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University Laboratory of Physiology, Oxford OX1 3PT, United Kingdom
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Isolated,
spontaneously beating rabbit sinoatrial node cells were subjected to
longitudinal stretch, using carbon fibers attached to both ends of the
cell. Their electrical behavior was studied simultaneously in
current-clamp or voltage-clamp mode using the perforated patch
configuration. Moderate stretch (~7%) caused an increase in
spontaneous beating rate (by ~5%) and a reduction in maximum
diastolic and systolic potentials (by ~2.5%), as seen in
multicellular preparations. Mathematical modeling of the stretch intervention showed the experimental results to be compatible with
stretch activation of cation nonselective ion channels, similar to
those found in other cardiac cell populations. Voltage-clamp experiments validated the presence of a stretch-induced current component with a reversal potential near 
11 mV. These data confirm, for the first time, that the positive chronotropic response of the
heart to stretch is, at least in part, encoded on the level of
individual sinoatrial node pacemaker cells; all reported data are in
agreement with a major contribution of stretch-activated cation
nonselective channels to this response.
heart rate; mechanoelectric feedback; stretch-activated channels; modeling; electrophysiology
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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IT HAS BEEN KNOWN FOR ALMOST A CENTURY that increased filling of the right atrium causes heart rate acceleration (2). Still, the (sub)cellular mechanisms that give rise to this response, commonly referred to as the "Bainbridge effect," remain uncertain.
Initially, the heart's positive chronotropic response to stretch was believed to be caused by an autonomic reflex. With the confirmation of qualitatively similar responses in isolated heart and sinoatrial node (SAN) preparations, however, it became obvious that the pacemaker's response to stretch must be, at least in part, caused by mechanisms that are intrinsic to the heart and the SAN (4, 11).
Typically, the SAN responds to stretch with an increase in beating rate and a reduction in both maximum diastolic and systolic potentials (MDP and MSP, respectively; Refs. 11 and 20). This response could be caused by stretch activation of ion channels with a reversal potential between MDP and MSP.
There are at least two major groups of stretch-activated channels
(SACs) in cardiac cells: cation nonselective (reversal potential between 0 and 20 mV) and potassium selective (reversal potential negative to MDP). Cation nonselective SACs could therefore form a
plausible candidate for the SAN's response to stretch. These channels
have, however, not yet been directly identified in SAN cells
(15).
Another group of cardiac ion channels with a reversal potential between MDP and MSP, which are frequently assumed to be mechanically operated, have been identified in rabbit SAN cells: cell-volume activated chloride channels (13).1 Unlike SACs, these channels require an increase in cytosolic volume for their activation (8, 28). Although volume-activated channels are likely to play a role in cell volume regulation, they are understood to be of little bearing in the context of beat-by-beat variations in cell (or tissue) length and tension, as cell volume is not assumed to change during the cardiac cycle of relaxation or contraction. Swelling of rabbit SAN cells, however, has been shown to actually decrease their spontaneous beating rate (22).
Finally, there is the possibility that cardiac nonmyocytes contribute to the positive chronotropic response to stretch. This could include electrical interactions with mechanosensitive connective tissue cells, paracrine effects from endothelial cells, or intracardiac neuronal reflexes (1, 18, 19, 25).
This raises the question of whether the heart's positive chronotropic response to stretch is a consequence of pacemaker cell properties or whether it necessarily requires the interaction of groups of cells. This study investigates the effects of direct longitudinal stretch on the electrophysiology of isolated, spontaneously beating rabbit SAN pacemaker cells.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Cell isolation. Cells were isolated according to the procedures described previously by Brown (5). Briefly, 600- to 1,000-g New Zealand White rabbits were killed by cervical dislocation; hearts were excised quickly and placed in HEPES-buffered oxygenated Tyrode solution and washed for 3 min by Langendorff perfusion at 37°C. After atrioventricular dissection, the right atrium was positioned in a perfused preparation dish with the endocardial side pointing upward. The SAN area was separated, and four to five thin tissue strips (~3 × 1 mm) were cut from the node, perpendicular to the crista terminalis. Tissue strips were continuously superfused with Tyrode solution until reoccurrence of spontaneous beating activity could be confirmed (1-3 min).
Spontaneously active SAN tissue strips were placed, for 5 min, in nominally Ca2+-free Tyrode solution before the now quiescent tissue strips were incubated for 35-40 min at 37°C in 400 U/ml collagenase (Yakult) and 3.4 U/ml elastase (Sigma-Aldrich) dissolved in nominally Ca2+-free Tyrode solution. Tissue strips were then washed in Kraft-brühe (KB) storage medium and kept at 4°C for at least 1 h. Single cells were released from the strips directly into the KB-filled perfusion chamber, using either microforceps or pipette suction for agitation. Reexposure to normal Tyrode solution was preceded by superfusion with low-Ca2+ Tyrode solution; the changeover between solutions was graded and occurred over a period of 5 min. During experiments, the bath (volume <0.5 ml) was perfused with Tyrode solution at a rate of 2.5-3 ml/min while the superfusate temperature was servo-controlled at 36 ± 0.5°C.Solutions. Normal Tyrode solution contained (in mM) 140 NaCl, 5.4 KCl, 1.8 CaCl2, 1 MgCl2, 11 glucose, and 8 HEPES and was titrated with NaOH to pH 7.4. Ca2+-free solution contained (in mM) 140 NaCl, 5.4 KCl, 1 MgCl2, 11 glucose, and 8 HEPES titrated with NaOH to pH 7.4. KB solution contained (in mM) 30 KOH, 25 KCl, 80 L-glutamic acid, 10 taurine, 14 oxalic acid, 18 KH2PO4, 0.5 MgSO4, 0.5 EGTA, 10 glucose, and 10 HEPES titrated to pH 7.2 with KOH. The pipette solution contained (in mM) 80 KOH, 50 KCl, 90 aspartic acid, 1 MgCl2, 5 MgATP, 2.5 phosphocreatine di-tris, 2.5 creatine disodium phosphate, 0.1 EGTA, and 10 HEPES titrated to pH 7.4 with KOH. Amphotericin B (200 µg/ml) was added to the pipette solution immediately before the experiments.
Current- and voltage-clamp recordings. The perforated patch-clamp mode was used for electrical recordings from single SAN cells. Patch pipettes were made from 1-mm square, glass capillaries with a 0.5 × 0.5 mm opening (Friedrich & Dimmock) using a Narishige (PB-7) electrode puller. Electrode tip diameters were ~1-2 µm and resistances ranged from 4 to 8 M
. Patch pipettes were positioned with the drift-free PatchMan electronic manipulator (Eppendorf), and
electrical signals were recorded with an Axopatch-200B patch-clamp amplifier (Axon Instruments). Data were digitized at 10 kHz with a
Digidata 1200B (Axon Instruments) and displayed and analyzed with the
help of pCLAMP 8 software (Axon Instruments).
Mechanical stimulation.
A pair of carbon fibers, attached to opposite ends of an isolated cell,
was used to apply longitudinal stretch while electrophysiological recordings were obtained via a patch pipette positioned half way along
the cell (see Fig. 1). This allowed application of bidirectional stretch while reducing transversal shift of the membrane patch under
the pipette.
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Statistics. All results are presented as means ± SE. Statistical significance was determined by ANOVA for repeated measures and Dunnett's test for multiple comparisons, using Prism software (GraphPad). A probability of P < 0.05 was considered to indicate rejection of the null hypothesis, therefore denoting a significant difference between means.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Current-clamp data.
Direct longitudinal stretch of moderate amplitude (5-10% of
resting cell length) was applied to eight spontaneously beating rabbit SAN cells, using the carbon fiber technique (Fig.
1). Moderate mechanical stimulation
was chosen to avoid cell damage, as witnessed by the reversal of
stretch-induced responses on return to control length (see Table 1).
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Mathematical modeling.
Using the Oxsoft Heart v4.8 model (Cell MicroControls, Virginia Beach,
VA), we simulated moderate stretch of a spontaneously active SAN
pacemaker cell (24). We used the standard single SAN cell
model contained in the Oxsoft software suite and a previously developed
algorithm for modeling of stretch effects on cardiac cells
(17), which is an integral part of the package. For the simulations, the following settings were specified:
Kmode = 9 to simulate the delayed rectifier potassium
current as consisting of both rapidly and slowly activating
components iKr and
iKs, STmode = 2 to
introduce stretch-activated conductances, GST = 0.00035 to define
the maximum stretch-activated conductance as 350 pS, EST = 20 to
set the reversal potential of this conductance to 20 mV, and HST = 1.8 to define half activation of the stretch-activated conductance to
occur at a sarcomere length of 1.8 µm (for a detailed account on the
mathematical apparatus, see Ref. 17). These settings are
based on the attempt to assess stretch effects in a previously established and publicly available mathematical model by modifying as
few settings as possible to avoid "overcustomization," using the
most pessimistic of parameters of a plausible range (e.g., a reversal
potential of 20 mV).
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20 mV), the current is outward during
systole (i.e., when SAN cell membrane potential is positive to the
current's reversal potential) and inward during diastole (Fig. 2,
bottom). In the model, this causes a reduction in both maximum upstroke velocity (Fig. 2, middle trace, positive
maxima) and late repolarization velocity (Fig. 2, middle
trace, level of plateau after negative velocity maximum). The
latter changes were also observed in the current-clamp study of stretch
effects on spontaneous SAN cell activity (Table 1). There was no
prominent change in spontaneous diastolic depolarization rate, neither
in the model nor in the experiments (Table 1), indicating that the effects of stretch-induced activation of a diastolic inward current have been counteracted by other changes, like a reduction in activation of the hyperpolarization-activated inward current and inactivation of
the delayed rectifier potassium current (as a consequence of the
decrease in MDP). This balance of primary and secondary stretch-induced responses could change with the level of mechanical stimulation and/or
properties of stretch-activated currents and vary between species or
pacemaker sites. Still, the response shows that an increase in beating
rate can be observed in the absence of a significant change in
diastolic depolarization rate. Under our experimental conditions, the
increase in beating rate is brought primarily about by the reduction in
potential maxima, in particular, by reducing the distance between MDP
and excitation threshold, as witnessed by the predominant reduction in
spontaneous depolarization time, as seen in our experiments (see Table
1).
If these simulations sensibly reproduce a (sub)cellular mechanism of
the positive chronotropic response of SAN cells to stretch, then it
should be possible in voltage-clamp experiments to observe a
stretch-induced inward current at MDP and a stretch-induced outward current at MSP levels (Fig. 2, bottom).
Voltage-clamp data. This series of experiments used the same SAN cell selection criteria as applied in the current-clamp studies.
A first study design was based on attempting to hold the membrane potential of isolated SAN cells at various levels and to repetitively apply stretch to the cell. This proved to be very difficult, as application of reproducible levels of stretch is complicated [potential changes in cell attachment, membrane "softening," rearrangement of tension-bearing elements, release of autocrine blocking agents, and so forth (3)]. The application of well-controlled levels of "external" stretch does not, by itself, guarantee reproducible levels of "internal" stretch activation of (sub)cellular mechanisms (27). In our experiments, isolated SAN cells were voltage clamped to either +40 mV (n = 5) or60 mV (n = 6) to
mimic MSP and MDP conditions before moderate stretch was applied. In
all cases, stretch elicited an outward current at +40 mV and an inward
current at 60 mV. This is in keeping with the proposed activation of an ion channel population with a reversal potential between MSP and MDP.
To obtain a more quantitative measure of stretch effects on whole cell
currents, a second study design was introduced, based on repetitively
performing voltage-clamp step protocols at different levels of
longitudinal stretch.
Five SAN cells were subjected to a sequence of depolarizing voltage
steps (from a holding potential of 60 to +40 mV, in steps of 10 mV),
in the presence and absence of stretch (Fig.
3, A and B). The
difference current (Fig. 3C) shows the presence of an inward
current at the holding level of 60 mV, which was reduced and turned
outward by progressive depolarization (for clarity, Fig. 3,
A-C, shows 20-mV steps only). The amplitude of the
stretch-induced current ranges from 30 to +20 pA, which is the same
order of magnitude as predicted by the modeling.
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11.0 mV (the 95% confidence
interval for the reversal potential ranges from 4.4 to 17.8 mV).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Thus moderate stretch of rabbit SAN pacemaker cells, by 5-10% of their resting length, causes a fully reversible increase in their spontaneous beating rate and a reduction in MDP and MSP. This is the first observation of a cellular substrate for the Bainbridge effect (2), the positive chronotropic response of the heart to stretch.
Both experimental studies and mathematical modeling suggest that this
response may be caused by activation of cation nonselective SACs with a
reversal potential between MDP and MSP of the SAN cell. There is no
evidence of a predominant role of potassium-selective SACs, as this
would be predicted to cause an outward current at all potential levels
tested, therefore shifting both MDP and MSP in a negative direction.
Our voltage-clamp data suggest a reversal potential for the
stretch-induced current roughly between 0 and 20 mV, which, again, is
typical for cation nonselective SACs observed in mammalian ventricular
myocytes (9, 10, 27). However, because the stretch-induced
whole cell current was obtained as a difference current, we cannot
exclude that this net current is made up of more than one underlying
current component. This theory will require further investigation [for
example, using specific SAC blockers such as GsMTx-4
(26)].
When the most "pessimistic" (i.e., least "depolarizing") of
these levels is used to simulate SAC effects on SAN cell activity, the
mathematical model predicts that a stretch-activated current in the
10
11-A region would be sufficient to cause a positive
chronotropic response. This is consistent with the experimentally
observed stretch-induced currents. Thus it is likely that SACs are an
important subcellular mechanism of the positive chronotropic response
to stretch.
Alternatively, a stretch-induced increase in cAMP (6) could cause enhanced activation of the hyperpolarization-activated "pacemaker" current, (12), which should cause a significant increase in the diastolic depolarization rate. The latter could not be confirmed in this study. Also, the time course of cAMP synthesis would suggest that this mechanism is less likely to explain the pacemaker's instant response to stretch.
Furthermore, it is interesting to see that the stretch-dependent current component, revealed as the current difference between stretched and nonstretched states (Fig. 3C), is almost completely flat. This makes it unlikely that, under our experimental conditions, other voltage- or time-dependent currents were significantly affected by stretch. This, together with the reduction in maximum upstroke velocity during stretch (Table 1), does not support the notion of a stretch-induced increase in open probability of the L-type Ca2+ channel in rabbit SAN pacemaker cells (23) during moderate stretch.
Finally, we would like to stress the importance of working in perforated patch mode and of selecting only SAN pacemaker cells that show spontaneous rhythmical beating and steady action potential parameters, as these investigations depend crucially on cell quality.
Thus we have shown that the Bainbridge effect has its origins, at least in part, at the level of individual SAN cells and that it does not necessarily require interaction with other cells. This does not, however, exclude an additional contribution of other (multi)cellular mechanisms to the positive chronotropic response to stretch (11, 16, 18).
In conclusion, the heart's positive chronotropic response to stretch is, at least in part, accomplished by mechanisms present at the level of individual SAN pacemaker cells. The electrophysiological data are consistent with a significant contribution of cation nonselective SACs, similar to those reported in other cardiac cell populations. We have found no indication of prominent stretch modulation of other, voltage-dependent ion conductances. The confirmation of an involvement of cation nonselective ion channels in this response will require further experiments, using direct longitudinal stretch of isolated cardiac pacemaker cells, ideally in combination with newly identified selective blockers of these SACs (26).
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ACKNOWLEDGEMENTS |
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We are indebted to Prof. LeGuennec, Tours University, for kindly providing carbon fibers and thank both him and Dr. White, Leeds University, for helpful comments.
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FOOTNOTES |
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This work was supported by the British Heart Foundation (PG/98053, PG/99060) and the Medical Research Council. P. Kohl is a Royal Society University Research Fellow.
Address for reprint requests and other correspondence: P. Kohl, Univ. Laboratory of Physiology, Univ. of Oxford, Oxford OX1 3PT, UK (E-mail: peter.kohl{at}physiol.ox.ac.uk).
1 Please note that some of the earlier reports portray cell volume manipulations as "stretch" of cells, which calls for caution when assessing the published literature.
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 28 July 2000; accepted in final form 21 August 2000.
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TOP
ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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