Download Angiotensin II Increases Norepinephrine Release

699
Angiotensin II Increases Norepinephrine
Release From Atria by Acting on Angiotensin
Subtype 1 Receptors
Helmut Brasch, Ludwig Sieroslawski, Peter Dominiak
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Norepinephrine stores in electrically driven guinea pig isolated atria were loaded with [3H] norepinephrine, and norepinephrine release was deduced from the radioactivity efflux. Electrical field stimulation of
sympathetic nerve endings was applied during the refractory period of atrial contractions. The
stimulation-induced release of norepinephrine was increased by angiotensin II (Ang II) (10"* to 10*"'
mol/L) in a concentration-dependent manner. The maximum observed effect was a 55% augmentation.
The effects of 10"7 and 10"6 mol/L Ang II were abolished by 10' 6 and 10"5 mol/L of the subtype 1 Ang II
receptor antagonist losartan, respectively. Losartan by itself (10~6 mol/L) caused a 14% reduction of
norepinephrine release. The subtype 2 Ang II receptor ligand PD 123319 (l-[[4-(dimethylamino)-3methylphenyl] methyl] -5-(diphenylacetyl)-4,5,6,7-tetrahydro-l//-imidazo [4,5 -c]pyridine-6-carboxylic
acid ditrifluoroacetate) in a concentration of 10~4 mol/L had no detectable influence on transmitter
release and did not antagonize the effect of Ang II. Angiotensin I (10~6 and 10"5 mol/L) increased
norepinephrine release maximally by 23%. This effect was antagonized by 10"5 mol/L losartan and did not
appear in the presence of 10~6 mol/L of the converting enzyme inhibitor ramiprilat. These results suggest
that Ang II increases norepinephrine release by an activation of subtype 1 receptors, whereas angiotensin
I is converted to Ang II to become effective. (Hypertension. 1993;22:699-704.)
KEY WORDS • heart atrium • norepinephrine • angiotensin II • receptors, angiotensin •
losartan
I
n plasma, angiotensin I (Ang I) is metabolized to
the vasoconstricting octapeptide angiotensin II
(Ang II) by a circulating converting enzyme. Additional amounts of Ang II are produced by local
renin-angiotensin systems in a variety of tissues.'-3 In
the heart, for instance, messenger RNA for the synthesis of renin has been detected, and a tissue-bound
converting enzyme is also present, as well as Ang II, its
precursor Ang I, and the metabolite angiotensin III. 3 5
Such a local renin-angiotensin system may be responsible for a variety of physiological and pathophysiological effects. For instance, Ang II increases protein
synthesis in chick heart cells.6 Thus, the local production of the peptide may contribute to the development
of cardiac hypertrophy, which can be prevented or
reversed by converting enzyme inhibitors in experimental and human hypertrophy.7-8 Other effects of Ang II
are a release of catecholamines from the adrenal medulla9'10 and from dopaminergic neurons in the central
nervous system" and a facilitation of the release of
norepinephrine from sympathetic nerve terminals in
field-stimulated guinea pig, rat, and mouse atria. 1214
The positive inotropic effect of Ang II, which, according
to Kuschinsky and Liillmann15 and Theyson and
Received February 15, 1993; accepted in revised form June 16,
1993.
From the Institute of Pharmacology, Medical University of
Lubeck (FRG).
Correspondence to Helmut Brasch, Institut fur Pharmakologie,
Medizinische Universitat zu Lubeck, Ratzeburger Allee 160,
D-23538 Lubeck, FRG.
Klaus,16 does not appear in the presence of /3-adrenergic receptor antagonists, may therefore be caused by an
increase of the local norepinephrine concentration.
However, a direct influence of the peptide on calcium
channels has also been suggested.1718
The first aim of this study was to determine whether the
prejunctional effect of Ang II on norepinephrine release is
mediated by Ang II subtype 1 (AT,) or subtype 2 (AT2)
receptors in the isolated guinea pig atrium. To this end,
the ATrselective receptor antagonist losartan19 and the
AT2-selective receptor ligand211 PD 123319 (l-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)4,5,6,7-tetrahydro-li/-imidazo[4,5-c]pyridine-6-carboxylic
acid ditrifluoroacetate) were used. Further experiments
with Ang I and the converting enzyme inhibitor ramiprilat
suggest that a converting enzyme that continuously produces small amounts of endogenous angiotensin is active
in the isolated atrium.
Methods
Experimental Procedure
Two hundred male Pirbright white guinea pigs were
used for the study. They were bought from the Lippische
Versuchstierzuchtanstalt, Extertal, FRG, had free access
to Altromin standard diet and tap water until used, and
weighed 300 to 500 g on the day of experiments.
The animals were killed by a blow on the head, and the
hearts were rapidly removed. The left atrium was dissected out and mounted in a 10-mL organ bath that
contained Krebs-Henseleit solution of the following com-
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Hypertension
Vol 22, No 5 November 1993
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position (mmol/L): NaCl, 117.6; KC1, 5.8; NaHCO3, 25;
NaH2PO4,1.2; MgSO4,1.2; Cad 2 , 2.5; and glucose, 5.5 as
well as 0.1 mmol/L Ca-EDTA and 0.06 mmol/L ascorbic
acid as antioxidants. The solution was gassed with 95% O2
and 5% CO2. The atria were stimulated at a rate of 0.5 Hz
through platinum electrodes in direct contact with the
muscle with square pulses of 2-milliseconds duration and
1.5 times threshold voltage (Stimulator T, Hugo Sachs,
Hugstetten, FRG). The resting tension was adjusted to 10
mN, and the force of contraction was registered isometrically with a K 30 force-displacement transducer (Hugo
Sachs) on a Helcoscriptor HE 16 (Hellige, Freiburg,
FRG). After an equilibration period of 15 minutes, 10 /xCi
of 7-pHlnorepinephrine was added to establish a drug
concentration between 5xlO~8 and 10"7 mol/L in the
loading bath (calculated from the specific activity of 10 to
20 Ci/mmol, see below). After a loading period of 1 hour,
the atria were carefully rinsed with Krebs-Henseleit solution and transferred to a 20-mL organ bath for the release
experiments.
During the release experiments, the atria were stimulated at a rate of 0.5 Hz as described above (continuous myocardial driving stimulation). The myocardial
driving stimuli triggered a second Stimulator T that
produced square pulses of 30-V strength and 0.2millisecond duration. To evoke norepinephrine release
from sympathetic nerve endings, these supramaximal
stimuli (field stimuli) were applied 10 milliseconds after
the driving stimulus, ie, during the myocardial refractory period, through two parallel platinum electrodes
(1.5 cm long, 0.5 mm in diameter, 1 cm apart, one on
each side of the muscle). For 1 hour, only myocardial
driving stimulation was used, and the bathing solution
was changed every 10 minutes to wash away all
[3H]norepinephrine that had not been taken up into the
storage vesicles. Thereafter, a single field stimulus (2
milliseconds, 30 V) was applied during each refractory
period for 10 minutes. Atria that did not give a significant positive inotropic response or that developed arrhythmia were discarded after this test stimulation
period.
For all other atria, the experiment proper began 15
minutes later. Cocaine (3xl0~ 5 mol/L) and atropine
(10~7 mol/L) were added to the organ bath to prevent
neuronal reuptake of norepinephrine and cholinergic
effects of electrical field stimulation, respectively. Norepinephrine release from sympathetic nerve endings
was stimulated three times in each atrium by applying
one 0.2-millisecond field stimulus during each myocardial refractory period. The stimulation periods lasted 5
minutes each and were separated by 15-minute intervals. The first and second stimulation periods (Si and S2)
served as individual controls, and the various test drugs
were added 15 minutes before the third stimulation
period (S3).
Five minutes before the start and immediately after
the end of S1; S2, and S3, the organ bath was filled with
fresh Krebs-Henseleit solution. Samples (1 mL) of the
bathing fluid were collected immediately before the
beginning and at the end of each stimulation period and
again 5 minutes later for the determination of radioactivity efflux.
Calculations and Statistics
The stimulation-induced radioactivity efflux from the
atrium into the organ bath was taken as an indicator of
the stimulation-induced norepinephrine release. For
measurement of the radioactivity in the bathing fluid,
the 1-mL samples were mixed with 9 mL scintillation
fluid (Hydroluma, Baker, Deventer, the Netherlands)
and counted for 10 minutes in a scintillation counter
(BF 5003, Laboratorium Dr Bertold, Wildbad, FRG).
Results are given as disintegrations per minute (dpm)
per milliliter bathing fluid. The basal, unstimulated
outflow of radioactivity was determined in the samples
from the 5-minute collection periods immediately before and after each stimulation period. To obtain the
stimulation-induced radioactivity efflux, we subtracted
the mean basal outflow from the total radioactivity
measured in the sample from the stimulation period.
To compare the effects of the consecutive stimulation
periods, we calculated the S2-S, and S3-S1 ratios for the
stimulation-induced radioactivity release for each experiment. Their means and associated standard errors
(n=7 to 11 muscles per group) are presented in the
figures. Friedman's analysis of variance with ranks21 was
used to compare the predrug (S2-S,) release ratios from
the different groups of atria. To evaluate drug effects,
we compared the S3-S| and S^-Si ratios from the same
group of atria with the U test for paired data. A value of
P^.05 for the two-tailed test was considered to indicate
statistical significance throughout.
Drugs
The following drugs were used in the study: L-7[3H]norepinephrine hydrochloride (10 to 20 Ci/mmol,
Du Pont de Nemours, Dreieich, FRG); Ca-EDTA,
ascorbic acid, cocaine hydrochloride (all E Merck,
Darmstadt, FRG); atropine sulfate (Pharma Hameln,
Hameln, FRG); Ang I, Ang II (Sigma Chemie, Deisenhofen, FRG); losartan (kindly donated by Du Pont,
Wilmington, Del); PD 123319 (provided by ParkeDavis, Mich); and ramiprilat (donation from Hoechst
AG, Frankfurt, FRG). All drugs were dissolved in
double-distilled water. Stock solutions of the peptides (1
mg/mL) were stored at -22°C until use. All other
solutions were prepared daily, and microliter amounts
were added to the organ bath.
Results
Predrug Control Values for Basal Outflow and
Stimulated Release of Radioactivity
Even when the sympathetic nerve endings were not
depolarized by field stimulation, there was a continuous
efflux of radioactivity from the atria. This basal outflow
is thought to consist mainly of inactive norepinephrine
metabolites.22-23 In 22 groups of atria, the mean unstimulated efflux measured for the 5-minute period immediately preceding S, ranged between 87±8 and 178±54
dpm/mL (lowest and highest value, respectively). It
decreased by approximately 10% to 25% during the
time course of the experiments and was not significantly
influenced by any of the drugs under study.
Field stimulation released additional amounts of radioactivity, and this stimulation-induced release can be
regarded as a reliable indicator of an exocytotic release
of norepinephrine from sympathetic nerve terminals. 2224 For the first stimulation period (S,), mean
release rates between 116±16 and 263±69 dpm/mL
were obtained (highest and lowest mean and SEM,
Brasch et al
Increase of Norepinephrine Release by Angiotensin
Control
P0 10"4
701
ANG I I 10"7
+ P0 10"4
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FIG 1. Bar graph shows influence of angiotensin II (ANG
II) on radioactivity release from left atria caused by three
consecutive field-stimulation periods (S, to S3). Means of
S2-S, release ratio (open columns) and ^-St release ratio
(filled columns) are shown for each group of atria (n=8 to
9). Vertical bars indicate associated SEM. Angiotensin II
was added 15 minutes before S,. *Significant difference
(Ps.05, two-tailed) between S3-S, and SrS, ratio (U test
for paired data). Drug concentrations are in moles per
liter.
FIG 3. Bar graph shows influence of angiotensin II (ANG
II) in combination with PD 123319 (PD) on radioactivity
release from left atria caused by three consecutive fieldstimulation periods (S, to S3). Means of S2-S! release
ratio (open columns) and S3-S, release ratio (filled columns) are shown for each group of atria (n=8 to 9).
Vertical bars indicate associated SEM. Drugs were added
15 minutes before S3. *Significant difference (Ps.05,
two-tailed) between S3-S, and S2-S, ratio (U test for paired
data). Drug concentrations are in moles per liter.
respectively). Field stimulation also produced a significant positive inotropic effect, increasing the force of
contraction by between 7.93±1.38 and 17.70±2.36 mN
(highest and lowest mean value measured for Si).
Although no drugs were added before S2, less radioactivity was released during the second stimulation period
than during S, in most experiments, so that mean ^ - S ,
release ratios between 0.85±0.08 and 0.98±0.07 were
calculated (Figs 1 through 5).
ing from 0.81 ±0.09 to 0.89±0.07) were not significantly
different from the corresponding S2-S, ratios (Figs 1
through 5).
Control Experiments
In control experiments, when no drug was added
before S3, there was a further small decrease of the
stimulation-induced release of radioactivity. But the
resulting mean S3-S, ratios in five groups of atria (rang-
Effects of Angiotensin II
Ang II increased the stimulation-induced release of
radioactivity in a concentration-dependent manner (Fig
1). The effect became apparent at a concentration of
3xlO" 8 mol/L and reached its maximum at a concentration of 10"6 mol/L. However, because of its large
variability, the influence of 10"6 mol/L was not significantly different from the effect of 10"7 mol/L, and
concentrations beyond 10~6 mol/L were not tested. The
S3-S| release ratio of 1.28±0.19 obtained with 10~6
mol/L underestimates the maximum drug effect because
FIG 2. Bar graph shows influence of
angiotensin II (ANG II) in combination
with losartan (LOS) on radioactivity release from left atria caused by three
consecutive field-stimulation periods
(S, to S3). Means of S2-S, release ratio
(open columns) and S3-S, release ratio
(filled columns) are shown for each
group of atria (n=9). Vertical bars indicate associated SEM. Drugs were
added 15 minutes before S 3 . *Signrficant difference (Ps.05, two-tailed) between S3-S, and S2-S, ratio (U test for
paired data). Drug concentrations are
in moles per liter.
3
Control
LOS 10-«
ANG I I IO- 7
ANG I I lO" 7
AW I I 10-* ANG I I 10"*
+ LOS I 0 " 7
+ LOS 10-*
+ LOS 10" 6
+ LOS I 0 " 5
702
Hypertension
Vol 22, No 5 November 1993
FIG 4. Bar graph shows influence of
angiotensin I (ANG I) and angiotensin I
plus losartan (LOS) on radioactivity release from left atria caused by three
consecutive field-stimulation periods
(S, to S3). Means of S2-S, release ratio
(open columns) and S3-S, release ratio
(filled columns) are shown for each
group of atria (n=7 to 11). Vertical bars
indicate associated SEM. Drugs were
added 15 minutes before S 3 . *Significant difference (Ps.05, two-tailed) between S3-S, and S2-S, ratio (U test for
paired data). Drug concentrations are
in moles per liter.
Control
ANG
1 io-»
uc 1 10-5
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ANG 1 i<r*
+ LOS io-«
the release during S2 was smaller than during S, (see
above). Compared with S2, Ang II caused a 55%
increase of the stimulation-induced release. The effect
of Ang II was accompanied by a small (12%) augmentation of the positive inotropic effect of field stimulation, but the slight influences of the test drugs on atrial
contractility are not further described or discussed.
The nonpeptidic AT,-specific receptor antagonist
losartan reduced the stimulatory influence of Ang II on
transmitter release (Fig 2). A concentration of 1CT6
mol/L losartan was sufficient to suppress completely the
effect of lfT7 mol/L Ang II, whereas 10"5 mol/L was
needed to abolish the influence of 1CT6 mol/L of the
peptide. By itself, 10"7 mol/L losartan had no effect on
transmitter release (data not shown), but 10"6 mol/L
Control
RAM 10"*
RAM 10"*
+ ANG I 10"*
FIG 5. Bar graph shows influence of ramiprilat (RAM)
and ramiprilat plus angiotensin I (ANG I) on radioactivity
release from left atria caused by three consecutive fieldstimulation periods (S, to S3). Means of S2-S, release
ratio (open columns) and S3-S, release ratio (filled columns) are shown for each group of atria (n=7 to 10).
Vertical bars indicate associated SEM. Drugs were added
15 minutes before S3. *Significant difference (P^.05,
two-tailed) between S3-S, and S2-S, ratio (U test for paired
data). Drug concentrations are in moles per liter.
ANG I i<r*
+ LOS 10-5
caused a 14% reduction of the stimulation-induced
release of radioactivity (Fig 2).
In contrast to losartan, the AT2-specific receptor
ligand PD 123319 in concentrations up to 10"4 mol/L
had no detectable influence on the effect of Ang II and
was also without effect when applied alone (Fig 3).
Effects of Angiotensin I
The precursor of Ang II, Ang I, also increased the
stimulation-induced release of radioactivity (Fig 4).
However, the concentrations of the decapeptide needed
to produce a significant change were approximately 10
times greater than those of the octapeptide. Although
no clear-cut effect was seen in some preliminary experiments with 10~7 mol/L (not shown), 1CT6 and 10~5
mol/L produced a 23% and 18% increase, respectively.
The effect of 1(T6 mol/L Ang I was abolished by 1CT5
mol/L losartan (Fig 4) and did not appear when 10~6
mol/L of the converting enzyme inhibitor ramiprilat was
applied simultaneously (Fig 5). Ramiprilat by itself did not
modify the stimulation-induced release of radioactivity.
Discussion
It has been concluded from in vivo experiments that
Ang II increases the release of norepinephrine in the
heart23; the effect has also been demonstrated directly
in isolated heart tissues.1426 The present results are in
line with previous studies that have demonstrated a 50%
increase of transmitter release by 10"8 mol/L Ang II in
guinea pig atria,12 a doubling by 3xl0~ 7 mol/L in rat
atria,13 and a 50% increase by 10"8 to 10"7 mol/L in
mouse atria.14 Obviously, the renin-angiotensin system
modulates sympathetic tone not only by acting on the
central nervous system11 or by increasing the release of
catecholamines from the adrenal medulla9'10 but also by
a local effect on sympathetic nerve endings in the
tissues. As autoinhibition of norepinephrine release by
stimulation of prejunctional a2-adrenergic receptors was
not excluded, the true maximum of this local stimulatory effect may even have been underestimated in our
experiments and in the earlier in vitro studies.1214
Clearly, the influence of Ang II on norepinephrine
Brasch et al
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release in the presence of a r adrenergic receptor antagonists deserves further investigation.
In previous investigations,12-13 the effect of Ang II
could be prevented by the nonselective angiotensin
receptor antagonist saralasin. In our experiments, the
effect of Ang II was abolished by losartan, a competitive
Ang II antagonist with a high selectivity for AT, receptors.19-27 We did not construct complete concentrationresponse curves because the maximum increase of
norepinephrine produced by the peptide was relatively
small, but the results shown in Fig 2 are compatible with
the assumption of a competitive antagonism between
losartan and Ang II. This suggests that in guinea pig
atria the influence of Ang II on the release of norepinephrine is mediated by prejunctional AT, receptors.
Apparently, AT2 receptors are not involved, because the
ligand PD 123319, which is selective for AT2 receptors,20
had no effect. AT2 receptors are present in the heart
and account for up to 30% of the total angiotensin
receptor population.19-28-29 Their physiological role is
still uncertain, but AT2 receptors located on human
cardiac fibroblasts have recently been shown to stimulate collagen synthesis.30
The precursor of Ang II, Ang I, was also able to
increase the stimulation-induced release of norepinephrine. The antagonism by losartan shows that this effect
also is caused by a stimulation of AT, receptors. Ang I
has a low affinity to angiotensin receptors,31 but it is
unlikely that it was the active compound in our experiments because its effect was not seen in the presence of
the converting enzyme inhibitor ramiprilat. We conclude that Ang I must be converted to Ang II, which
then acts as the receptor stimulant, as has already been
suggested from experiments in guinea pig and rat
atria12-14 and rat Langendorff-perfused hearts,32 in
which the norepinephrine-releasing effect of Ang I
could be prevented by saralasin, captopril, and ramiprilat. In these studies, Ang I was found to be 10 to 20
times less effective than Ang II, whereas both compounds were roughly equipotent in increasing the beating frequency of isolated guinea pig right atria.33 In our
experiments we needed 10-fold greater concentrations
of the decapeptide to produce roughly the same increase of transmitter release as with the octapeptide.
Only approximately 7% of the administered dose of Ang
I is metabolized to Ang II in perfusion experiments with
isolated organs.3 This small conversion rate seems to be
a reasonable explanation for the lower efficacy of Ang I
but makes it difficult to understand why 10"5 mol/L
losartan was needed to antagonize the effect of Ang I.
As judged from the experiments with Ang II (Fig 2),
10~6 mol/L should have been sufficient. We cannot
explain this discrepancy at the moment.
The small reduction of norepinephrine release
caused by losartan is an interesting finding. The drug is
lipophilic (octanol/water partition coefficient of 7.77 at
physiological pH; unpublished results) and, in principle,
might act like a local anesthetic to inhibit membrane
depolarization and subsequent exocytosis at the sympathetic nerve endings. However, the effect was fully
overcome by increasing concentrations of Ang II (Fig
2), which makes such an unspecific influence unlikely.
We suggest, therefore, that losartan antagonizes, at AT,
receptors, the stimulating effect of small amounts of
endogenous Ang II that are produced continuously by
Increase of Norepinephrine Release by Angiotensin
703
the tissue converting enzyme. In contrast to our findings, no reduction of the transmitter release was observed in guinea pig atria in the presence of saralasin.12
But as saralasin is a partial agonist, the remaining
intrinsic activity of this compound may have prevented
the expected reduction. Perhaps more important, ramiprilat, in a concentration sufficient to inhibit the converting enzyme, did not reduce the transmitter release in
our experiments, and several converting enzyme inhibitors, including captopril, were found to be ineffective by
others.12-32 But this too does not necessarily contradict
our hypothesis. An admittedly speculative explanation
can be suggested for the lack of effect of the converting
enzyme inhibitors. The converting enzyme is a rather
unspecific dipeptidase that also inhibits the inactivation
of bradykinin.34-35 Bradykinin is known to stimulate
norepinephrine release from nerve terminals,36 and
thus the stimulating influence of an increased bradykinin concentration and the inhibitory effect of a reduced
Ang II concentration could cancel each other out. The
fact that in pithed rats converting enzyme inhibitors do
not change the stimulation-induced release of catecholamines37-38 and may even increase the norepinephrine
spillover rate in conscious spontaneously hypertensive
rats39 supports this idea. If Ang II produced in the tissue
causes a significant modification of the norepinephrine
release via prejunctional AT, receptors in the isolated
atrium, a similar effect may occur also in vivo. Because
of its implications for the local regulation of sympathetic
tone, this idea clearly deserves further investigation.
In conclusion, our results have shown that in fieldstimulated guinea pig atria, Ang II applied to the
bathing solution increases the release of norepinephrine
by an activation of prejunctional AT, receptors. Ang I is
converted to Ang II to produce a similar effect. In
addition, a continuous production of endogenous Ang
II may be responsible for a certain degree of AT,
receptor activation in the untreated atrium.
Acknowledgment
This work was supported by the Sandoz-Stiftung fur therapeutische Forschung.
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H Brasch, L Sieroslawski and P Dominiak
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Hypertension. 1993;22:699-704
doi: 10.1161/01.HYP.22.5.699
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