(Hypertension. 1997;29:1344-1350.)
© 1997 American Heart Association, Inc.
Articles |
Possible Participation of Nitric Oxide in the Increase of Norepinephrine Release Caused by Angiotensin Peptides in Rat Atria
From Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires (M.M.G.), and Instituto de Investigaciones Farmacológicas (CONICET), Buenos Aires, Argentina.
Correspondence to Dr Edda Adler-Graschinsky, Instituto de Investigaciones Farmacológicas, Junín 956, 5o piso, Buenos Aires (1113), Argentina. E-mail eadler{at}huemul.ffyb.uba.ar
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Abstract |
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Abstract In rat atria isolated with their cardioaccelerans nerves and labeled with [3H]norepinephrine, exposure to 1x10-7 mol/L angiotensin II (Ang II) and 1x10-7 mol/L Ang-(1-7) increased the release of radioactivity elicited by nerve stimulation (0.5-millisecond-long square-wave pulses at 2 Hz during 2 minutes) by 90% and 60%, respectively. The facilitatory effect on noradrenergic neurotransmission caused by both peptides was stereospecifically prevented by N
-nitro-L-arginine methyl ester
(1x10-4 mol/L), an inhibitor of
nitric oxide synthase that catalyzes the conversion of
L-arginine to nitric oxide, as well as by
1x10-5 mol/L methylene blue, a substance that
inhibits the guanylate cyclase considered as the final
target of nitric oxide action. On the other hand, the precursor of
nitric oxide synthesis, L-arginine
(1x10-3 mol/L), reversed the prevention
produced by N-nitro-L-arginine
methyl ester on the increased release of norepinephrine
caused by Ang II and Ang-(1-7). The present results suggest that
nitric oxide could be involved in the neuromodulatory function elicited
by both Ang II and Ang-(1-7) in rat atria. The
physiological role of this observation is still
under study.
Key Words: nitric oxide • norepinephrine • heart rate • angiotensin II
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Introduction |
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In addition to Ang II, which is accepted as the main bioactive end product of the renin-angiotensin system, other angiotensin metabolites, such as Ang-(1-7), have been proposed to possess biological activity.1 2 3 This heptapeptide, which lacks the phenylalanine present at position 8 in Ang II, is a product of Ang I metabolism via an enzymatic pathway independent of the angiotensin-converting enzyme.4 5
As observed for Ang II, the heptapeptide has been shown to possess vasopressin6 and prostaglandin7 8 releasing activities and to have natriuretic9 and diuretic10 11 effects as well as excitatory neuronal activity12 and central13 and peripheral14 cardiovascular effects comparable to those of Ang II. Nevertheless, some effects of Ang-(1-7) are opposite of those induced by Ang II. For instance, the heptapeptide is devoid of significant pressor,15 dipsogenic,16 and aldosterone secretory15 effects. Furthermore, Ang-(1-7) but not Ang II17 18 induces NO-dependent vasodilation in several preparations, such as porcine coronary artery rings17 and mesenteric and hindquarters vascular beds isolated from cats.18
NO is a neuronal messenger in the central and peripheral nervous systems,19 20 and in some tissues, such as the rat mesenteric vasculature, it stimulates the release of NE elicited by transmural nerve stimulation.21 22 Since an interaction between NO and either Ang II or Ang-(1-7) has been proposed in several tissues,17 18 23 24 the aim of the present study was to investigate whether NO participates in the reported increase of NE release elicited by Ang II and Ang-(1-7) in rat atria submitted to electrical nerve stimulation.14
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Methods |
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Ang-(1-7) Synthesis
For Ang-(1-7) synthesis, the Merrifield solid-phase procedure25 was used with Boc-amino acid derivatives. The crude peptide was purified by high-performance liquid chromatography (HPLC) in a C18 column eluted with an acetonitrile gradient of 0% to 40% at a flow rate of 1.8 mL/min. The purified product was characterized as a single component by HPLC and thin-layer chromatography. It showed aspartic acid as the amino-terminal residue as well as the correct amino acid composition and sequence.
Tissue Preparation
Female Wistar rats (180 to 200 g) were anesthetized
with ether, and the heart was rapidly removed. Both atria were
dissected with their cardioaccelerans nerves in modified Krebs'
solution of the following composition (x10-3
mol/L): NaCl 118.0, KCl 4.7, CaCl2 2.6, MgCl2
1.2, NaHCO3 25.0, glucose 11.1, EDTA 0.004, and ascorbic
acid 0.11. Atropine (1.4x10-6 mol/L) was
added to the Krebs' solution to exclude any influence of muscarinic
receptors on NE release. The atria were set up in a 5-mL isolated organ
bath equipped with platinum electrodes for nerve stimulation.
Incubations were carried out in the modified Krebs' solution at 37°C
with continuous bubbling of 95% O2/5%
CO2.
Spontaneous contractions of the preparation were recorded through a Grass FT03C transducer connected to a Grass polygraph. An equilibration period was allowed to elapse until the basal resting rate did not differ by more than 10 beats per minute during a 10-minute interval.
[3H]NE Overflow Measurement
Endogenous NE stores were labeled by incubation of
the tissue at 37°C for 30 minutes with 5 µCi/mL of
(+)-7-[3H]NE (specific activity, 14.3 Ci/mmol; New
England Nuclear Corp) as described by Adler-Graschinsky et
al.26 After the incubation, eight consecutive 1-minute
washes and then 10 consecutive 5-minute washes with Krebs' solution
were performed in every tissue.
Eighty minutes after the end of the incubation of atria with the 3H transmitter, two consecutive stimulation periods (S1 and S2) were applied 30 minutes apart (0.5-millisecond-long square-wave pulses at 2 Hz and supramaximal voltage during 2 minutes).
Inhibitors and peptides were added 4 and 2 minutes, respectively, before S2, except for methylene blue, which was added 12 minutes before S2. Inhibitors and peptides were replaced every 2 minutes whenever the bath fluid was renewed.
The spontaneous outflow of tritium was measured in 0.5-mL samples collected every 5 minutes. The tritium release induced by nerve stimulation was calculated by subtracting the spontaneous outflow assumed to have occurred in each sample during and after the stimulation period; it was expressed as the fractional release per shock (FR), that is, total evoked overflow (nanocuries) per pulse divided by the total nanocuries remaining in the tissue at the onset of stimulation. This last value was calculated by addition of the radioactivity lost during the successive washes to that measured in the tissue at the end of the experiment. The spontaneous outflow was the basal resting release obtained in the period immediately before the stimulation.
In some experiments, 4.5 mL of the bathing solution was used for chromatographic separation of NE and its metabolites through alumina and Dowex 50Wx4 (200-400 mesh) columns, according to the method described by Graefe et al.27 Five fractions were isolated: unmetabolized [3H]NE, [3H]3,4-dihydroxyphenylglycol, [3H]3,4-dihydroxymandelic acid, [3H]normetanephrine, and [3H]O-methylated deaminated fraction, which represents [3H]4-hydroxy-3-methoxyphenylglycol plus [3H]4-hydroxy-3-methoxymandelic acid.
Measurement of Chronotropic Responses
To study the effects of both Ang II and Ang-(1-7) on the
chronotropic responses triggered by nerve stimulation, we determined
two consecutive frequency-response curves with each preparation. The
cardioaccelerans nerves were stimulated for 20 seconds at different
frequencies with 0.5-millisecond-long square-wave pulses at
supramaximal voltage. The interval between each period of nerve
stimulation at the different frequencies was 20 minutes, this being
enough for the atrial rate to return to its resting values. The second
curves were separated by six washes, each 10 minutes long, with Krebs'
solution. The peptides were added during the second curves, 2 minutes
before each nerve stimulation frequency was applied.
In some experiments, two consecutive concentration-response curves to exogenous NE, separated by six 10-minute-long washes, were determined. The interval between each addition of NE was 20 minutes, and the peptides were present during the second curves, 2 minutes before each NE concentration added to the organ bath.
Statistical Analysis
All values are mean±SEM. Data were submitted to one-way ANOVA.
Post hoc analysis with the Scheffé test was carried out,
and probability values less than .05 were considered significant.
Drugs
Ang II, L-NAME, D-NAME, L-arginine, and methylene
blue were purchased from Sigma Chemical Co.
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Results |
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Effects of Angiotensin Peptides on Basal and Stimulated [3H]NE Release in Rat Atria
The overflow of tritium in response to nerve stimulation was increased by 90% (P<.05) in the presence of 1x10-7 mol/L Ang II (Fig 1
)
and by 60% (P<.05) in the presence of
1x10-7 mol/L Ang-(1-7) (Fig 2). The increase in [3H]NE release caused
by both peptides was prevented by the addition of L-NAME
(1x10-4 mol/L), the specific
inhibitor of NO synthesis, and was restored when
L-arginine (1x10-3 mol/L), the
precursor of NO synthesis, was added together with L-NAME (Figs 1 and 2).
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On the other hand, the inactive stereoisomer D-NAME
(1x10-4 mol/L) had no effect on the increase
on stimulated NE release elicited by either Ang II or Ang-(1-7) (Fig 3). In addition, neither L-NAME nor D-NAME modified the
release of tritium evoked by nerve stimulation, according to ANOVA
analysis (S2/S1=0.96±0.06, n=5,
and 0.72± 0.06, n=4, respectively).
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Moreover, when the stimulatory activity of the
angiotensin peptides on noradrenergic
neurotransmission was assayed in the presence of methylene blue
(1x10-5 mol/L), an inhibitor of
the soluble guanylate cyclase considered as the target for
the action of NO, a complete prevention of the facilitatory effects of
both peptides was observed (Fig 4). Methylene blue did
not modify the release of tritium in the stimulated atria (Fig 4).
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None of the substances assayed modified the basal spontaneous release
of [3H]NE (B1 and B2) (Table 1).
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Effects of Angiotensin Peptides on Atrial Chronotropic
Responses to Nerve Stimulation
To study whether the increase in [3H]NE
release caused by the angiotensin peptides was accompanied
by a potentiation of the atrial chronotropic responses to nerve
stimulation, we determined consecutive frequency-response curves and
carried out second curves either in the presence of saline in the
controls or after incubation with the peptides in the experimental
groups. As shown in Fig 5, the concentrations of Ang II
and Ang-(1-7) that induced a significant increase in the overflow of
[3H]NE (Figs 1
and 2) did not modify the chronotropic
responses induced by nerve stimulation of the rat atria. It is of
interest to note that Ang II, but not Ang-(1-7), induced a small but
significant increase in basal atrial rate (Table 2).
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) were carried out
either in saline in controls (n=5) or after a 2-minute incubation with
1x10-7 mol/L Ang II (n=6) or
1x10-7 mol/L Ang-(1-7) (n=6). Mean
values±SEM are shown. Maximal increases in atrial rate (beats per
minute) during the first curves were as follows: controls, 164±7; Ang
II, 146±9; Ang-(1-7), 136±6.
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Moreover, whereas the sensitivity of the atria to exogenous NE was
reduced by exposure to 1x10-7 mol/L Ang II,
it was not modified by the addition of 1x10-7
mol/L Ang-(1-7) (Fig 6).
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The possibility that the lack of effect of angiotensin
peptides to enhance the atrial rate resulted from an alteration in the
metabolic pattern of the neurotransmitter released is
apparently precluded from the results shown in Fig 7, which indicate that the proportion of radioactivity collected as
unmetabolized [3H]NE was the same in controls as
during Ang-(1-7) stimulation (S1, control: 77.3±2.1%;
S2, Ang-(1-7): 62.1±11.7%). A similar proportion of
radioactivity collected as unmetabolized tritiated NE was obtained when
the second stimulation was performed in the presence of Ang II
(S1, control: 60.8±17%; S2, Ang II:
72.1±9.5%) (Fig 8).
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Discussion |
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NO is generally considered as the biological mediator of nonadrenergic-noncholinergic neurotransmission.28 29 In addition, a role for NO has been proposed in either the facilitation or inhibition of sympathetic neurotransmission. In this regard, whereas increases in the release of NE linked to NO have been reported in rat mesenteric vasculature21 22 and rat hippocampus,30 decreases in sympathetic activity somehow connected to NO have been described in canine and rat renal nerves31 32 as well as in the rat tail artery33 and rat brain stem nuclei.34
The present results show that in rat atria labeled with [3H]NE, exposure to L-NAME, which inhibits NO synthase, as well as to methylene blue, which inhibits the guanylate cyclase that is the target for NO action,35 prevents the increase in NE release by nerve stimulation caused in this tissue by either Ang II or Ang-(1-7). These observations suggest that the effects of angiotensin peptides in rat atria are at least partially mediated through a cGMP-dependent NO-linked mechanism. In support of this view is the observation that L-arginine, the precursor of NO formation, reverses the preventive effect of L-NAME on the facilitation of noradrenergic neurotransmission caused by both peptides. These results, taken together with the observation that the inactive stereoisomer D-NAME had no effect on angiotensin facilitation of NE release, suggest that NO could be involved in the positive modulation of NE release elicited by both peptides in the rat atria. It is of interest to note (M.M.G. et al, unpublished observations, 1996) that the NO donor sodium nitroprusside does not potentiate in the rat atria the effects of angiotensin peptides on [3H]NE release by nerve stimulation, thus suggesting that in cardiac myocytes (for review, see Reference 3636 ), the NO generator drugs are not suitable tools for the study of the effects of endogenous generation of NO. Participation of NO in the enhancement of NE release has also been reported for the N-methyl-D-aspartate–stimulated release of [3H]NE in rat brain slices.37
Several reports demonstrate an interaction between NO and the effects of either Ang II or Ang-(1-7) in different tissues. For instance, the vasodilation caused by Ang-(1-7) in porcine coronary arteries,17 in feline mesenteric and hindquarters vascular beds,18 and in both normotensive and hypertensive dogs38 has been proposed to arise from NO release. On the contrary, the vasoconstrictor responses to Ang II have been reported to be counteracted by NO formation in several vascular preparations, such as in the perfused rabbit heart,39 in canine preglomerular and postglomerular vessels,23 and in the rabbit aorta.24 On the other hand, a stimulatory effect of Ang II on NO release from human proximal tubular cells40 and dog coronary blood vessels41 has been reported.
The fact that L-NAME did not modify by itself the overflow of NE in response to nerve stimulation (present results) could suggest that endogenous NO does not play a major physiological role in regulating NE release in the rat heart. Nevertheless, Schwarz et al42 have reported that the NO synthase inhibitor NG-nitro-L-arginine increases the NE release evoked by nerve stimulation in the rat heart. The difference between this observation and our present results could be due to not only the chemical structure of the NO synthase inhibitors used but also differences in experimental design. For instance, Schwarz et al42 used perfused rat hearts rather than isolated atria; even more important, we conducted our experiments in the presence of atropine, a substance that could interfere with the NO generation reported for acetylcholine in mammalian cardiac tissue.43
The observation that both Ang II and Ang-(1-7) caused an increase
in [3H]NE release without modifying the chronotropic
responses elicited by nerve stimulation of the rat atria was
unexpected. Although in the case of Ang II the lack of enhancement of
the chronotropic responses could result from the decreased sensitivity
caused by this peptide on the atrial sensitivity to exogenous NE (Fig 6), this was not the case for Ang-(1-7), which did not modify the
atrial responses to the exogenous sympathetic neurotransmitter.
Moreover, the possibility that the lack of effect of
angiotensin peptides to increase the sympathetic responses
to nerve stimulation resulted from the fact that they were tested at
near maximal levels of stimulation (ie, 2 Hz during 2 minutes) was
disregarded because they were also unable to potentiate the atrial
responses when tested at very low frequencies of nerve stimulation,
such as those indicated in Fig 5. It is of interest to note that a
similar lack of correlation between the increase in
[3H]NE release and lack of enhancement of atrial
responses has been reported in the guinea pig atria for the blockade of
presynaptic 
-adrenoceptors with
phentolamine.44
The observation that the increase in NE release had not been
accompanied by an enhancement of the atrial responses could rely on
alterations in the metabolic pattern of the
noradrenergic neurotransmitter, due to the fact that
the metabolites of NE are devoid of effect on postsynaptic
adrenoceptors.45 Nevertheless, this possibility is
disregarded because the metabolic pattern of NE was not
modified by either Ang II or Ang-(1-7) (Figs 7 and 8). The possibility
that angiotensin peptides had inhibited the neuronal uptake of NE is
apparently precluded from the observation that the release of the
glycol deaminated 3,4-dihydroxyphenylglycol is increased during nerve
stimulation. This metabolite, that is formed during nerve stimulation
through the neuronal reuptake of the released transmitter, is not
present when the latter mechanism is inhibited for substances such
as cocaine (for review, see Reference 4646 ).
One possibility to explain the discrepancy between increases in NE release caused by angiotensin peptides and the lack of potentiation of atrial responses is that during nerve stimulation, the activation of angiotensin receptors resulted in the release of another neurotransmitter or neuromodulator, such as acetylcholine or adenosine, which are known to exert negative chronotropic effects.47 48 Although the interference of acetylcholine on atrial rate could be precluded from the present results because all the experiments were performed in the presence of atropine, the possible participation of adenosine cannot be ruled out. In this regard, the Ang II–induced dilatation in isolated perfused rabbit heart has been linked to the accumulation of adenosine.39
We conclude that NO probably participates in the increase of [3H]NE caused by angiotensin peptides in the rat atria. The physiological role of this observation is presently unclear and constitutes the aim of forthcoming studies.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grant 339700092 from CONICET, Argentina. The excellent technical assistance of Mónica Ferrari is gratefully acknowledged.
Received July 3, 1995; first decision August 21, 1995; accepted November 21, 1996.
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 J. Stegbauer, V. Oberhauser, O. Vonend, and L. C. Rump Angiotensin-(1-7) modulates vascular resistance and sympathetic neurotransmission in kidneys of spontaneously hypertensive rats Cardiovasc Res, February 1, 2004; 61(2): 352 - 359. [Abstract] [Full Text] [PDF]
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 E. M. Mbaku, L. Zhang, W. J. Pearce, S. P. Duckles, and J. Buchholz Chronic hypoxia alters the function of NOS nerves in cerebral arteries of near-term fetal and adult sheep J Appl Physiol, February 1, 2003; 94(2): 724 - 732. [Abstract] [Full Text] [PDF]
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 M. M. Gironacci, M. Vatta, M. Rodriguez-Fermepin, B. E. Fernandez, and C. Pena Angiotensin-(1-7) Reduces Norepinephrine Release Through a Nitric Oxide Mechanism in Rat Hypothalamus Hypertension, June 1, 2000; 35(6): 1248 - 1252. [Abstract] [Full Text] [PDF]
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 E. N. Mbaku, L. Zhang, S. P. Duckles, and J. Buchholz Nitric-Oxide Synthase-Containing Nerves Facilitate Adrenergic Transmitter Release in Sheep Middle Cerebral Arteries J. Pharmacol. Exp. Ther., May 1, 2000; 293(2): 397 - 402. [Abstract] [Full Text]
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