Exp Hypertens. 1998;20:733–749.
27.
Fareh S,
Benardeau A, Thibault B, et al. The T-type
Ca2+ channel blocker mibefradil prevents the
development of a substrate for atrial fibrillation by
tachycardia-induced atrial remodeling in dogs.
Circulation. 1999;100:2191–2197.
28.
McDonald TF,
Pelzer S, Trautwein W, et al. Regulation and modulation of calcium
channels in cardiac, skeletal, and smooth muscle cells.
Physiol Rev. 1994;74:365–507.
29. Schwartz A. Calcium antagonists: review and perspective on mechanism of action. Am J Cardiol. 1989;64:3I–9I.[Medline] [Order article via Infotrieve]
30. van Zwieten PA. Vascular effects of calcium antagonists: implications for hypertension and other risk factors for coronary heart disease. Am J Cardiol. 1989;64:117I–121I.[Medline] [Order article via Infotrieve]
31. Wynsen JC, Shimshak TM, Preuss KC, et al. Cardiovascular actions of a new dihydropyridine calcium antagonist, 8363-S: comparison with nifedipine and nicardipine in awake, unsedated dogs. J Cardiovasc Pharmacol. 1987;10:30–37.[Medline] [Order article via Infotrieve]
32. Takata Y, Kato H. Comparative study on acute antihypertensive effects and pharmacokinetics of nisoldipine, nifedipine, nimodipine and nicardipine administered orally to conscious renal hypertensive dogs. Arzneimittelforschung. 1986;36:1464–1471.[Medline] [Order article via Infotrieve]
33.
Frustaci A,
Chimenti C, Bellocci F, et al. Histological substrate of atrial
biopsies in patients with lone atrial fibrillation.
Circulation. 1997;96:1180–1184.
34. Thiedemann KU, Ferrans VJ. Left atrial ultrastructure in mitral valvular disease. Am J Pathol. 1977;89:575–604.[Abstract]
35. Unverferth DV, Fertel RH, Unverferth BJ, et al. Atrial fibrillation in mitral stenosis: histologic, hemodynamic and metabolic factors. Int J Cardiol. 1984;5:143–154.[Medline] [Order article via Infotrieve]
36. Scholz W, Albus U, Counillon L, et al. Protective effects of HOE642, a selective sodium-hydrogen exchange subtype 1 inhibitor, on cardiac ischaemia and reperfusion. Cardiovasc Res. 1995;29:260–268.[Medline] [Order article via Infotrieve]
37. Mathur S, Karmazyn M. Interaction between anesthetics and the sodium-hydrogen exchange inhibitor HOE 642 (cariporide) in ischemic and reperfused rat hearts. Anesthesiology. 1997;87:1460–1469. [Medline] [Order article via Infotrieve]
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U. Schotten, M. Greiser, D. Benke, K. Buerkel, B. Ehrenteidt, C. Stellbrink, J. F Vazquez-Jimenez, F. Schoendube, P. Hanrath, and M. Allessie Atrial fibrillation-induced atrial contractile dysfunction: a tachycardiomyopathy of a different sort Cardiovasc Res, January 1, 2002; 53(1): 192 - 201. [Abstract] [Full Text] [PDF]
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