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1 Institute for Cardiovascular Research, Laboratory for Physiology, 1081 BT Amsterdam, The Netherlands; and 2 Department of Physiology and Medicine, University of Antwerp, B2020 Antwerp, Belgium
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The role of
stretch-activated ion channels (SACs) in coronary perfusion-induced
increase in cardiac contractility was investigated in isolated
isometrically contracting perfused papillary muscles from Wistar rats.
A brief increase in perfusion pressure (3-4 s, perfusion pulse,
n = 7), 10 repetitive perfusion pulses
(n = 4), or a sustained increase in perfusion pressure
(150-200 s, perfusion step, n = 7) increase
developed force by 2.7 ± 1.1, 7.7 ± 2.2, and 8.3 ± 2.5 mN/mm2 (means ± SE, P < 0.05),
respectively. The increase in developed force after a perfusion pulse
is transient, whereas developed force during a perfusion step remains
increased by 5.1 ± 2.5 mN/mm2 (P < 0.05) in the steady state. Inhibition of SACs by addition of gadolinium
(10 µmol/l) or streptomycin (40 and 100 µmol/l) blunts the
perfusion-induced increase in developed force. Incubation with 100 µmol/l N
-nitro-L-arginine
[nitric oxide (NO) synthase inhibition], 10 µmol/l sodium
nitroprusside (NO donation) and 0.1 µmol/l verapamil (L-type
Ca2+ channel blockade) are without effect on the
perfusion-induced increase of developed force. We conclude that brief,
repetitive, or sustained increases in coronary perfusion augment
cardiac contractility through activation of stretch-activated ion
channels, whereas endothelial NO release and L-type Ca2+
channels are not involved.
mechanotransduction; gadolinium; nitric oxide; papillary muscles; streptomycin
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE EXISTENCE OF AN INTERACTION between coronary perfusion and cardiac contractility is well established (22). An increase in coronary perfusion with a concomitant increased filling of the coronary vessels leads to an increase in cardiac contractility and cardiac oxygen consumption known as the Gregg effect (1, 3, 14, 18, 22, 36). Filling of the coronary vessels will change hoop (circumferential) stress in the vessel wall, thereby mechanically deforming the membranes of myocardial cells. Mechanical deformation of cardiomyocytes activates stretch-activated ion channels (SACs) (24, 27, 28, 37, 39, 40), thereby conducting Ca2+, Na+, or K+ cations (7, 8, 35, 37, 39, 40), which may affect the contractile state of the myocardium. Besides hoop stress, a change in perfusion will change also shear stress and may thereby induce endothelium-dependent nitric oxide (NO) release. Because NO has been shown to have positive inotropic effects at low concentration and negative inotropic effects at high concentration (26, 30), there could be an effect of perfusion-induced NO release on the contractility of cardiomyocytes.
Therefore, we investigated the role of SACs and NO on the coronary
perfusion-induced increase in cardiac contractility. In isolated
perfused papillary muscles of the rat, coronary perfusion pressure was
increased via a brief "perfusion pulse," repetitive perfusion
pulses, or a sustained perfusion increase "perfusion step." The
effects of the perfusion increase on isometric force development were
tested before and after addition of the SAC blockers gadolinium (III)
chloride hexahydrate (Gd3+) and streptomycin, the NO
synthase (NOS) inhibitor
N-nitro-L-arginine
(L-NNA), the NO donor sodium nitroprusside (SNP), and the
L-type Ca2+ channel blocker verapamil. Our results indicate
that a brief, repetitive, or sustained increase in coronary perfusion
augments cardiac contractility through activation of stretch-activated ion channels, whereas endothelial NO release and L-type
Ca2+ channels are not involved.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Preparation and setup. All animals were treated according to guidelines of the Animal Experimental Committee of the Vrije Universiteit of Amsterdam, The Netherlands. Under ether anesthesia, the hearts of 50 male Wistar rats (300-400 g body wt) were quickly removed and perfused via the aorta with a crystalloid solution (for composition, see below). To prevent contraction of the heart, external Ca2+ concentration ([Ca2+]) was kept at 0.5 and 25 mmol/l, respectively, and 2,3-butanedione monoxime was added. A papillary muscle with part of the septum and septal artery was removed from the right ventricle and transferred to the experimental superfusion bath. The septum was clamped on a Perspex plate and the muscle tendon was attached to a force transducer (model KG4, Scientific Instruments; Heidelberg, Germany) with a piece of silk thread. The septal artery was cannulated using a glass cannula and connected to a pressurized reservoir through a pressure difference meter (model SCX01DN, Sensym) for flow measurements. Muscle diameter was determined with the use of a video analyzing system (36).
Bath (superfusion) and pressurized reservoir (perfusion) were filled with identical crystalloid solution containing (in mmol/l) 120 NaCl, 4.9 KCl, 1.2 MgSO4, 1.8 NaH2PO4, 1 CaCl2, 10 glucose, 5 HEPES, 20 NaHCO3, 15 choline chloride, and 0.01 adenosine, and then gassed with 95% O2-5% CO2. Solution was kept at 27°C and pH was set at 7.45. Muscles were stimulated via a pair of platinum electrodes at 0.2Hz to obtain muscle-isometric contractions. Passive force (Fpas; the force imposed on the resting muscle) and developed force (Fdev; the difference between the total force produced during contraction and Fpas) were measured at 95% Lmax, with Lmax being the muscle length at which maximal isometric force was developed.Experimental protocols. After an equilibration period of 60 min in control conditions, different perfusion protocols were tested to investigate adaptation processes and to exclude interference of preload changes. In the first protocol, a brief increase (3-4 s) from low (10 cmH2O) to high (80 cmH2O) coronary perfusion pressure (P-pulse or perfusion pulse) was applied between two isometric contractions. In the second protocol, coronary perfusion pressure was increased from low-to-high perfusion and sustained until force development reached a steady state (perfusion step). In four muscles of the Gd3+ group (see Experimental protocols), we performed an additional perfusion protocol to investigate a different application of the stretch (perfusion pressure). Four muscles were exposed to 10 consecutive perfusion pulses, and each pulse was given between two isometric contractions (repetitive perfusion pulses).
The minimal perfusion pressure of 10 cmH2O was used because at lower perfusion pressures the vasculature would collapse completely, resulting in endothelial damage, and thus affecting contractile state. The maximal perfusion pressure of 80 cmH2O (~65 mmHg) was used because this reflects normal perfusion pressure in the septal artery and it is the perfusion pressure at which the increase in Fdev is maximal. The perfusion protocols were performed in control conditions and were repeated after 30 min of incubation with one of the pharmacological agents. A first group of papillary muscles (n = 7) was incubated with Gd3+ (10 µmol/l), a nonspecific stretch-activated ion channel blocker. A second group of papillary muscles (n = 10) was incubated with the NOS inhibitor L-NNA (100 µmol/l), and a third group (n = 6) was incubated with the NO donor SNP (10 µmol/l). To support that the Gd3+-induced effects were related to SACs, a fourth group of muscles (n = 8) was incubated with streptomycin (40 and 100 µmol/l), which is also known to block SACs (19). In this group, only the perfusion step was performed. The role of inhibition of L-type Ca2+ channels by Gd3+ was investigated in a fifth and sixth group of papillary muscles. The fifth group (n = 6) was incubated with the L-type Ca2+ channel blocker verapamil (0.1 µmol/l) and again only a perfusion step was performed. The sixth group (n = 6) was loaded with the cell-permeant acetoxymethyl ester form of the fluorescent intracellular Ca2+-indicator fura 2 (Molecular Probes F1221, final concentration 10 µmol/l) and basal force development was measured. The ratio of fura 2 fluorescence at 520 nm after excitation at wavelengths 340 and 380 nm was collected with a photomultiplier (model MPS20/21, Zeiss) before and after addition of 10 µmol/l Gd3+, with acquisition rate of 66 Hz. In all experiments, the fura 2 signal was at least five times above background level (autofluorescence). Finally, in a seventh group of muscles, the effect of Gd3+ (10 µmol/l) on the perfusion step response was investigated under HEPES conditions (n = 7).Data analysis. Force (mN/mm2) was normalized by dividing measured force by muscle cross-sectional area (mm2). The peak 340-to-380-nm ratio for each muscle in control conditions was set to 1.00 and all other Ca2+ transients were normalized with respect to this value (normalized 340-to-380-nm ratio). The fluorescence signal was not converted to intracellular [Ca2+] ([Ca2+]i) values with an in vivo calibration procedure because accurate reproducible calibration procedures without compartmentalization problems are difficult (38) and our primary interest was in the relative changes of [Ca2+]i. Statistical differences within each group of muscles were tested with a one- or two-way repeated-measures analysis of variance, followed by a Bonferroni or Dunnett post hoc test; P < 0.05 was considered significant. All data are expressed as means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Perfusion step and perfusion pulse.
Raw data tracings of the effects induced by a perfusion pulse
(A) and perfusion step (B) are presented in Fig.
1. A perfusion pulse results in an
immediate increase in force, which slowly decreases and returns to
basal values after ~50-60 s. A perfusion step increases force
during the first 7-9 contractions; after 40 s, the force
slowly starts to decrease, reaching a steady state after ~125 s (25 contractions).
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Fmax
dev) after 40 s (Table 1 and
Fig. 2). Hereafter, the Fdev starts to decline but remains
significantly increased in the steady state (FSSdev) (Table 1 and Fig. 2). The time constant of the increase in
Fdev was not different for the three control groups
(8.9 ± 6.0 s for Gd3+ group, 10.9 ± 8.3 s for the L-NNA group and 16.2 ± 14.4 for
the SNP group).
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FSSdev: 0.8 ± 1.3 mN/mm2, Table 1)
and is dose dependently inhibited by streptomycin, another SAC blocker
(2.8 ± 1.0 and 1.3 ± 0.9 mN/mm2 at 40 and 100 µmol/l, respectively, Table 1). NOS inhibition, NO donation, or
L-type Ca2+ channel blockade has no effect on the
steady-state increase in Fdev to perfusion step (5.7 ± 3.2, 9.1 ± 4.1, and 6.9 ± 1.7 mN/mm2,
respectively, Table 1). In the steady state, the perfusion step results
in a significant but small increase in Fpas
(FSSpas, Table 1), which is not affected by the addition
of any of the pharmacological agents (Table 1).
Repetitive perfusion pulses.
The absolute increase in Fdev of 10 consecutive perfusion
pulses (the repetitive perfusion pulses, n = 4) on
Fdev is shown in Fig. 3.
Repetitive perfusion pulses result in an immediate increase in
Fdev of 1.5 ± 0.6 mN/mm2, which is not
significantly different from the perfusion pulse or step-induced
immediate increase in Fdev. After 40 s, when two pulses still are to be applied, the increase in Fdev
already starts to decrease. The maximal increase in Fdev of
the repetitive perfusion pulses is 7.8 ± 2.2 mN/mm2
with a time constant of 24.5 ± 16.3 s. Both values are not
significantly different from the perfusion step-induced values. SAC
blockade with Gd3+ completely blunts the repetitive
perfusion pulse-induced response. With Gd3+, the maximal
increase in Fdev is 1.0 ± 1.1 mN/mm2,
which is not significant from basal values.
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Basal muscle properties, characteristics, and Ca2+ transient. Table 1 shows that the averaged optimal muscle length (Lmax) and the averaged cross-sectional area of the muscles are statistically not different between the experimental groups. In basal conditions, i.e., low perfusion (10 cmH2O) and at 95% Lmax, Fpas (see Table 1) is not different between the groups and not affected by the addition of one of the pharmacological agents. The absolute values of Fdev at basal conditions (see Table 1) are not affected by addition of Gd3+, L-NNA, SNP, or streptomycin, whereas addition of verapamil and Gd3+ under HEPES conditions result in a decrease of basal Fdev of 56.0 ± 4.5% and 43.1 ± 8.5%, respectively (Table 1).
The last column in Table 1 shows that the absolute values of coronary flow at high perfusion (80 cmH2O) are not affected by the addition of Gd3+ or SNP, whereas L-NNA significantly reduced coronary flow. In the streptomycin, verapamil, or HEPES experiments, the relative flow values were not different between the control group and after addition of a pharmacological agent (data not shown); unfortunately, technical problems did not allow us to obtain accurate absolute flow measurements in these experiments. Figure 4 shows, from a separate series of experiments, that the addition of Gd3+ in basal conditions (low perfusion) does not affect the passive or peak [Ca2+]i transient.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Our study shows that a short-lived, a repetitive, and a sustained increase in coronary perfusion pressure result in an increase in Fdev. Similar immediate increases in Fdev are seen with all three perfusion protocols; the peak value and the time constant of the increase in Fdev, in response to the repetitive and sustained increase in perfusion, are not different. All three perfusion-induced increases in Fdev are completely blunted by SAC blockade (Gd3+), but not affected by NOS inhibition (L-NNA) or NO donation (SNP). Another SAC blocker, streptomycin, dose dependently inhibited the perfusion step-induced increase in Fdev, whereas blockade of L-type Ca2+ channels with verapamil did not affect the perfusion-induced increase in Fdev. We conclude that brief, repetitive, or sustained increases in coronary perfusion augment cardiac contractility through activation of stretch-activated ion channels, whereas endothelial NO release and L-type Ca2+ channels are not involved.
Perfusion-induced changes. In our isolated perfused papillary muscles, where autoregulation is restricted due to adenosine addition, an increase in coronary perfusion pressure results in an increase in Fdev, the Gregg effect, and is in line with earlier findings (13, 16, 36). From the literature it is known that in perfused papillary muscles an increase in oxygen delivery is not responsible (17, 36). It has also been suggested (2) that the perfusion-induced response is related to a change in sarcomere length ("garden hose" effect). Our perfusion pulse experiments show that at the second contraction after a perfusion pulse the increase in Fpas and muscle diameter (Fig. 1) have returned to basal values, whereas Fdev remains increased. Moreover, SAC blockade by either Gd3+ or streptomycin inhibits the perfusion-induced increase in developed tension with no effect on the small perfusion-induced increase in passive tension (Table 1), indicating that the perfusion-induced changes are not related to changes in myofilament overlap. Thus our experimental results are in line with literature (25) showing that the perfusion-induced response is not related to a change in sarcomere length.
In our experiments, NOS inhibition by L-NNA or NO donation by SNP did not affect the responses to a perfusion change, indicating that the increase in cardiac contractility to a perfusion change is not related to shear stress-induced NO release by endothelial cells. Coronary flow at high coronary perfusion was reduced by L-NNA, indicating that NOS inhibition by L-NNA was active (Table 1). The verapamil experiments show that L-type Ca2+ channel inhibition does not affect the perfusion-induced increase in Fdev (Table 1), which indicates that L-type Ca2+ channel activation does not underlie the Gregg effect. The SAC blocker Gd3+ completely blunts all three perfusion-induced increases in Fdev. Streptomycin, another SAC blocker (19), dose dependently inhibits the increase in Fdev to a perfusion step. The Gregg effect, therefore, involves activation of SACs. Cardiac myocytes exhibit activation of SACs, which is inhibited by Gd3+ (24, 37, 40). Activation of SACs in heart cells can lead to changes in fluxes of Ca2+, Na+, or K+ cations (7, 8, 35, 37, 39, 40), which may affect the myocardial contractile state. The involvement of SACs in the perfusion-induced increase in cardiac contractility is confirmed by comparable properties of SACs activation and perfusion-induced responses. An increase in perfusion results in an immediate (5 s) increase in Fdev of similar magnitude for all three perfusion protocols. Similarly, the stretch-induced inward cation current via SACs appeared within 10 ms in rat ventricular myocytes (5, 40), indicating that SACs activation is fast enough to account for the perfusion-induced response. The perfusion-induced increase in Fdev immediately starts to decrease when the perfusion pressure is lowered (data not shown), which is in accordance with the results that the SACs cation currents disappear when the stimulus is released (4, 40). The mechanisms by which the mechanosensitive activation of SACs is linked to the perfusion-induced increase in cardiac contractility are still speculative; they do not only involve changes in calcium availability and calcium sensitivity, but also cytoskeletal changes. Glogauer et al. (21) showed, in human gingival fibroblasts, that a single 1-s stretching force application resulted in a SACs-mediated increase of [Ca2+]i, which lasted 150 s. A similar mechanism may underlie the transient increase in Fdev by the P-pulse (Figs. 1 and 2) because Fdev remained increased for several contractions, whereas muscle diameter quickly returned to basal values. In chicken cardiomyocytes, a mechanical stimulus by pressing the membrane elicited an inward cation current, which slowly inactivated during the plateau phase, probably due to changes in the cytoskeleton (4), a process that is also seen at sustained perfusion pressures resulting in adaptation of SACs (34). In another study, Glogauer et al. (20) showed that repetitive force application progressively inhibited the amplitude of the force-induced [Ca2+]i increase, which is compatible with our observation that maximum value and time constant of the increase in Fdev are not different between repetitive perfusion pulses and perfusion step. From the present results we propose a likely mechanism for the Gregg effect. Increased coronary perfusion via hoop (circumferential) stress mechanically deforms (by stretching or changing shape) the membrane of cardiomyocytes. A basis for the deformation of the membrane of the cardiomyocytes by increased perfusion pressures is provided by the findings of Heslinga et al. (23), who showed in isolated perfused papillary muscles that an increase in coronary perfusion resulted in an increase in intramyocardial pressure. The membrane deformation changes ion fluxes through SACs, resulting in increased cardiac contractility. This hypothesis is supported by the findings that the Gregg response was related to capillary perfusion (13, 15) and changes in coronary vascular volume (3), but was not related to arterial endothelium or its released inotropic substances (12, 14, 32, 33). The identity of the coronary perfusion-induced increased cation influx is not yet clear and needs further experiments.Gadolinium. The use of Gd3+ to block stretch-activated ion channels has been questioned in literature (28, 9). Lacampagne et al. (28) showed that Gd3+ blocks L-type Ca2+ channels and Caldwell et al. (9) noted that most of the Gd3+ in the presence of bicarbonate is bound to bicarbonate due to the equilibrium dissociation constants for Gd3+. However, Caldwell et al.'s study (9) noted that it is a presumption that only free Gd3+ can block SACs and that the assumption that Gd3+ anion complexes, such as bicarbonate-Gd3+, can block SACs, cannot be excluded.
The results of our Gd3+ experiments, i.e., inhibiting the Gregg effect (Fig. 2 and Table 1), in bicarbonate conditions, show that Gd3+ does block SACs in these conditions. Our experiments with another type of SAC-blocker, streptomycin (19), show a dose-dependent inhibition of the perfusion-induced increase in Fdev (Table 1), confirming that SACs underlie the Gregg effect. These results also make it unlikely that the inhibition of the Gregg effect by Gd3+ is a nonspecific side effect, because two different types of SAC blockers, Gd3+ and streptomycin, would then have a similar nonspecific side effect. The findings of Nicolosi et al. (31) support the fact that Gd3+ blocks SACs in bicarbonate conditions: Gd3+ was able to eliminate the adverse effects of overstretching in isolated guinea pig papillary muscles using a solution with bicarbonate without affecting basal force development. The experiments with the L-type Ca2+ channel blocker verapamil (Table 1), which resulted in a decrease of basal force of 56.0 ± 4.5%, did not affect the perfusion-induced increase in Fdev. These results, together with the absence of a decrease of basal force development (Table 1) and no change in basal [Ca2+]i transient (Fig. 4) by the addition of Gd3+ in the presence of bicarbonate, indicates that L-type Ca2+ channel blockade by Gd3+ does not occur in bicarbonate conditions. Boland et al. (6) also showed that Gd3+ did not inhibit voltage-activated Ca2+ channels in the presence of bicarbonate. Our results and literature thus show clearly that Gd3+, in the presence of bicarbonate, does not block L-type Ca2+ channels. Gd3+ also reduces basal force development and inhibits the perfusion-induced increase in Fdev in the HEPES experiments (Table 1). This indicates that in bicarbonate free conditions, "free Gd3+" inhibits not only SACs but also L-type Ca2+ channels, as mentioned by Lacampagne et al. (28). This suggests that the inhibition of L-type Ca2+ channels by Gd3+ depend on its conformation: the "free" form inhibits L-type Ca2+ channels whereas the "bicarbonate-bound" form does not. Therefore, our results and other studies (6, 31) show clearly that Gd3+, in the presence of bicarbonate, does block SACs and that the perfusion-induced increase in Fdev (Gregg effect) is related to activation of SACs and not to L-type Ca2+ channel blockade or a nonspecific side effect of Gd3+.Implications. Dankelman et al. (10, 11) clearly showed that the Gregg effect is present under normal physiological conditions; however, it is not observable due to the speed of autoregulation. The Gregg effect will be uncovered during ineffective autoregulation (16), which can occur in pathological situations, such as the onset of hibernation or distal from a stenosis, where autoregulation is restricted. When coronary perfusion increases, stretch of the membranes of cardiomyocytes will activate SACs, and cardiac contractility and oxygen consumption will increase. When coronary perfusion decreases, reduced deformation of the membranes of cardiomyocytes will inactivate SACs, and cardiac contraction and oxygen consumption will be reduced. Therefore, the Gregg effect may constitute an immediate protective mechanism in preventing a mismatch between cardiac contractility and oxygen delivery. In low coronary perfusion conditions, when autoregulation is ineffective, the Gregg effect may constitute an immediate mechanism that increases the pump function of the heart after increased coronary perfusion. A similar statement was made by Merkus et al. (29), who found a shorter diastolic time fraction (earlier onset of relaxation) at lower perfusion pressures in anesthetized open-chest dogs. Changes in interstitial volume and changes in buffer capacity for ions were put forward as mechanisms, whereas the involvement of oxygen shortage or a NO pathway was excluded. These findings are similar for the Gregg effect, as mentioned in this study. Unfortunately, the role of SACs was not investigated by Merkus et al. (29), which would have provided more information on a common mechanism for the effect of perfusion changes on cardiac contraction. We conclude that brief, repetitive, or sustained increases in coronary perfusion augment cardiac contractility through activation of stretch-activated ion channels, whereas endothelial NO release and L-type Ca2+ channels are not involved.
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ACKNOWLEDGEMENTS |
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This study was supported by The Netherlands Heart Foundation Grant 96-024.
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FOOTNOTES |
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First published December 13, 2001;10.1152/ajpheart.00327.2001
Address for reprint requests and other correspondence: R. R. Lamberts, Laboratory for Physiology, Vrije Universiteit, Van der Boechorststraat 7, Amsterdam, 1081 BT, The Netherlands (E-mail: lamberts{at}physiol.med.vu.nl).
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.
Received 24 April 2001; accepted in final form 6 December 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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) and after
(
) addition of the following pharmacological agents:
1) 10 µmol/l gadolinium (Gd3+)
stretch-activated ion channel (SAC) blockade (top,
n = 7); 2) 100 µmol/l
N
