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Effect of Beta-Adrenergic Stimulation on Myocardial
Adenine Nucleotide Metabolism
By Heinz-Gerd Zimmer and Eckehart Gerlach
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ABSTRACT
The effects of isoproterenol, propranolol, and compound D600 (o-isopropyl-«-[(Nmethyl-Af-homoveratryl)-Y-aminopropyl]-3,4,5-trimethoxyphenytacetonitrile) on myocardial adenine nucleotide metabolism were studied in rat hearts in situ. Isoproterenol
in doses between 0.1 and 25 mg/kg induced an increase in heart rate concomitant with a
significant acceleration in the de novo synthesis of adenine nucleotides (ATP, ADP, and
AMP) and a diminution in their concentration. The effects of isoproterenol were antagonized by propranolol (1 and 50 mg/kg), which alone caused a reduction in the de novo
synthesis of adenine nucleotides without inducing a change in their concentration. Compound D600 (10 mg/kg) brought about a slight elevation in the concentration of adenine
nucleotides but did not influence the rate of de novo synthesis. The isoproterenol-induced
diminution in adenine nucleotide concentration was prevented by D600; under these conditions, the acceleration of de novo synthesis was attenuated. These findings indicate that
de novo synthesis of myocardial adenine nucleotides in the normal and the isoproterenolstimulated heart is regulated not only by a feedback mechanism dependent on the concentration of adenine nucleotides but also by j9-receptor-mediated alterations in carbohydrate
metabolism which can cause changes in the size of the available pool of 5-phosphoribosyl1-pyrophosphate.
KEY WORDS
de novo synthesis of adenine nucleotides
compound D600
isoproterenol
rats
cardiac hypertrophy
• Oxygen deficiency causes a breakdown of myocardial adenine nucleotides that results in the
formation of purine nucleosides and bases (1-6).
Since the dephosphorylated nucleotide breakdown
products can readily penetrate the myocardial cell
membrane (7-10), oxygen deficiency leads to a
remarkable diminution in the intracellular levels of
adenine nucleotides which can still be detected
during subsequent periods of postanoxic recovery
(11). Recently, we have demonstrated that de novo
synthesis of adenine nucleotides is enhanced in the
rat heart during recovery from oxygen deficiency
(12). Furthermore, we have observed an acceleration of the de novo formation of myocardial adenine nucleotides in rats during the development of
cardiac hypertrophy following aortic constriction.
Under this condition, a decline in myocardial
From the Department of Physiology, Medical Faculty, Technical University, 51 Aachen, Germany, and the Department of
Physiology, University of Munich, 8 Munich 2, Germany.
This work was supported by Grant Ge 129/8 from the
Deutsche Forschungsgemeinschaft.
These results were presented in part at the 40th and the 42nd
meetings of the German Physiologic Society (Pfluegers Arch
335:R5, 1972, and 343:R16, 1973).
Please address reprint requests to Dr. Zimmer, Department
of Physiology, University of Munich, 8 Munich 2, Pettenkoferstr.
14a.
Received March 6, 1974. Accepted for publication May 28,
1974.
536
propranolol
l-14C-glycine
adenine nucleotide levels (13) has been shown to
precede the enhancement of de novo synthesis of
adenine nucleotides (14, 15).
Since isoproterenol causes a reduction in myocardial high-energy phosphate stores (16, 17) and
induces cardiac hypertrophy (18, 19), we decided to
study its influence on the rate of de novo synthesis
of adenine nucleotides in the heart. We used the
(S-adrenergic blocking agent propranolol (20) and
the "calcium-antagonistic" compound D600 (21,
22), which both inhibit the isoproterenol-induced
diminution of adenine nucleotide levels, as tools for
establishing different cardiac adenine nucleotide
levels and elucidating the relationship between the
rate of de novo synthesis and the concentration of
adenine nucleotides in the myocardium. Thus, we
performed in vivo experiments utilizing these three
substances to determine whether de novo synthesis
of cardiac adenine nucleotides is controlled by a
nucleotide concentration-dependent feedback
mechanism (23, 24) alone or in combination with
some other mode of regulation of purine nucleotide
biosynthesis.
Methods
Female Sprague-Dawley rats (200-220 g) fed a diet of
Altromin were used in all experiments. l-14C-Glycine
(specific activity 56 mc/mmole) was purchased from the
Circulation Research, Vol. 35, October 1974
537
ADRENERGIC STIMULATION OF NUCLEOTIDE SYNTHESIS
Radiochemical Centre. Amersham, England. Isoproterenol was obtained from C. H. Boehringer Sohn,
Ingelheim, propranolol was a gift from Rhein-Pharma,
Heidelberg, and compound D600 (a-isopropyl-a[(iV-methyl-iV-homoveratryl)-7-aminopropyl]-3,4,5trimethoxyphenylacetonitrile) was generously supplied by Knoll AG, Ludwigshafen. All other chemicals
were obtained from Merck AG. Darmstadt, and were of
analytical grade.
EXPERIMENTAL PROCEDURES
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Isoproterenol dissolved in saline (0.9*7, w/v) was
injected subcutaneously in doses of 0.1, 5. and 25 mg/kg.
Propranolol (1 or 50 mg/kg) and compound D600 (10 or
15 mg/kg), also dissolved in saline, were administered
subcutaneously either alone or simultaneously with isoproterenol. Control rats were injected with 1 ml of saline.
Measurements of heart rate were performed using a
telemetric device consisting of a biotransmitter (S.X.R.
102 G, Sandev) in combination with a receiver (frequency 102.2-102.4 MHz). The signals were transmitted
to an oscilloscope (Tektronix Inc.) for visual control and
recorded as an electrocardiogram on a Clevite Brush
Mark 220 recorder. The frequency of the R spikes served
as a measure of heart rate.
At various times after administration of the drugs,
measurements of de novo synthesis of myocardial adenine nucleotides were performed. The rats, which had
been fasted for 12 hours, were intravenously injected
with l-14C-glycine (0.25 me/kg in 1 ml of saline). At the
end of a 60-minute exposure to l-"C-glycine, the rats
were anesthetized with diethyl ether and their hearts
were rapidly excised. The ventricles were freed of adhering blood and quickly frozen in liquid nitrogen. Blood
samples taken from each rat at the time of excision of the
heart were heparinized and immediately centrifuged for
separation of the plasma.
ANALYTICAL PROCEDURES
Extraction.—Ventricular myocardium was ground to
a fine powder under liquid nitrogen and extracted with
0.3N HC10* (5 minutes at 0°C). After centrifugation, the
extracts were neutralized with 3N KOH, kept in an ice
bath for 60 minutes, and separated from the KC1O,
precipitate.
Concentration of Adenine Nucleotides.—Adenosine
triphosphate (ATP), adenosine diphosphate (ADP). and
adenosine monophosphate (AMP) levels (nmoles/g wet
weight) were determined in samples of the extracts
according to methods described previously (25). To
exclude the consequences of experimentally induced
changes in tissue wet weight, appropriate corrections for
a constant dry weight of 20^ were made in all experiments.
De Novo Synthesis of Adenine Nucleotides.—Rates of
de novo synthesis of myocardial adenine nucleotides
(nmoles/g wet weight hour 1 ) were calculated from the
total radioactivity of the adenine nucleotides (dpm/g wet
weight) and the mean specific activity of the intracellular glycine (dpm/nmole). Wet weights were corrected as
indicated in the preceding section. Details of the
methods and calculations have been published previously (12).
Determination of Radioactivity.—MC-Activities were
measured in a Packard Tricarb liquid scintillation specCirculation Research, Vol. 35. October 1974
trometer (model 3:380). Each sample was made up to 10
ml with scintillation fluid prepared by dissolving 5.5 g of
2,5-diphenyloxazole and 0.15 gof 1,4-bis-2-(5-phenyloxazolyl)-benzene in 666 ml of toluene and 334 ml of Triton
X-100. Counting efficiencies ranged between 87*7 and
90^ under these conditions.
Results
Kinetic studies on rat hearts in vivo under
control conditions and 5 hours after administration
of a single high dose of isoproterenol (25 mg/kg)
revealed that the specific activity of intracellular
glycine (Fig. 1A) and the total radioactivity of
myocardial adenine nucleotides (Fig. IB) were
consistently higher in isoproterenol-stimulated
hearts. The total radioactivity of adenine nucleotides, however, was elevated to a much greater
extent than was the specific activity of the precursor glycine. Thus, the rate of de novo synthesis,
which rose linearly between 15 and 60 minutes of
exposure to l-'^C-glycine under both conditions,
was considerably enhanced after application of
isoproterenol (Fig. 1C).
Time course studies of the changes in the concentration and radioactivity of the precursor glycine
and the adenine nucleotides (Table 1) showed that
the concentration of glycine was significantly elevated 5, 12, and 24 hours after the administration
of isoproterenol, whereas the mean specific activity
of glycine was increased only after 5 hours. In
contrast, the concentration of ATP and of the sum
of adenine nucleotides decreased progressively during the 24-hour period following application of
isoproterenol, whereas the total radioactivity of
adenine nucleotides was considerably elevated over
the whole period with the highest value occurring
after 5 hours.
The alterations in the rate of adenine nucleotide
synthesis and heart rate which occurred during the
first 3 days subsequent to a single high dose of
isoproterenol exhibited a rather similar pattern
(Fig. 2). After a steep increase within the first 5
hours, both parameters remained elevated at a
high level up to 12 hours and declined gradually
thereafter.
Isoproterenol proved to be effective not only in
high doses but also in low doses: 5 mg/kg and even
0.1 mg/kg of isoproterenol caused an increase in the
total radioactivity of adenine nucleotides without
significantly affecting the mean specific activity of
precursor glycine (Table 2). The increase in de
novo synthesis of adenine nucleotides amounted to
630% and 2707c, respectively.
Table 2 also includes data from experiments with
propranolol. It is evident that propranolol in high
538
ZIMMER, GERLACH
to-
p
C
t
1000030-
/
205000-
10o
15
30
45
60
MIN
FIGURE 1
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Specific activity of intracellular glycine (A), total radioactivity of adenine nucleotides (B), and
rate of de novo synthesis of adenine nucleotides (C) in rat hearts. Solid circles indicate control measurements, and open circles indicate measurements made 5 hours after administration of 25 mg isoproterenol/kg. Measurements were taken after 5, 15, 30, 45, and 60 minutes of in vivo exposure to
l-ltC-glycine. Eac/i point represents a single experiment on an individual rat.
and also in low doses caused a strong diminution in
the total radioactivity of adenine nucleotides. The
mean specific activity of glycine, however, was not
changed. Consequently, the rate of de novo synthesis of adenine nucleotides was considerably diminished. According to separate kinetic experiments,
the time course of changes in the specific activity of
myocardial glycine during a 60-minute exposure to
^-MC-glycine was very similar in propranololtreated rats and control rats (Fig. 1).
Table 3 summarizes studies comparing the effects of isoproterenol, propranolol, and iso-
proterenol plus propranolol on de novo synthesis,
ATP concentration, and heart rate. It is particularly interesting that propranolol applied alone
caused a diminution in the synthesis of adenine
nucleotides without any apparent changes in the
concentration of ATP. Furthermore, propranolol
antagonized the isoproterenol-induced alterations
in de novo synthesis, ATP concentration, and heart
rate.
The main results of our studies on the effects of
compound D600 are given in Table 4. D600 did not
appreciably affect the rate of de novo synthesis
Time Course of Changes in the Concentration and Mean Specific Activity {MSA) of Intracellular
Glycine and in the Concentration and Total Radioactivity of Myocardial Adenine Nucleotides during
the First 24 Hours after Administration of Isoproterenol (25 mglkg)
Glycine
Adenine nucleotides
Concentration
Time after
isoproterenol
(hours)
Control
1
5
12
24
N
32
7
9
10
4
Concentration
(nmoles/g)
425
434
496
480
561
± 10
±40
± 13+
± 28+
±28t
MSA
(dpm/nmole)
ATP
(nmoles/g)
ZATP,
ADP, AMP
(nmoles/g)
Total
radioactivity
(dpm/g)
180 ± 5
192 ± 16
255 ± 11*
186 ± 6
151 ± 4
4340 ± 50
3800 ±90*
3370 ± 120*
3250 ± 120*
3170 ±50*
5700 ± 120
5360 ± 111+
4710 ± 100*
4300 ± 160*
4200 ± 130*
992 ±60
3294 ± 249*
9885 ±386*
6340 ± 569*
2396 ± 103*
The rats were exposed to l-"C-glycine (0.25 me/kg) for the last 60 minutes of the indicated time
after application of isoproterenol. The concentrations of adenine nucleotides were determined in
separate experiments which were identical except for the omission of l-14C-glycine and for the method
for excising the heart (13). Values are means ± SE. N - number of experiments.
* P < 0.0005.
+ P < 0.05.
%P < 0.01.
Circulation Research. Vol. 35. October 1974
539
ADRENERGIC STIMULATION OF NUCLEOTIDE SYNTHESIS
nmoles / g / h
DE NOVO-SYNTHESISOF ADENINE-NUCLEOTIDES
|(9)
5040
30
(O
20
i
10
H
increase in adenine nucleotide synthesis, there is
one common feature in both models of cardiac
hypertrophy—the initial reduction in the concentration of myocardial high-energy phosphate compounds (13, 16, 17, Table 1). It is thus not
surprising that a diminution in myocardial levels of
ATP has been suggested as a causal factor for the
stimulation of nucleic acid and protein synthesis
during the development of cardiac hypertrophy
II
HEART
min-1
(5)
(
f
RATE
TABLE
(2>
2
Influence of Different Doses of Isoproterenol and Propranolol on
the Mean Specific Activity of Intracellular Glycine and the
Total Radioactivity and De Novo Synthesis of Myocardial
Adenine Nucleotides
500
1
400-
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—.—.—.—II—
12
72 hours
ISOPROTERENOL
25mg /kg
Time
after
drug
Dose admin(mg/ istration
kg)
(hours)
Mean
specific
activity
ofglycine
(dpm/
N nmole)
FIGURE 2
Time course of changes in the rate of de novo synthesis of myocardial adenine nucleotides and in heart rate after administration
of a single dose (25 mg/kg) of isoproterenol. The control range
is indicated by the hatched areas. The number of experiments
is given in parentheses. Values are means ± SE.
Adenine nucleotides
Total
radioactivity
(dpm/g)
De novo
synthesis
(nmoles/
g hour"1)
Control
32
5
0.1
180 ± 5
992 ± 60
8
6
Isoproterenol
201 ± 9
7600 ± 370*
177 ± 8
3390 ± 310*
5
5
166 ± 19
152 ± 4
5.3 ± 0.34
38.6 ± 2.97*
19.5 ± 2.23t
Propranolol
when it was applied alone, although it caused a
slight elevation in the concentration of ATP. When
isoproterenol was administered simultaneously
with D600, the isoproterenol-induced decrease in
adenine nucleotide concentration was completely
prevented, but the increase in de novo synthesis
was only attenuated.
Discussion
The studies reported in this paper demonstrate
that isoproterenol is a powerful stimulator of de
novo synthesis of adenine nucleotides in the rat
heart. Since isoproterenol is known to cause cardiac hypertrophy in rats (18, 19), it is interesting to
compare the time course of isoproterenol-induced
changes in adenine nucleotide synthesis with those
occurring in the hypertrophying rat heart after aortic constriction (13-15). In this latter condition,
myocardial adenine nucleotide synthesis transiently decreases within 5 hours after banding of
the aorta, gradually increases after 24 hours, and
reaches a maximum on the third day. In contrast,
a single high dose of isoproterenol causes an almost immediate steep rise in the rate of adenine
nucleotide biosynthesis; maximal values are observed after 5 and 12 hours (Fig. 2).
Irrespective of the qualitative and the quantitative differences concerning onset and extent of the
Circulation Research, Vol. 35, October 1974
50
1
147 ± 55*
264 ± 791
0.8 ± 0.25f
1.8±0.57t
The rats were exposed to l-"C-glycine (0.25 me/kg) for the
last 60 minutes of the indicated time after administration of the
drugs. Values are means ± SE. N = number of experiments.
• P < 0.0005.
i P < 0.005.
TABLE 3
Influence of Isoproterenol (25 mg/kg) and Propranolol (50
mg/kg) on De Novo Synthesis of Adenine Nucleotides, Concentration of ATP in the Myocardium, and Heart Rate in Rats
Control
Isoproterenol
De novo
synthesis
(nmoles/g
hour"')
ATP
(nmoles/g)
Heart rate
(beats/min)
5.3 ± 0.34
(N - 32)
39.3 ± 2.31*
4340 ± 50
(N - 32)
3370 ± 120*
388 ± 7.5
(N = 8)
502 ± 8.7*
( N ~ 9)
(N-4)
Propranolol
0.8 ± 0.25*
(N= 5)
4390 ± 150
Isoproterenol +
Propranolol
5.3 i 1.20
4370 ± 50
354 ± 5.6t
(N = 6)
362 ± 2.4t
(N = 6)
(N=9)
(N= 5)
(N = 6)
(N-6)
Measurements were taken 5 hours after drug administration.
Values are means ± SE. N = number of experiments.
* P < 0.0005.
+ P < 0.005.
\P < 0.01.
ZIMMER, GERLACH
540
Downloaded from http://circres.ahajournals.org/ by guest on June 15, 2017
(26, 27). Our experiments indicate that the acceleration of de novo synthesis of adenine nucleotides
which occurs concomitantly with or subsequently
to the initial diminution in myocardial adenine
nucleotide levels (13-15, Fig. 2) is a further obligatory event among those metabolic processes which
finally lead to an enhanced synthesis of nucleic
acids and proteins. In this connection some observations deserve attention. (1) After banding of the
aorta, the enhancement of the de novo synthesis of
myocardial adenine nucleotides precedes the increase in the synthesis of deoxyribonucleic acid
(DNA) (28) and proteins (13) and occurs at about
the same time that nuclear ribonucleic acid (RNA)
polymerase activity (29) and RNA labeling become
enhanced (30). (2) In the isoproterenol-stimulated
heart, de novo synthesis of adenine nucleotides
increases prior to the acceleration of the synthesis
of DNA, RNA and proteins (31, 32). (3) Enhanced
incorporation of low molecular weight precursors of
de novo synthesis into DNA (MC-formate, 2-MCglycine, 4-1;|C-aspartate) has been shown to occur
as early as 6 hours after administration of isoprotereno! (31), i.e., at the same time that the de
novo synthesis of myocardial adenine nucleotides
reaches its maximum.
The results of our studies concerning the influence of isoproterenol, propranolol, and compound
D600 on cardiac adenine nucleotide metabolism
provide some particular information with respect
to the mechanisms by which the pathway of de
TABLE 4
Rates of De Novo Synthesis and Concentrations of Myocardial
Adenine Nucleotides under Normal Conditions and 5 Hours
after Administration of Isoproterenol and Compound D600
Applied Either Alone or Simultaneously
De novo
synthesis
(nmoles/g
hour ')
Control
Isoproterenol
(5 mg/kg)
D600(10
mg/kg)
Isoproterenol
(5 mg/kg)
+ D600
(15 mg/kg)
5.3 ±0.34
(N - 32)
38.6 ± 2.97*
(N-8)
4.7 ± 1.03
(N -, 5)
22.6 ± 2.88*
(N = 6)
Values are means ± SE. N
* P < 0.005.
t P < 0.05.
ATP
(nmoles/g)
4340 ± 5 0
(N = 32)
3520 ±92*
(N - 6 )
4650 ± 126t
( N = 6)
4300 ± 9 8
( N = 7)
2ATP,
ADP, AMP
(nmoles/g)
5700 =t 120
(N =. 32)
4900 =t 100*
(N =• 6 )
6020 =b 134
(N-•6)
5590 =t 7 4
(N-•7)
number of experiments.
novo adenine nucleotide synthesis may be regulated in the myocardium. Two mechanisms are
known to be involved in the control of purine
biosynthesis: (1) feedback control of 5-phosphoribosyl-1-pyrophosphate amidotransferase (EC
2.4.2.14), the activity of which depends on the
concentration of adenine nucleotides (23, 24), and
(2) changes in the available pool of 5-phosphoribosyl-1-pyrophosphate (PRPP) (33). In trying to
explain the acceleration of de novo synthesis elicited by isoproterenol, one has to take into account
the interactions between the effects of this /3-receptor-stimulating compound on heart function, myocardial carbohydrate metabolism, and adenine nucleotide concentrations. Some of the pertinent
interrelationships are summarized in Figure 3. It is
well documented that isoproterenol increases myocardial contractility due to its calcium-dependen.
positive inotropic effect (Fig. 3, route b); this
change is paralleled by a moderate diminution in
the concentrations of adenine nucleotides (16, 17,
21, Table 1). Such a diminution of adenine nucleotide concentration (Fig. 3, route c) can cause an
acceleration of the de novo synthesis of adenine
nucleotides, since it can result in a release of
feedback inhibition of PRPP amidotransferase
(Fig. 3, route d). In addition, isoproterenol, like
other catecholamines, is known to stimulate adenyl
cyclase (Fig. 3, route a) to produce greater amounts
of 3',5'-cyclic AMP (cAMP) (34, 35). cAMP is
intimately involved in the enhancement of glycogenolysis which results in an increased formation of
glucose-6-phosphate (36, 37). Glucoses-phosphate, however, is one of the substrates of the
pentose phosphate pathway, which has been shown
to be activated under the influence of isoproterenol
(38). Thus, it seems conceivable that isoproterenol
may lead via an enhancement of glycogenolysis to
an increase in the formation of ribose-5-phosphate
and consequently of PRPP, although another mode
of action cannot be excluded. Due to the greater
availability of PRPP, the de novo formation of
adenine nucleotides should be accelerated. Unfortunately, the assumed series of metabolic reactions
can hardly be proved directly, since it is not
possible as yet to determine in cardiac tissue the
concentration of PRPP because of its high instability during the extraction procedure.
The results of our experiments with isoproterenol
and propranolol do not permit an estimate of the
respective contributions of the two possible mechanisms to the observed enhancement of de novo
synthesis, because propranolol antagonizes the effects of isoproterenol on both heart function and
Circulation Research, Vol. 35, October 1974
541
ADRENERGIC STIMULATION OF NUCLEOTIDE SYNTHESIS
ISOPROTERENOL
PROPRANOLOl
COMPOUND D600
ADENYL CYCLASE —
I
•
i
©
i
— POSITIVE INOTROPIC EFFECT
CA**-DEPENDENT
j
cAMP
•
GLYCOGENOLYSIS
•
G-l-P
•
\
[ATP], [ADP], [AMP], [IMP]
HCO3"
G-6-P
GLYCOLYSIS
PENTOSE
PHOSPHATE
PATHWAY
I
Downloaded from http://circres.ahajournals.org/ by guest on June 15, 2017
•
R-5-P
PRPP
SYNTHETASE
r
PRPP AMIDO TRANSFERASE
-PRPP-
r
ATP
-PRA
GLU
FIGURE 3
Schematic illustration of the effects of isoproterenol, propranolol, and compound D600 on the de
novo synthesis of myocardial adenine nucleotides. Solid arrows = metabolic reactions, and broken
arrows - primary and secondary effects of isoproterenol. Route a = primary effect on the activity
of myocardial adenyl cylase. Route b = primary effect on heart function. Route c = secondary
effect on the concentration of cardiac adenine nucleotides, which results in changes in the activity of
PRPP amidotransferase (route d). The inhibitory' actions of propranolol and compound D600 on the
primary effects of isoproterenol are symbolized at the top of the figure. For further details see text.
G-l-P = glucose-1-phosphate, G-6-P = glucose-6-phosphate, R-5-P - ribose-5-phosphate, PRPP 5-phosphoribosyl-l-pyrophosphate, GLU = glutamine, PRA = 5-phosphoribosylamine, GLY = glycine, GAR - glycineamide ribonucleotide, and ASP = aspartate.
carbohydrate metabolism (Fig. 3, routes a and b).
In contrast, the studies with compound D600 and
isoproterenol make it possible to indirectly distinguish between the two kinds of regulation of de
novo synthesis. Compound D600 inhibits predominantly the calcium-dependent positive inotropic
effect of isoproterenol (Fig. 3, route b) and thus
abolishes the reduction in adenine nucleotide concentration by preventing an additional utilization
of ATP (Table 4). Therefore, it probably attenuates
the isoproterenol-mediated acceleration of de novo
synthesis that is dependent on feedback regulation
(Fig. 3, route d). Thus, the attenuated elevation of
de novo synthesis under the influence of D600 and
isoproterenol (Table 4) may reflect the pure action
of isoproterenol on carbohydrate metabolism (Fig.
3, route a), which is supposed to finally result in a
greater availability of PRPP. It appears that the
effects of isoproterenol on cardiac performance and
carbohydrate metabolism can actually be dissociated by use of compound D600, which inhibits
transmembrane calcium movements (22). Similar
to our experimental approach with compound
D600, lanthanum has recently been shown to be a
Circulation Research, Vol. 35, October 1974
suitable tool for dissociating the inotropic and
glycogenolytic responses (activation of myocardial
phosphorylase) to isoproterenol (39).
All our findings favor the concept that the
greater availability of PRPP can be regarded as an
important factor in the isoproterenol-induced acceleration of de novo synthesis of myocardial adenine nucleotides. It is of particular interest that in
normal hearts, too, de novo synthesis seems to be
greatly dependent on the available pool of PRPP.
As is evident from our observations, propranolol
does not cause changes in the concentration of
adenine nucleotides but does suppress de novo
synthesis of adenine nucleotides considerably,
whereas compound D600, which induces a slight
elevation in ATP and adenine nucleotide concentrations, does not appreciably affect de novo synthesis. Hence, propranolol influences de novo synthesis not through an adenine nucleotide concentration-dependent feedback inhibition of PRPP
amidotransferase but rather through an inhibition
of the effects of endogenous catecholamines on
carbohydrate metabolism at the /3 receptor. Provided this interpretation is valid, it seems reasona-
542
ZIMMER. GERLACH
ble to assume that endogenous catecholamines can
play an important role in the regulation of the
biosynthesis and in the maintenance of the levels of
cardiac adenine nucleotides.
Acknowledgment
The excellent technical assistance of Miss G. Steinkopff,
Miss A. Maier, and Mrs. U. Nitsche is gratefully acknowledged.
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Effect of Beta-Adrenergic Stimulation on Myocardial Adenine Nucleotide Metabolism
HEINZ-GERD ZIMMER and ECKEHART GERLACH
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Circ Res. 1974;35:536-543
doi: 10.1161/01.RES.35.4.536
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