Department of Physiology, and Institute of Cardiovascular Sciences and Medicine, Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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ABSTRACT |
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To study the effects of -opioid receptor stimulation on
intracellular Ca2+ concentration
([Ca2+]i)
homeostasis during extracellular acidosis, we determined the effects of
-opioid receptor stimulation on
[Ca2+]i
responses during extracellular acidosis in isolated single rat
ventricular myocytes, by a spectrofluorometric method. U-50488H (10-30 µM), a selective
-opioid receptor agonist, dose
dependently decreased the electrically induced
[Ca2+]i
transient, which results from the influx of
Ca2+ and the subsequent
mobilization of Ca2+ from the
sarcoplasmic reticulum (SR). U-50488H (30 µM) also increased the
resting
[Ca2+]i
and inhibited the
[Ca2+]i
transient induced by caffeine, which mobilizes
Ca2+ from the SR, indicating that
the effects of the
-opioid receptor agonist involved mobilization of
Ca2+ from its intracellular pool
into the cytoplasm. The Ca2+
responses to 30 µM U-50488H were abolished by 5 µM
nor-binaltorphimine, a selective
-opioid receptor
antagonist, indicating that the event was mediated by the
-opioid
receptor. The effects of the agonist on
[Ca2+]i
and the electrically induced
[Ca2+]i
transient were significantly attenuated when the extracellular pH
(pHe) was lowered
to 6.8, which itself reduced intracellular pH
(pHi) and increased
[Ca2+]i.
The inhibitory effects of U-50488H were restored during extracellular acidosis in the presence of 10 µM ethylisopropyl amiloride, a potent
Na+/H+
exchange blocker, or 0.2 mM Ni2+,
a putative
Na+/Ca2+
exchange blocker. The observations indicate that acidosis
may antagonize the effects of
-opioid receptor stimulation via
Na+/H+
and
Na+/Ca2+
exchanges. When glucose at 50 mM, known to activate the
Na+/H+
exchange, was added, both the resting
[Ca2+]i
and pHi increased. Interestingly,
the effects of U-50488H on [Ca2+]i
and the electrically induced
[Ca2+]i
transient during superfusion with glucose were significantly attenuated; this mimicked the responses during extracellular acidosis. When a high-Ca2+ (3 mM) solution
was superfused, the resting
[Ca2+]i
increased; the increase was abolished by 0.2 mM
Ni2+, but the
pHi remained unchanged. Like the
responses to superfusion with high-concentration glucose and
extracellular acidosis, the responses of the
[Ca2+]i
and electrically induced
[Ca2+]i
transients to 30 µM U-50488H were also significantly attenuated. Results from the present study demonstrated for the first time that
extracellular acidosis antagonizes the effects of
-opioid receptor
stimulation on the mobilization of
Ca2+ from SR. Activation of both
Na+/H+
and
Na+/Ca2+
exchanges, leading to an elevation of
[Ca2+]i,
may be responsible for the antagonistic action of extracellular acidosis against
-opioid receptor stimulation.
sodium/hydrogen exchange; sodium/calcium exchange; sarcoplasmic reticulum
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INTRODUCTION |
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ACIDOSIS IS WELL KNOWN TO affect the cardiac functions (9, 12, 24). During myocardial ischemia, extracellular acidosis occurs with a lowered intracellular pH (pHi), which decreases contractility (3, 33). It has been shown that intracellular acidosis activates Na+/H+ exchange, leading to an increased extrusion of H+ in exchange for an influx of Na+ (9, 25, 29). The increased activity of Na+/H+ exchange in turn activates the reverse mode of Na+/Ca2+ exchange, leading to an increased influx of Ca2+ and an elevation of intracellular Ca2+ concentration ([Ca2+]i) (5, 30). The altered [Ca2+]i homeostasis may account, at least in part, for the altered contractility during extracellular acidosis (31, 42).
Both -opioid receptors (27, 44, 45, 53, 54) and
-opioid peptides
(48) are present in the heart. Previous studies have shown that during
myocardial ischemia the
-opioid receptor is activated
presumably because of an increased release of
-opioid peptides from
the heart (50, 51). It has been shown previously that
-opioid
receptor stimulation with a selective
-opioid receptor agonist
increases
[Ca2+]i
by mobilizing Ca2+ from the
sarcoplasmic reticulum (SR) via the phospholipase
C/Ca2+ pathway (7, 36-38, 43,
46, 47). It has been shown that
-opioid receptor
stimulation also negatively modulates the stimulatory effects of
-adrenoreceptor stimulation on cardiac contractility (52). Depletion
of Ca2+ from SR and negative
modulation of the
-adrenoreceptor are responsible, at least in part,
for the inhibitory action of
-opioid receptor stimulation on cardiac contractility.
Because both acidosis and -opioid receptor activation occur during
myocardial ischemia, it would be important to study the interaction between acidosis and
-opioid receptor stimulation and
the underlying mechanisms. The effect of acidosis on
-opioid receptor stimulation is, however, not known. In the present study we
determined the Ca2+ responses to
-opioid receptor stimulation in the heart during extracellular
acidosis. We measured the
[Ca2+]i
transients induced electrically and with caffeine, in addition to the
resting
[Ca2+]i,
in a single isolated ventricular myocyte preparation. The electrically
induced
[Ca2+]i
transient results from the influx of
Ca2+ on membrane depolarization,
which triggers Ca2+ release from
the SR via a Ca2+-induced
Ca2+-release mechanism, and has
been shown to correlate directly to the contraction of the myocyte
(52). The caffeine-induced
[Ca2+]i
transient is an index of the Ca2+
content in the SR because caffeine depletes SR of
Ca2+ (4, 40). We also determined
the Ca2+ responses to
-opioid
receptor stimulation after manipulations that stimulate or
mimic Na+/H+ exchange and
Na+/Ca2+
exchange in normal extracellular pH
(pHe). In addition, we
determined the Ca2+ responses
during extracellular acidosis when these two exchanges were inhibited.
Results from the present study showed that extracellular acidosis
antagonizes the effects of
-opioid receptor stimulation on
Ca2+ responses in the heart. This
action may result from activation of
Na+/H+
and
Na+/Ca2+
exchanges, which elevates the
[Ca2+]i.
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MATERIALS AND METHODS |
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Isolation of ventricular myocytes. Ventricular myocytes were isolated from the hearts of male Sprague-Dawley rats (190-210 g), by a collagenase perfusion method described previously (14). Immediately after decapitation, the hearts were rapidly removed from the rats and perfused in a retrograde manner at a constant flow rate (10 ml/min) with oxygenated Joklik MEM supplemented with 1.25 mM CaCl2 and 10 mM HEPES, pH 7.2, at 37°C for 5 min; this was followed by 5 min with the same medium free of Ca2+. Collagenase was then added to the medium to a concentration of 125 U/ml with 0.1% (wt/vol) BSA. After 35-45 min of perfusion with a medium containing collagenase, the atria were discarded. The ventricular tissue was transferred to an oxygenated solution that was the same as that described above but without collagenase; the tissue was cut into small pieces with a pair of scissors, and then the solution was stirred with a glass rod for 5 min to separate the ventricular myocytes from each other. The residue was filtered through 250-µm mesh screens, sedimented by centrifugation at 100 g for 1 min, and resuspended in fresh Joklik solution with 2% BSA. More than 70% of the cells were rod shaped and impermeable to trypan blue. The Ca2+ concentration of the Joklik solution was increased gradually to 1.25 mM in 40 min.
Measurement of [Ca2+]i. Ventricular myocytes were incubated with fura 2-AM (5 µM) in Joklik solution supplemented with 1.25 mM CaCl2 for 30 min. The unincorporated dye was removed by washing the cells twice in fresh incubation solution. The loaded cells were kept at room temperature (24-26°C) for 30 min before measurements of [Ca2+]i to allow the fura 2-AM in the cytosol to deesterify. Loading with a low concentration of fura 2-AM and at a relatively low temperature of 24-26°C was done to minimize the effects of the compartmentalization of the esters (39).
The ventricular myocytes loaded with fura 2-AM were transferred to the stage of an inverted microscope (Nikon) in a superfusion chamber at room temperature. The inverted microscope was coupled with a dual-wavelength excitation spectrofluorometer (Photo Technical International). The myocytes were perfused with a Krebs bicarbonate buffer containing (in mM) 118 NaCl, 5 KCl, 1.2 MgSO4, 1.2 KH2PO4, 1.25 CaCl2, 25 NaHCO3, and 11 glucose, with 1% dialyzed BSA and a gas phase of 95% O2-5% CO2, pH 7.4. To produce extracellular acidosis, HCl was used to adjust to pH 6.8, which was chosen on the basis of previous studies (1, 11, 28). The myocytes selected for the study were rod shaped with clear striations. They were quiescent but exhibited a synchronous contraction (twitch) in response to suprathreshold 4-ms stimuli at 0.2 Hz delivered by a stimulator (Grass S88) through two platinum field stimulation electrodes in the bathing fluid. Fluorescence signals obtained at 340-nm (F340) and at 380-nm (F380) excitation wavelengths were stored in a computer for data processing and analysis. The F340/F380 ratio was used to represent [Ca2+]i changes in the myocytes. In some experiments, the resting [Ca2+]i was observed while the electrical stimulation was off.Measurement of pHi. The pHi was measured in a single myocyte as described previously (10). The apparatus and optical arrangement used for the measurement of fluorescent light emission and the preparation procedure were similar to those described in the previous section except that the cells were loaded with the membrane-permeable 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF)-AM as the fluorescence indicator at 5 µM for 30 min. The loaded cells were transferred to the stage of an inverted microscope in the superfusion chamber at room temperature. Myocytes were continuously superfused with a Krebs solution (normal solution; pHe = 7.4) or an acidic solution (pHe = 6.8), as described above, according to the requirement of the experiment. The pH-dependent signal of BCECF was obtained by illuminating at 490 and 435 nm, and the fluorescence emission wavelength was measured at 520 nM. The ratio of fluorescence at 490 nm (F490) to F435 was used to represent pHi.
At the end of each experiment, the calibration of BCECF signals was performed. pHi was set to the pHe with 10 µM nigericin in the calibration solution (in mM: 12 HEPES, 140 KCl, 1 MgCl2, 11 glucose). The pHe values were adjusted to 8, 7, 6, and 5 with KOH or HCl.Drugs and chemicals. U-50488H {trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide}, fura 2-AM, type I collagenase, and nigericin were purchased from Sigma. The nor-binaltorphimine (nor-BNI) was purchased from Tocris Cookson. BCECF-AM and ethylisopropyl amiloride (EIPA) were purchased from Research Biochemicals Incorporated.
Fura 2-AM, BCECF-AM, and EIPA were dissolved in DMSO, nigericin was dissolved in ethanol, and the rest were dissolved in distilled water. U-50488H at the dose range of 10-30 µM was administered for 10 min because preliminary studies showed that the effects of the opioid were obvious at 2-3 min and reached maximum before 10 min. In experiments conducted during extracellular acidosis theStatistical analysis. Values are expressed as means ± SE. The paired Student's t-test was used to determine the difference between control and drug treatment groups. The unpaired Student's t-test was employed to determine the difference among groups. The significance level was set at P < 0.05.
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RESULTS |
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Effects of extracellular acidosis on pHi
and
[Ca2+]i.
When the ventricular myocyte was superfused with a Krebs solution at
pHe 6.8, the
pHi dropped slowly to a steady
state (from 7.03 ± 0.03 to 6.65 ± 0.04;
P < 0.01) with a half time of 2.2 ± 0.42 min (n = 5). After this
short period, during which the pHi
remained at the low level, the pHi
rose gradually by 0.14 ± 0.04 (n = 8; P < 0.01) within 10 min during
acidosis (Fig. 1). The
recovery in pHi was abolished by
10 µM EIPA, a blocker of Na+/H+
exchange (29) (Fig. 1).
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[Ca2+]i
responses to U-50488H during extracellular acidosis.
In this series of experiments we determined the resting
[Ca2+]i
and the
[Ca2+]i
transients induced electrically and with caffeine in a single ventricular myocyte. In view of the fact that the changes in the electrically induced
[Ca2+]i
transient were large and easily quantified, the dose-related response
was determined by observing the responses of the electrically induced
[Ca2+]i
transient. In agreement with previous observations (23,
38), 10-30 µM U-50488H, a selective -opioid receptor agonist,
suppressed the electrically induced
[Ca2+]i
transient in a concentration-dependent manner (Fig.
2). The effect of the
-agonist at 30 µM was abolished by 5 µM nor-BNI, a selective
-opioid receptor
antagonist (Fig. 2).
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Effects of U-50488H on
[Ca2+]i
and electrically induced
[Ca2+]i
transients during superfusion with a high-glucose solution.
To further delineate the role of
Na+/H+
exchange in mediating the action of extracellular acidosis on the
Ca2+ responses to -opioid
receptor stimulation, a solution containing a high glucose
concentration, known to activate
Na+/H+
exchange as a result of acute osmotic stimulation (49), was superfused.
Both the
[Ca2+]i
and electrically induced
[Ca2+]i
transient in response to U-50488H were determined. In agreement with
previous observations (34, 41), both the
pHi (Fig.
6A) and
the fura 2 fluorescence ratio (Fig.
6B) increased gradually on
superfusion with a 50 mM glucose solution. The
pHi and the resting fura 2 fluorescence ratio increased by 0.14 ± 0.04 (n = 5;
P < 0.01) and 0.12 ± 0.05 (n = 5;
P < 0.01), respectively, within 10 min. More importantly, the high glucose concentration abolished the
effects of 30 µM U-50488H on
[Ca2+]i
(Fig. 6B), and significantly
attenuated its effects on the electrically induced
[Ca2+]i
transient (Fig. 6, C and
D), in the ventricular myocyte. The effects were similar to those of extracellular acidosis.
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Effects of U-50488H on
[Ca2+]i
and electrically induced
[Ca2+]i
transients in extracellular high
Ca2+.
This series of experiments was performed to further determine the roles
of
[Ca2+]i
and
Na+/Ca2+
exchange in mediating the action of acidosis. Superfusion with a high
(3 mM) extracellular Ca2+ solution
gradually increased the resting fura 2 fluorescence ratio by 0.21 ± 0.06 within 10 min (n = 5;
P < 0.01; Fig.
7B), whereas the pHi remained the same
(Fig. 7A). The rise in
[Ca2+]i
was abolished by 0.2 mM Ni2+ (Fig.
7B).
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DISCUSSION |
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The most important finding of the present study was that the effects of
-opioid receptor stimulation with the selective
-opioid receptor
agonist U-50488H on resting
[Ca2+]i
and on
[Ca2+]i
transients induced electrically and with caffeine were significantly attenuated during extracellular acidosis, which decreased
pHi (13, 20) but increased the
resting
[Ca2+]i
(10, 18, 21) via activation of the
Na+/H+
and
Na+/Ca2+
exchanges (2, 15, 22, 32, 35). The observations demonstrate for the
first time that extracellular acidosis antagonizes the Ca2+ responses to
-opioid
receptor stimulation in the heart. This is also the first demonstration
that extracellular acidosis antagonizes the
Ca2+ response to stimulation of a receptor.
Previous studies have shown that -opioid receptor stimulation
increases the resting
[Ca2+]i
and decreases the electrically induced
[Ca2+]i
transient, which is due to an initial influx of
Ca2+ upon membrane depolarization
and a subsequent release of Ca2+
from the SR, and the caffeine-induced
[Ca2+]i
transient, which is an index of
Ca2+ content in the SR (37, 38,
47). The observations indicate that
-opioid receptor stimulation
mobilizes Ca2+ from its
intracellular store, leading to an increase in the cytosolic Ca2+. In the present study we
found that extracellular acidosis antagonizes all these responses to
-opioid receptor stimulation, suggesting that extracellular acidosis
may inhibit mobilization of Ca2+
from the intracellular store upon
-opioid receptor stimulation.
In the present study we made two interesting observations. First,
blockade of these two exchanges by their respective blockers, EIPA and
Ni2+, restored the effects of
U-50488H during extracellular acidosis. Second, activation of
Na+/H+
exchange with an osmotic stimulation by a high extracellular glucose
concentration, which increased pHi
and resting
[Ca2+]i
(34, 41, 49), or an increase in extracellular
Ca2+ concentration
([Ca2+]o),
known to activate the reverse mode of
Na+/Ca2+
exchange and to increase the resting
[Ca2+]i
(26), mimicked the influence of extracellular acidosis on the
Ca2+ responses to U-50488H. The
observations suggest that extracellular acidosis may activate
Na+/H+ exchange, which in turn may activate
Na+/Ca2+exchange. In summary, extracellular
acidosis may antagonize the effects of -opioid receptor stimulation
on Ca2+ mobilization from its
intracellular store via
Na+/H+
and
Na+/Ca2+
exchanges, thus reducing the inhibitory effects of
-opioid receptor stimulation on muscle contraction. On the other hand, acidosis is well
established to inhibit the binding of
Ca2+ to troponin, thus decreasing
contractility (8, 19, 31). However, the functional implication of the
antagonism of extracellular acidosis against
-opioid receptor
stimulation and its effect on the contractility of the heart,
especially during myocardial ischemia, need further study.
Another interesting observation in the present study is that
extracellular acidosis, which reduced
pHi and elevated
[Ca2+]i,
high extracellular glucose, which increased both
pHi and
[Ca2+]i,
and high
[Ca2+]o,
which only elevated resting [Ca2+]i
without affecting pHi, all attenuated the
Ca2+ response to U-50488H. The
observations suggest that the elevation of resting
[Ca2+]i,
not pHi, may mediate the
inhibitory action of extracellular acidosis on the
Ca2+ response to -opioid
receptor stimulation. Because it was found that cytosolic
Ca2+ inhibits the release of
Ca2+ from the SR (16, 17), further
studies are needed to determine whether or not the elevation in the
resting
[Ca2+]i
during extracellular acidosis inhibits directly the mobilization of
Ca2+ from the SR on
-opioid
receptor stimulation.
One possible shortcoming of the present study was the use of a high
glucose concentration to activate Na+/H+
exchange because a high glucose concentration has metabolic effects. In
the present study we found that a high glucose concentration, which
increased
[Ca2+]i,
attenuated the action of -opioid receptor stimulation, an effect
similar to that of extracellular acidosis and a high
[Ca2+]o.
In view of the fact that there is no specific activator of Na+/H+
exchange, a high glucose concentration is the only choice available.
In conclusion, the present study has provided evidence for the first
time that acidosis antagonizes the effects of -opioid receptor
stimulation on mobilization of
Ca2+ from SR in the heart. Both
Na+/H+
exchange and
Na+/Ca2+
exchange are involved in the process, leading to an elevation of
[Ca2+]i,
which may inhibit Ca2+ release
from the SR induced by
-opioid receptor stimulation. Further study
is needed to determine the physiological implication of the antagonism
of extracellular acidosis on the effects of
-opioid receptor
stimulation and to verify the role of
[Ca2+]i
in the mobilization of Ca2+ from
its intracellular store and delineate the underlying mechanisms.
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ACKNOWLEDGEMENTS |
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We thank Dr. Fanny Mo for advice on the measurement of intracellular pH, Dr. I. Bruce for advice on English, and C. P. Mok for assistance.
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FOOTNOTES |
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This study was supported by the Research Grant Council, Hong Kong, China.
This study was performed when J.-M. Pei was on leave from the Department of Physiology, Fourth Military Medical University, Xi'an, China.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: T.-M. Wong, Dept. of Physiology, Faculty of Medicine, The Univ. of Hong Kong, Li Shu Fan Bldg., Sassoon Road, Hong Kong, China (E-mail: wongtakm{at}hkucc.hku.hk).
Received 25 January 1999; accepted in final form 27 May 1999.
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