Vol. 273, Issue 4, H1956-H1961, October 1997
Taurine depletion, a novel mechanism for cardioprotection from
regional ischemia
Simon N.
Allo1,
Lillian
Bagby2, and
Stephen W.
Schaffer2
Departments of 1 Internal
Medicine and 2 Pharmacology,
School of Medicine, University of South Alabama, Mobile, Alabama
36688
 |
ABSTRACT |
Three processes that have been implicated in
ischemic injury are impaired Ca2+
movement, altered osmoregulation, and membrane remodeling. Because the
amino acid, taurine, affects all three processes, it seemed logical
that changes in the myocardial content of taurine might affect ischemic
injury. To test this hypothesis, infarct size and areas at risk were
compared in isolated hearts from control and taurine-depleted rats
after a 45-min ligation of the left anterior descending coronary artery
and 2 h of reperfusion. Hearts of rats treated for 4 wk with the
taurine inhibitor,
-alanine, exhibited a 57% reduction in the
infarct size-to-risk area ratio. The degree of cardioprotection was
found to correlate (r = 0.85) with the
extent of taurine depletion, the latter dependent on the length of
-alanine feeding. When the taurine-depleted rats were fed taurine,
myocardial taurine levels were restored and the cardioprotection was
lost. However, addition of neither
-alanine (3%) nor taurine (20 mM) to the perfusion medium altered infarct size. We conclude that
taurine depletion renders the heart resistant to injury caused by
regional ischemia.
-alanine; infarct size; osmoregulation
 |
INTRODUCTION |
THE UBIQUITOUS sulfur-containing amino acid, taurine,
is found in high concentrations in the heart, where it accounts for ~50% of the free amino acid pool (12). The exact role of taurine in
cardiac function is not fully understood, although it has been purported to mediate a plethora of effects at the physiological, biochemical and molecular level (2, 12). Among its most important "physiological" actions in the heart are the modulation of
Na+ and
Ca2+ homeostasis (2, 9), the
alteration in membrane structure and function (8), and the regulation
of intracellular osmolality (24). The importance of these actions is
borne out by nutritional studies showing that cats fed a
taurine-deficient diet develop a cardiomyopathy (21).
Pharmacological doses of taurine also mediate several effects. One
important action is its ability to exert a positive inotropic effect,
which is independent of adenosine 3',5'-cyclic
monophosphate or
Na+-K+-adenosinetriphosphatase
(2). Of equal importance is the finding that taurine treatment protects
against injury in several models of heart failure, including the
Ca2+ paradox, cardiomyopathic
hamster, isoproterenol cardiotoxicity, and doxorubicin-induced cardiac
damage (2, 16, 23). However, the most dramatic effect of taurine is
observed in experimental heart failure, in which taurine treatment is
reported to significantly reduce mortality (29). These animal studies
have encouraged the use of taurine as a therapeutic agent. The most
clinically relevant role of taurine to date has been its use for
congestive heart failure in Japan, where clinical trials have revealed
an improvement in New York Heart Association classification of
patients, who have been treated with or without digoxin (1).
Although most studies to date have supported the notion that
maintenance of high intracellular taurine levels in the heart is
beneficial to normal myocardial function, recent studies by Chapman et
al. (5) suggest that taurine efflux may help eliminate excess
Na+ from the myocyte. Moreover,
under pathological conditions in which the intracellular osmotic
pressure rises, it is likely that the heart should benefit from a loss
of the osmolyte, taurine. Thus, because both water and
Na+ accumulate during ischemia and
are thought to contribute to the severity of injury, it is logical to
assume that changes in the size of the intracellular taurine pool
should affect the outcome of an ischemic insult. To test this
hypothesis, we examined the effect of drug-induced taurine depletion on
cellular necrosis in a regional model of ischemia.
 |
METHODS |
Hearts from male Wistar rats weighing 250-300 g were taurine
depleted by maintaining the rats on tap water containing 3%
-alanine for 4-28 days (9, 25). Some rats, referred to as the
taurine-replete group, were maintained for 8 days on tap water
containing 1.5% taurine after a 28-day treatment with 3%
-alanine.
Control rats were age matched and maintained on normal tap water for
the duration of the experiment. Neither taurine depletion nor repletion
significantly altered rat body weight relative to the controls; body
weight was 382 ± 28, 350 ± 21, and 365 ± 31 g for the
control, taurine-depleted, and taurine-replete groups, respectively.
Moreover, the dry weight of the heart was identical (0.29 ± 0.01 g)
in all three groups. However, the protocols led to an alteration in the
wet-to-dry weight ratio of the heart, which was 4.76 ± 0.06, 5.05 ± 0.10, and 4.73 ± 0.06 for the control, taurine-depleted, and
taurine-replete groups, respectively.
After the appropriate period of taurine depletion and repletion, most
hearts were perfused on a Langendoff apparatus with Krebs-Henseleit
buffer containing 118 mM NaCl, 27.1 mM
NaHCO3, 2.8 mM KCl, 1 mM
KH2PO4,
1.2 mM MgSO4, 2.5 mM
CaCl2, and 11 mM glucose, which
was saturated with 95% O2-5%
CO2 and maintained at 37°C.
However, when the effect of exogenous taurine and
-alanine on
ischemic injury of untreated, control hearts was examined, the
Krebs-Henseleit buffer was supplemented with either 20 mM taurine or
3%
-alanine. For all experiments, the coronary perfusion pressure
was fixed at 100 cmH2O.
To initiate the experiment, a 2-O silk suture was loosely placed around
the left main coronary artery and passed through a small vinyl tubing
to form a snare. The hearts were then perfused under normal conditions
for 20 min. After the stabilization period, coronary occlusion was
effected in some of the hearts by pulling the suture through the snare
and clamping the snare with a hemostat. The desired period of coronary
artery occlusion (45 min) was followed by reperfusion for 2 h. The
experiment was terminated by retightening the snare and infusing a
0.2% solution containing 1-10 µm zinc-cadmium fluorescent
particles (Duke Scientific, Palo Alto, CA) into the aorta. The
fluorescent particles were able to delineate the risk zone, which was
defined as the region lacking fluorescence when observed with a 366-nm
fluorescent lamp. After administration of the fluorescent particles,
the hearts were removed from the perfusion apparatus and frozen for at
least 2 h before being cut into 2-mm-thick slices. The slices were
incubated for a period of 20 min at 37°C in a 1% solution of
triphenyltetrazolium chloride dissolved in phosphate buffer (pH 7.4).
The slices were then placed between glass plates, and the areas of the
risk zones (delineated as nonfluorescent zones) and infarcted areas
(lacking staining with tetrazolium) were determined by planimetry. The
volumes of the risk and infarcted zones were determined by multiplying
the area by the slice thickness. The infarct size was expressed as a
percentage of the risk zone that was infarcted.
Determination of taurine levels.
Cardiac taurine content was measured by the method of Shaffer and
Kocsis (25). Hearts were perfused with Krebs-Henseleit buffer via
aortic cannulation to remove the blood and then blotted, weighed, and
frozen. After freeze drying, the samples were reweighed and homogenized
with 2% perchloric acid. After neutralization with
K2CO3,
the supernatant was used for taurine determination.
An aliquot of the supernatant (20 µl) was diluted to 400 µl and
then reacted with 0.1 ml of 2,4-dinitrofluoro-1-benzene (DNFB) in the
presence of 0.1 ml of 1 M NaOH and 0.5 ml of dimethyl sulfoxide. The
reaction was terminated after 30 s by the addition of 0.1 ml of 3 M
HCl, which lowered the pH to 1.5-2.0. Deionized water was added to
a final volume of 5 ml. Samples were then extracted with ethyl acetate
(20 ml) for 10 min to remove the derivatized carboxylic amino acids and
unreacted DNFB. The optical density at 355 nm of the aqueous fraction
containing 2,4-dinitrophenyltaurine was determined. A taurine standard
curve using 2-40 µg taurine was obtained for each assay.
Hemodynamic measurements.
Hearts from control, taurine-depleted, and taurine-replete rats were
perfused on a standard working heart apparatus with Krebs-Henseleit buffer supplemented with 11 mM glucose. After a 20-min stabilization period, several hemodynamic parameters were measured. Peak ventricular systolic pressure and heart rate were measured with a Statham P23 Gb
pressure transducer by inserting a 22-gauge needle through the
ventricular wall. Coronary flow was determined by collecting the
coronary effluent.
Statistical analysis.
All data involving multiple groups (control, taurine depleted, and
taurine replete) were analyzed by analysis of variance, with the
Newman-Keuls test used to determine the source of the significant
difference. When only the taurine-depleted and control groups were
compared, the Student's t-test was
used to determine significant differences.
 |
RESULTS |
Taurine depletion.
Previous studies have shown that cardiac taurine pools can be
significantly reduced by treating rats with the taurine transport inhibitor,
-alanine (9, 25). In accordance with those studies, we
found that cardiac taurine levels were reduced from 105.0 ± 2.2 to
63.2 ± 5.3 µmol/g dry wt after 4 wk of
-alanine treatment (Table 1). This process is readily
reversible, since the addition of taurine to the drinking water rapidly
restored the myocardial taurine pool.
The degree of taurine depletion was dependent on the length of time the
animals received
-alanine in their drinking water. Within the first
few days after treatment with
-alanine, myocardial taurine levels
fell abruptly. Thereafter, there was a slow decline in the size of the
myocardial taurine pool, which reached a new steady state by ~2 wk of
treatment (Fig. 1).

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Fig. 1.
Time course for partial depletion of myocardial taurine pool by
-alanine treatment. After indicated period of -alanine treatment,
hearts were isolated, perfused to remove blood, and then freeze dried.
After extraction with 2% perchloric acid and neutralization with
K2CO3,
taurine levels were determined. Values shown represent means ± SE
of 4-5 hearts. Significant decreases in taurine levels were noted
by 4 days of -alanine feeding (P < 0.05).
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Table 2 demonstrates that the baseline
hemodynamic parameters were unaffected by either taurine depletion or
repletion.
Effect of taurine depletion and repletion on myocardial infarct
size.
The size of the risk zone after ligation of the left anterior
descending coronary artery was ~0.4
cm3 in all hearts examined (Table
3). After 45 min of ischemia and 2 h of
reperfusion, control hearts exhibited an infarct size-to-risk area
ratio of 55.68 ± 2.04%, which is similar to the value reported by
other investigators for the same period of ischemia (4, 11, 17).
Significantly, a 40% reduction in the size of the myocardial taurine
pool resulted in a 57% decrease in the infarct size-to-risk area ratio
(Table 3).
To further delineate the effect of taurine depletion on infarct size,
we evaluated hearts whose taurine content was varied by treating rats
with
-alanine for different intervals. Infarct size was maximally
reduced after 2 wk of
-alanine feeding, coinciding with maximal
depletion of the myocardial taurine pool (Figs. 1 and
2). Continuous feeding with
-alanine
beyond 2 wk neither altered myocardial taurine levels nor affected the
extent of cardioprotection from regional ischemia. However, exposure to
-alanine for shorter periods of time resulted in less taurine
depletion and a corresponding smaller decline in infarct size.

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Fig. 2.
Effect of -alanine treatment on infarct size reduction. Hearts were
isolated from rats treated for various periods of time with
-alanine. After a 20-min stabilization perfusion period, control and
taurine-depleted hearts were subjected to 45 min of regional ischemia
by occlusion of left main coronary artery. Hearts were then reperfused
for 2 h before determination of area of risk and infarcted volume. Data
are expressed as percent infarct size-to-risk area. Values shown
represent means ± SE of 4-6 hearts. Significant decreases in
percent infarct size-to-risk area were found by 4 days of -alanine
treatment (P < 0.05).
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Figure 3 reveals that a significant
correlation (r = 0.85) exists between
cardiac taurine levels and the infarct size-to-risk area ratio. Because
-alanine does not accumulate in the heart (data not shown), the
observed reduction in the infarct size-to-risk area ratio appears to be
caused by taurine depletion. This is supported by the observation that
acute exposure to
-alanine (3%) in vitro had no effect on infarct
size (Table 4). Similarly, addition of 20 mM taurine to the perfusion buffer throughout the experimental protocol
did not alter infarct size. However, repletion of the cardiac taurine
pool by maintaining taurine-depleted rats for 8 days on water
containing 1.5% taurine completely eliminated the cardioprotective
effects of taurine depletion (Table 3).

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Fig. 3.
Correlation between myocardial taurine levels and infarct size-to-risk
area ratio for control and -alanine-treated hearts. Rats were
subjected to varying periods of -alanine feeding, resulting in
differing degrees of taurine depletion. These hearts also showed
varying infarct sizes after an ischemic-reperfusion insult. Shown is
correlation curve for infarct size and taurine content data obtained
after various periods of taurine depletion
(r = 0.85).
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 |
DISCUSSION |
The present study is the first investigation examining the effect of
taurine in a myocardial regional ischemia model. The relevance of this
study is that it uncovers a new and novel means of cardioprotection. It
also introduces a new model to investigate mechanisms that contribute
to cardioprotection against ischemic-induced cell necrosis.
The effects of taurine on the ischemic heart has been an area of
controversy. In the first study examining this question, Kramer et al.
(16) reported that addition of 10 mM taurine to the perfusion medium
did not improve the recovery of cardiac work in isolated rat hearts
subjected to severe global ischemia. The data in Table 4 showing that
addition of 20 mM taurine to the perfusion medium did not attenuate the
degree of ischemic injury is consistent with that finding. However,
both studies are in apparent conflict with the work of Franconi et al.
(6), who reported an improvement in the recovery of contractile
function after a 30-min hypoxic insult in guinea pig hearts perfused
with glucose-free buffer. Recently, Raschke et al. (23) also observed no improvement in recovery of cardiac work after 15 min of global ischemia when 15 mM taurine was included in the reperfusion buffer. However, they found that taurine prevented the decline in mechanical function induced by addition of neutrophils to the reperfusion medium.
This protective effect of taurine was attributed to its ability to
scavenge hypochlorous acid, thereby reducing the degree of oxidant
damage mediated by the neutrophils. Similarly, the antioxidant effect
of taurine has been implicated in taurine-mediated reductions in cell
damage that occur during coronary artery bypass grafting (19).
Interestingly, in the latter two studies, cardioprotection was only
observed when extracellular taurine levels were significantly elevated,
suggesting that the neutrophil neutralizing effect of taurine
represents a pharmacological, rather than a physiological effect.
The present study contrasts with all previous ischemia studies because
the experimental protocol focuses on changes in the intracellular
taurine pool. A standard procedure was used to slowly lower the
intracellular taurine pool. The value of this procedure was twofold. It
permitted the regulation of myocardial taurine levels over a fairly
wide concentration range and also allowed the reversal of the taurine
defect merely by adding taurine to the animals' water supply.
The most significant finding of this study is that taurine depletion
results in cardioprotection from regional ischemia. The maximal effect,
a 57% reduction in risk zone infarcted, is comparable in scope to
other cardioprotective procedures. One of the most widely studied
cardioprotective mechanisms, preconditioning, has been reported to
reduce infarct size-to-risk area between 63 and 73% after 45 min of
regional ischemia (4). Equally effective in reducing infarct
size-to-risk area have been the
Na+/H+
exchange inhibitors (4, 13). Two procedures that are slightly less
potent in mediating cardioprotection are hyperthermia, a form of
heat-shock protein induction, and streptozotocin-induced diabetes,
whose mechanism of cardioprotection is unknown; both conditions
diminish the infarct size-to-risk area ratio ~33% (11, 17).
Although taurine depletion significantly reduces infarct size in the
reperfused heart, it does not significantly improve recovery of
contractile function (data not shown). Two explanations can be provided
to account for this paradoxical observation. First, the area at risk is
not fixed in the regional ischemia model, causing considerable
variability in the recovery of mechanical function even among the
control group. Second, taurine affects myocardial contractile function
through alterations in Ca2+
movement and increased sensitivity of the myofibrils to
Ca2+ (2, 9, 26). Although the
degree of taurine depletion achieved in the
-alanine-treated rats
does not induce a change in mechanical function (Table 2), more severe
decreases in the intracellular taurine pool are associated with the
development of a cardiomyopathy (21). This is relevant because massive
amounts of taurine efflux the heart during an ischemic-reperfusion
insult (16, 18). Thus, although the protected regions of the heart do
not die, they exist in an unusually severe state of stunning. Consequently, the favorable effect of reduced infarct size may be
balanced by the unfavorable effect of taurine depletion on contractile
function.
Several factors support the conclusion that the
-alanine-mediated
reduction in infarct size is directly related to taurine depletion.
First, a negative correlation exists between taurine levels and the
extent of cardioprotection (Fig. 3). Second, the cardioprotection is
completely reversed by repleting the cardiac taurine pool. Third, the
only known cardiovascular effects of
-alanine relate to the
inhibition of taurine transport and the promotion of taurine efflux
from the myocyte (9, 25). Fourth, the effects of
-alanine feeding
cannot be duplicated by acute exposure of the isolated heart to either
3%
-alanine or 20 mM taurine (Table 4).
The mechanism by which taurine depletion is cardioprotective remains to
be completely examined. One attractive hypothesis is that taurine, an
effective osmolyte, plays a critical role in osmoregulation during
ischemia-reperfusion (5). It has been established that taurine is
rapidly lost from the heart after ligation of the circumflex branch of
the left main artery (18) or after global ischemia followed by
reperfusion (16). This ischemia-induced taurine loss may merely reflect
a response of the ischemic heart to the accumulation of osmotically
active agents, such as Na+,
Pi, and lactate. Because taurine
is an important osmolyte, its efflux from the cell effectively reduces
the intracellular osmotic load, thereby diminishing the osmotic
gradient across the cell membrane. According to Jennings and co-workers
(14, 27), the intracellular osmotic load can lead to excessive cell
swelling, which is thought to play a critical role in irreversible cell damage.
Several investigators have attempted to reduce infarct size by
decreasing the osmotic gradient across the cell membrane by raising the
osmolality of the extracellular medium. This strategy has led to mixed
results. Kloner et al. (15) and Garcia-Dorado et al. (7) have reported
a decline in infarct size in the hyperosmotically treated heart,
whereas Harada et al. (10) found no influence of hyperosmolar mannitol
on infarct size in the baboon heart. The present approach is seemingly
related to that strategy; however, instead of raising the extracellular
osmotic load, taurine depletion reduces the intracellular osmotic load.
Nonetheless, two findings suggest that the cardioprotection noted in
the taurine-depleted heart may not be related solely to the change in
the osmotic pressure gradient. First, addition of hyperosmolar
concentrations of
-alanine to the perfusate failed to reduce infarct
size. Second, addition of 20 mM taurine to the perfusion medium with
the aim of eliminating the taurine gradient across the myocyte
membrane, did not influence infarct size.
Because the process of taurine depletion in the
-alanine-fed rat is
complex, it is not surprising that multiple factors could contribute to
the observed cardioprotection. An important consideration is that the
taurine-depleted heart, to maintain an osmotic balance, presumably
undergoes an adjustment involving modifications in the content of
intracellular organic osmolytes as well as the activity of transporters
involved in osmoregulation.
A transporter whose activity is altered after an osmotic pressure
insult is the
Na+/H+
exchanger (3). This transporter is of particular interest because
inhibitors of the
Na+/H+
exchanger protect the heart against ischemic injury (13). Moreover, reduction in flux through the exchanger, either by manipulation of the
cation composition of the myocyte or the intrinstic activity of the
transporter, invariably leads to less cell damage during an
ischemic-reperfusion or hypoxic-reoxygenation insult (13). Because
taurine depletion appears to induce an osmotic stress, one would
predict that the activity of the
Na+/H+
exchanger should be affected by
-alanine feeding.
Another important osmotic-sensitive transporter is the
Na+/Ca2+
exchanger (30). Previously, we demonstrated that the activity of the
Na+/Ca2+
exchanger is depressed in the taurine-depleted myocardium (9). Because
this transporter is thought to play a pivital role in Ca2+ overload-induced myocardial
injury, it is a logical candidate for the cardioprotection of taurine
depletion.
Taurine has another potential link to the regulation of intracellular
cation homeostasis. The process of taurine uptake by the heart involves
cotransport with Na+. According to
Chapman et al. (5), taurine efflux utilizes this same
Na+-taurine cotransporter. This
scenario would dramatically affect the ischemic heart because taurine
efflux would be accompanied by a significant decrease in intracellular
Na+ concentration. Thus damage to
the heart would be minimized because both the osmotic and
Na+ loads would be reduced.
Although this scenario is attractive, in most noncardiac cells taurine
efflux occurs via a
Na+-independent "volume
sensitive organic osmolyte anion channel" rather than the
taurine-Na+ cotransporter (28).
Nonetheless, because the mode of taurine efflux during ischemia remains
to be established, this interesting concept deserves further
consideration.
The final possibility is that taurine depletion could influence the
stability of the sarcolemmal membrane. Hamaguchi et al. (8) have
reported that taurine serves as a potent inhibitor of phospholipid
N-methyltransferase, the enzyme
catalyzing the conversion of phosphatidylethanolamine to
phosphatidylcholine. Because phosphatidylcholine is a bilayer
former, whereas phosphatidylethanolamine is a nonbilayer former,
taurine can cause local changes in the bilayer-to-nonbilayer content of
the membrane. Recently, Post et al. (22) have argued that an elevation
in the membrane content of bilayer formers protects the ischemic
myocardium by stabilizing the membrane. Thus local changes in
phospholipid content could occur in the taurine-depleted heart, which
could affect the activity of a key enzyme or transporter and modulate
the response to an ischemic-reperfusion insult.
 |
ACKNOWLEDGEMENTS |
This study is supported in part by grants from the Southern Medical
Association (S. N. Allo) and the American Heart Association (S. W. Schaffer).
 |
FOOTNOTES |
Address for reprint requests: S. W. Schaffer, Dept. of Pharmacology,
School of Medicine, University of South Alabama, Mobile, AL 36688.
Received 15 September 1996; accepted in final form 11 June 1997.
 |
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