role of the sarcoplasmic reticulum in the modulation of rat cardiac action potential by stretch

Role of the sarcoplasmic reticulum in the modulation of rat

cardiac action potential by stretch

C . H A N , 1 , 2 P . T A V I 1 and M . W E C K S T R OÈ M 1 , 2

1 Department of Physiology, Division of Biophysics, and Biocenter Oulu, University of Oulu, Oulu, Finland

2 Department of Physical Sciences, Division of Biophysics, and Biocenter Oulu, University of Oulu, Oulu, Finland

ABSTRACT

We have investigated the role of sarcoplasmic reticulum (SR) in the modulation on rat action

potentials by stretch. The action potentials were recorded intracellularly from rat atrial myocytes in an

isolated atrial preparation with small, physiological stretch produced by pressure (1±3 mmHg) inside

the atria. The SR function was inhibited by pharmacological interventions, either with ryanodine

(100 nmol L±1), thapsigargin (10 nmol L±1) or caffeine (1 mmol L±1). The duration of action potentials

was increased by stretch from 1 to 3 mmHg. The repolarization indices APD30% (P < 0.05), APD60%

(P < 0.01), and APD90% (P < 0.01) were all increased signi®cantly (n� 10). Ryanodine, thapsigargin,

and caffeine inhibited this prolongation, or even reversed the effect with repolarization indices

APD30% (P < 0.05) and APD60% (P < 0.05) which decreased in stretch with thapsigargin treatment.

As a conclusion, we suggest that the SR and the intracellular calcium balance play an important role in

the modulation of the shape of the rat atrial action potential during stretch.

Keywords caffeine, membrane potential, ryanodine, sarcoplasmic reticulum, thapsigargin.

Received 8 October 1998, accepted 24 June 1999

The effects of stretch on the shape of the action

potential (AP) of the myocytes are important

concerning, e.g. the arrhythmogenesis caused by stretch

(Tavi et al. 1996). In species with long AP plateau, such

as the guinea-pig and the rabbit, stretch reduces the

duration of the AP (Lerman et al. 1985, Dean & Lab

1990, White et al. 1993, Tung & Zou 1995, Wang et al.

1996). In contrast, stretch of cat papillary muscle

increases the duration of the APs at 80% repolarization

level (Allen 1977).

The stretch-sensitivity of the cardiac cells has

previously been explained on the basis of stretch-

activated ion channels (SACs) (Bustamante et al. 1991,

Sasaki et al. 1992, Kim 1992, 1993, Ruknudin et al.

19931 ) that would directly, by introducing an additional

conductance, change the shape of APs. Using the

so-called monophasic AP recordings from isolated

rabbit heart, combined with computer simulation that

included the SACs, Zabel et al. (1996) found that

stretch shortened the APs in early repolarization, but

increased the duration at late repolarization. However,

in cardiac myocytes the waveform of APs has also been

shown to be dependent on the size of the Ca2+ tran-

sients, via modulation in the Na+±Ca2+ exchange

current (Schouten & ter Keurs 19852 , DuBell et al.

1991). Interestingly, stretch increases the (systolic) Ca2+

transients after stretch (Allen & Kurihara 1982, Hongo

et al. 1995, 1996, Kentish & Wrzosek 1998, Tavi et al.

1998), suggesting that the sarcoplasmic reticulum (SR)

Ca2+ load is in¯uenced by stretch. This is because the

Ca2+ transients mainly develop from the Ca2+ released

from the SR (Delbridge et al. 1996, Bers 1997).

Supporting this, by using rapid cooling contractures,

Bluhm & Lew (1995) found that the Ca2+ content in

the SR is larger after stretch. Because the amount of

Ca2+ released is strongly dependent on the amount

stored in the SR (Janczewski et al. 1995), we postulated

that the SR should play an important role in the

modulation of cardiac APs in stretch. This hypothesis is

strongly supported by a recent study from our labora-

tory (Tavi et al. 1998), which suggested that in rat

atrium small, physiological stretch modulates the shape

of APs mainly via changes in the Na+/Ca2+ exchanger

current that are caused by increased calcium transients.

While this is in contrast to the proposed direct effects

of stretch-activated conductances on the APs in the

rabbit ventricle (Zabel et al. 1996), we investigated in

this study how the APs change during stretch when the

Correspondence: Prof. Matti WeckstroÈm MD PhD, Department of Physiology, University of Oulu, Kajaanintie 52 A, FIN-90220 Oulu, Finland.

Acta Physiol Scand 1999, 167, 111±117

Ó 1999 Scandinavian Physiological Society 111

SR is incapacitated by pharmacological interventions.

The main hypothesis was that with small, physiological

stretch the changes in calcium balance in the rat atrial

myocytes are more prominent than the direct effects of

any stretch-activated conductances on the shapes of the

APs. Thus, by incapacitating the SR, we should be able

to abolish the stretch-sensitivity of the APs.

MATERIALS AND METHODS

Animals, preparation and superfusion

Male Sprague±Dawley rats (n > 50) weighing 290±

400 g were used. The rats were decapitated, and their

hearts were rapidly removed and placed in oxygenated

cool (25 °C) buffer. The methods and the set-up used

to simulate the physiological stretch effect in rat left

atrium have been described in detail previously (Laine

et al. 1994, Tavi et al. 1996). Brie¯y, an X-branch

polyethylene adapter was inserted into the lumen of the

left auricle, and the tissue was placed in a constant

temperature (37 °C) organ bath. Another tube with

smaller diameter was inserted inside the adapter in

order to carry perfusate in¯ow into the lumen of the

auricle. The out¯ow from the lumen came from one

crossbranch of the X-cannula. The out¯ow tube was

connected to the chamber of a pressure generator

(WGA-200, Millar Instrument, USA), by which the

increased pressure could be generated into the lumen of

the atrium. The other crossbranch of the X-cannula

was connected to a pressure transducer (TCB 100,

Millar Instruments, USA), so that the pressure could be

monitored with an oscilloscope. In¯ow and out¯ow

(3 mL min±1) both to the auricle lumen and to the

organ bath (with constant temperature) were controlled

by a peristaltic pump (7553±85, Cole-Parmer Instru-

ment, USA).

Electrophysiological recordings

Intracellular APs were recorded at 37 °C with standard

glass microelectrodes with tip resistances of 70±

120 MW when ®lled with a solution 2 mol L±1

K-acetate and 5 mmol L±1 KCl (pH 7.0). To record

from moving (contracting and stretched) tissue, a

¯exible holder attachment for the microelectrodes was

used. The left atrial appendix was stimulated electrically

through bipolar Ag/AgCl electrodes placed in contact

with the auricle. Electrical stimulation (steps of 1-ms

duration, 50% over threshold voltage) was provided by

a stimulator (S44, Grass Instruments, USA). Membrane

potential signals were ampli®ed with an intracellular

ampli®er (Dagan 81001±1, Dagan, USA) and sampled

at 5 kHz with a 12-bit analogue-to-digital converter

(DT2821, Data Translation, USA). Data analysis was

done with MATLAB (The Math Natick, MA, USA) and

Origin (Microcal, USA) programs. The criteria for

accepted APs were: the resting potential at least

±70 mV and the overshoots of the APs at least 10 mV.

The APs were analysed with a MATLAB-based ana-

lysing program, and the durations determined were

APD15%, APD30%, APD60% and APD90% (where APD

means `action potential duration' and the following

number stands for the percentage of repolarization at

the determined time).

Experimental protocols

To study the physiological effects of stretch in the rat

atria all preparations were paced continually and were

left to stabilize in constant (diastolic) 1 mmHg pressure

level at least half an hour after preparation. Thereafter

the pressure inside of the atria was gradually but rapidly

increased from 1 to 3 mmHg. The pressure was held at

this level at least 10 min before recording. In phar-

macological interventions, ryanodine (100 nmol L±1),

thapsigargin (10 nmol L±1) and caffeine (1 mmol L±1)

were added to the normal superfusion solution at the

beginning and throughout the experiments. The

recordings were made not earlier than 30 min of

superfusion with a solution containing these agents, but

normally even later. The suf®cient depletion of the SR

was checked by monitoring the contraction of the atria,

which was abolished in all cases with all the pharma-

cological treatments used. The effectiveness of the SR

depletion may also be judged from the drastic effect

the treatments have on the shape of the APs (see

Table 2).

Solutions and agents

In all experiments we used a Krebs±Henseleit solution

of the following composition (as mmol L±1): 113.8

NaCl, 4.7 KCl, 17.6 NaHCO3, 1.2 KH2PO4, 1.1

MgSO4, 2.5 CaCl2, 11.0 glucose. Gassing this solution

with 95% O2 and 5% CO2 adjusted the pH to 7.4.

Ryanodine was obtained from Calbiochem (San Diego,

USA), thapsigargin from Alomone Labs (Jerusalem,

Israel), and caffeine from Sigma (USA).

Statistics

All results are given as mean � SE. The statistical tests

were done using either SigmaStat (USA) or Origin

(Microcal, USA) software. ANOVA, followed by

Student±Newman±Keuls test, or the student's t-test,

where appropriate, were used to evaluate the statistical

signi®cance of the results. P < 0.05 was accepted as the

level of signi®cance.

Sarcoplasmic reticulum and stretch � C Han et al. Acta Physiol Scand 1999, 167, 111±117

112 Ó 1999 Scandinavian Physiological Society

RESULTS

Effects of stretch on the action potentials

In the present study we investigated the changes in the

electrophysiological properties of myocytes in the

isolated rat left atrium when they were subjected to

small (physiological) stretch from (diastolic) intra-atrial

pressure of 1±3 mmHg. Stretch modulated the shape of

the APs after 10 min of stretch. As shown in Fig. 1 and

Table 1, stretch signi®cantly prolonged all phases of

repolarization, except the earliest one. When compared

with control (pressure level 1 mmHg), moderate stretch

(3 mmHg) increased the APD30% (n� 10, P < 0.05),

the APD60% (n� 10, P < 0.01) and the APD90%

(n� 10, P < 0.01). There was no signi®cant change in

the resting potentials or the amplitudes of the APs.

Effects of stretch after SR depletion

To study the role of the SR in the stretch-induced

changes in the shape of the APs, we treated the atria

with pharmacological agents known to interfere with

the intracellular Ca2+ balance in a way that reduces the

effects of calcium release from the SR by emptying the

calcium stores. Firstly, we wanted to know the effects

of these drugs on the APs at control pressure

(1 mmHg). The drugs we used were ryanodine, an

agent that locks the calcium release channels (the

so-called ryanodine receptors, Bers et al. 1987, Lewar-

towski et al. 1990) into a semi-open state in the

concentration used (100 nmol L±1) thereby depleting

the calcium stores, thapsigargin, an inhibitor of the SR

calcium-ATPase that is required to replenish the stores

(Thastrup et al. 1990, Kirby et al. 1992), or caffeine that

increases the calcium leakage from SR via the ryano-

dine-sensitive channels (Chapman and LeÂoty 1976,

Smith et al. 1988). Figure 2 shows that after 10 min of

treatment, ryanodine, thapsigargin and caffeine all

signi®cantly prolonged the duration of the APs at

control pressure of 1 mmHg (see Table 2 for statistics).

Ryanodine had a more prominent effect on the early

than late repolarization phase, but thapsigargin's effect

was almost the same in early and late repolarization.

Low concentration of caffeine (1 mmol L±1) prolongs

moderately all repolarization phases, in a similar

manner as does ryanodine and thapsigargin. High

concentration of caffeine (10 mmol L±1) mainly effects

the early repolarization and was thus not used in the

further analysis (data not shown), because it can be

assumed that these additional effects are caused by

other, unspeci®c effects of the drug. We may conclude

in this part of the study that the intact function of SR

calcium release has a signi®cant contribution to the

shape of the APs, and the inhibition of the release by

depletion of the calcium stores, however, achieved,

prolongs the repolarization. These results are inde-

pendent of whether the SR was fully depleted or not,

and in this context a depletion that is able to inhibit the

contraction of the muscle, which was achieved in all

preparations treated (see Methods), is effective enough.

Second, experiments were conducted to ®nd out the

effects of stretch on the shape of the AP under

conditions where the SR calcium release in incapaci-

tated. Figure 3 and Table 3. show, respectively, the

averaged APs and the repolarization indices from these

experiments. When small stretch (again from 1 to

3 mmHg) is applied, the effects of the pharmacological

interventions persist. However, as apparent from the

®gures and from the repolarization indices, we did not

®nd signi®cant prolongation of the APs by stretch

under those conditions. The conclusion from this

second set of experiments is that when SR calcium

release is non-functional, the sensitivity of the APs to

stretch is abolished. In addition, it has to be noted that

Table 1 Effect of stretch on the voltage and duration parameters of

rat atrial action potential

1 mmHg (n = 10) 3 mmHg (n = 10)

Resting Potential (mV) )76.2 � 0.6 )75.6 � 0.8

Amplitude (mV) 91.7 � 0.8 89.6 � 1.0

Overshoot (mV) 15.5 � 0.8 14.0 � 1.0

APD10% (ms) 5.2 � 0.5 7.0 � 0.4

APD15% (ms) 6.6 � 0.6 8.9 � 0.5

APD30% (ms) 10.4 � 0.6 14.0 � 0.7*

APD60% (ms) 20.2 � 1.6 29.8 � 1.3**

APD90% (ms) 53.7 � 4.2 73.4 � 2.2**

*P < 0.05; **P < 0.01 (t-test).

Figure 1 Effect of stretch on action potentials of rat atrial myocytes.

Small, physiological stretch (3 mmHg, dotted line) increases the

duration of action potentials of rat atrium when compared with the

control (1 mmHg, solid line). The resting potentials of the recordings

were set to be the same to facilitate comparison of AP shape. The

®gure shows two individual action potentials, for statistics, see

Table 1.


Acta Physiol Scand 1999, 167, 111±117 C Han et al. � Sarcoplasmic reticulum and stretch

in case of thapsigargin treatment the APD30% and

APD60%, and in the case of ryanodine, the APD30%,

values are actually decreased (repolarization is acceler-

ated) by stretch (for statistics, see Table 3).

DISCUSSION

The main ®nding from this study was that the duration

of rat atrial AP was prolonged during small, physio-

logical stretch, and that this change was abolished by

pharmacological treatments that deplete the intracel-

lular calcium stores and thereby render the stores non-

functional. An immediate conclusion from this is that

stretch of the myocytes is mediated, at least in the case

of the rat left atrium, via a change in the intracellular

calcium balance into changes in the shape of APs.

When the SR function is incapacitated, stretch is not

able to change the APs. This ®nding points to mech-

anisms that are able to modulate the intracellular

calcium transients during stretch, possibly by changing

the amount of Ca2+ in the stores.

Stretch-induced changes in the action potential

Many investigations have found that the duration of the

cardiac AP is reduced after stretching the cardiac

muscle (Nakagawa et al. 1988, Dean & Lab 1990, White

et al. 1993, Tung & Zou 1995, Wang et al. 1996). Both

rapid and gradual stretch is also able to trigger

arrhythmias owing to stretch-induced depolarizations

(Stacy et al. 1992, Franz et al. 1992). The change in

membrane voltage in response to stretch suggests that

stretch was able to activate a conductance change in the

plasma membrane. Based on these observations,

changes in the APs during stretch have been explained

by activation of stretch-activated channel in the plas-

malemma (Hansen et al. 1991). Using MAP-recordings,

Zabel et al. (1996) found that the duration of the early

repolarization phase decreased and the late repolariza-

tion phase increased after stretch in the guinea-pig

ventricle. They were able to mimic this observation by

introducing the stretch-activated channels (SACs) into a

mathematical model in computer simulations.

Following this logic, the introduction of a signi®cant

calcium conductance into the membrane should lead to

an increase in stored calcium. In fact, using the rapid

cooling method, Bluhm & Lew (19953 ) showed that the

amount of Ca2+ in the SR is increased by stretch.

Mechanisms of stretch-sensitivity

The present work emphasizes the importance of the

intracellular calcium balance in response to stretch, in

contrast to direct modulation of the APs by stretch-

activated ionic channels. One possibility is that stretch

causes an increase in the SR calcium stores. Many

Table 2 Change of the duration of the action potentials by phar-

macological treatments (ryanodine at 100 nmol L)1, thapsigargin at

10 nmol L)1 and caffein at 1 mmol L)1) incapacitating the SR

Control

(n = 10)

Ryanodine

(n = 10)

Thapsigargin

(n = 10)

Caffeine

(n = 10)

APD30% (ms) 10.4 � 0.9 21.1 � 1.2** 15.9 � 0.7** 12.5 � 0.2

APD60% (ms) 20.2 � 1.6 33.2 � 1.6** 30.4 � 1** 24.7 � 0.9

APD90% (ms) 53.7 � 4 59.7 � 2.6* 67.6 � 2.6* 62.8 � 1.4*

*P < 0.05; **P < 0.01 (ANOVA).

Figure 2 Effect of (a) ryanodine

(100 nmol L±1), (b) thapsigargin

(10 nmol L±1), and (c) caffeine (1 mmol L±1)

(dotted lines) on the action potential of the

rat atrium at the low stretch level (1 mmHg)

compared with untreated controls (contin-

uous lines). All these pharmacological

interventions prolong the duration of action

potential of rat atrial myocytes. For statis-

tics, see Table 2.



experiments have shown that the Ca2+ transients

increase during stretch (Allen & Kurihara 1982, Hongo

et al. 1995, 1996, Kentish & Wrzosek 1998). Allen et al.

(19884 ) suggested that the Ca2+ transient augmentation

is caused by activation of cation-permeable stretch-

activated ion channels during stretch. By rising diastolic

[Ca2+] this would lead to an increase of the SR Ca2+

content (Frampton et al. 1991). Stretch-activated chan-

nels are found in various tissues, including the

mammalian heart (Bustamante et al. 1991, Sasaki et al.

1992, Kim 1992, 1993, Ruknudin et al. 1993). It has

been suggested that the activation of a cationic

conductance, large enough to change the membrane

voltage signi®cantly, would be responsible for the

introduction of calcium into the cell and into the SR

(Zabel et al. 1996). This idea is opposed by the fact that

diastolic [Ca2+]i seems to remain unaltered during

stretch (Hongo et al. 1996, Kentish & Wrzosek 1998,

Tavi et al. 1998). Also, in the present study, we did not

®nd any change in the resting potentials of the cells

during stretch, which should have been prominent with

a large stretch-activated conductance (Table 1.). Our

results suggest that stretch-induced changes in the rat

atrial AP are mediated by SR Ca2+ loading. This would

clearly require some additional Ca2+ in¯ux during

stretch. However, this Ca2+ in¯ux can be mediated

either by SA-channel activation or by some other

(unknown) mechanism. The results are supported by

recent ®ndings combining experimental results and a

mathematical modelling (Tavi et al. 1998).

Species differences in the mechanisms

In species other than the rat, and also in parts of the

heart other than the atrium, the calcium balance is likely

to be somewhat different (cf. Bers 1993). In species

with long APs the direct effect of SAC-activation may

be more prominent, because the calcium causing the

contraction of the myocyte is more weighted in favour

of the outside source (Bers 1997). Thus the effect of

intracellular calcium stores is probably much smaller

that in the rat atrium we have used. However,

therelationship between the calcium transients and

theshape of the APs is fairly complex. Depending on

the amount of calcium in the stores, the changes in the

size of the transient can plausibly be suggested to

modulate the repolarization either way. If the stores are

well loaded (or, if the released calcium plays a major

Figure 3 Effect of (a) ryanodine

(100 nmol L±1), (b) thapsigargin

(10 nmol L±1) and (c) caffeine

(1 mmol L±1) on the stretch-

induced changes in the action

potentials in the rat atrial

myocytes. Dotted lines show

representative APs with stretch

caused by pressure of 3 mmHg

and the continuous lines show

control APs at 1 mmHg. For

statistics, see Table 3

Table 3 The effect of stretch on the

duration of the action potentials when

the SR is incapacitated (ryanodine at

100 nmol L)1, thapsigargin at

10 nmol L)1 and caffeine at

1 mmol L)1)

Ryanodine Thapsigargin Caffeine

1 mmHg 3 mmHg 1 mmHg 3 mmHg 1 mmHg 3 mmHg

APD30% (ms) 21.1 � 1.2 20.8 � 0.9* 15.9 � 0.7 13.9 � 0.3* 12.5 � 0.4 13.8 � 0.2

APD60% (ms) 33.2 � 1.6 33.2 � 1.1 30.4 � 1 27.5 � 0.7* 24.7 � 0.9 27.4 � 0.8

APD90% (ms) 59.7 � 2.6 57.9 � 1.8 67.6 � 2.6 65 � 2.4 62.8 � 1.4 66.5 � 1.3

*P < 0.05 with ANOVA.



role), the inward current via the Na+±Ca2+ exchanger is

dominating. Conversely, if the stores are depleted,

the effects of the changes in the calcium transients via

the L-type calcium current are more prominent. This is

supported by our ®nding that in SR-depleted situations

stretch is able to accelerate the repolarization (Table 3.),

an effect which is opposite to that found in the

untreated preparations.

In conclusion, this study showed that the duration

of APs in rat atrial myocytes is prolonged by stretch,

and that this effect can be inhibited by pharmacological

agents that deplete the SR calcium stores. This is

consistent with the hypothesis that in rat atrial

myocytes the effects of stretch on AP shape are

mediated by a change in the calcium balance.

The authors are grateful for the help of Prof. Heikki Ruskoaho during

this work, to Anneli Rautio and Eero Kouvalainen for technical

assistance. The work was supported by the Academy of Finland

(M.W.) and Orion-Farmos Scienti®c Foundation (P.T.).

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role of the sarcoplasmic reticulum in the modulation of rat cardiac action potential by stretch

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