(Hypertension. 1999;33:914-919.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Cardiovascular Effects of Nociceptin in Unanesthetized Mice
From Clinica Medica (P.M.) and Farmacologia (P.M., M.B.S., A.F.M., C.E.), University of Sassari; National Laboratory of the National Institute of Biosystems and Biostructures (P.M., C.E.), Osilo; Department of Pharmaceutical Sciences (R.G.) and Department of Experimental and Clinical Medicine (D.R., G.C.), Section of Pharmacology, University of Ferrara; Laboratory of Vascular Pathology (P.M., M.B.S., C.E.), Istituto Dermopatico dell'Immacolata, Rome, Italy.
Correspondence to Paolo Madeddu, MD, Clinica Medica, University of Sassari, Viale S. Pietro 8, 07100 Sassari, Italy. E-mail madeddu{at}ssmain.uniss.it
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Abstract |
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Abstract—We evaluated the systemic hemodynamic effects induced by nociceptin (NC) and NC-related peptides, including the NC receptor antagonist [Phe1
(CH2-NH)Gly2]NC(1–13)NH2
([F/G]NC(1–13)NH2) in unanesthetized
normotensive Swiss Morini mice. Bolus intravenous injection
of NC decreased mean blood pressure and heart rate. The hypotensive
response to 10 nmol/kg NC lasted <10 minutes, whereas a more prolonged
hypotension was evoked by 100 nmol/kg (from 114±3 to 97±2 mm Hg
at 10 minutes, P<0.01). The latter dose reduced heart
rate from 542±43 to 479±31 beats/min (P<0.05) and
increased aortic blood flow by 41±5% (P<0.05).
Hypotension and bradycardia were also evoked by
NC(1–17)NH2 and NC(1–13)NH2 fragments,
whereas NC(1–13)OH and NC(1–9)NH2 were ineffective.
Thiorphan, an inhibitor of neutral
endopeptidase 24.11, enhanced the hypotension induced
by NC(1–13)NH2 and revealed the ability of NC(1–13)OH to
decrease mean blood pressure. [F/G]NC(1–13)NH2, a
recently synthesized antagonist of the NC receptor, did not
alter basal mean blood pressure or heart rate, but it prevented the
hypotension, bradycardia, and increase in aortic blood flow evoked by
NC. In contrast, [F/G]NC(1–13)NH2 did not alter the
hypotension induced by bradykinin or endomorphin-1 (a µ-receptor
agonist), and the bradycardia induced by leu-enkephalin (a 
-receptor
agonist) or U504885 (a synthetic 
-receptor agonist). In
conclusion, NC and some of its fragments cause hypotension and
bradycardia and increase aortic blood flow in mice, with
the NC(1–13) sequence being critical for these biological effects. Our
results also demonstrate that the compound
[F/G]NC(1–13)NH2 is a potent and selective
antagonist of the NC receptor in vivo.
Key Words: hypotension • blood pressure • heart rate • nociceptin • [Phe1(CH2-NH)Gly2]NC(1–13)NH2 • mouse
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In 1994, a new opioid receptor, referred to as opioid receptor–like 1 (ORL1), was identified; 1 year later, the heptadecapeptide nociceptin (NC) (also known as orphanin FQ) was demonstrated to be the endogenous ligand for this receptor (hereafter called NC receptor).1 Peripheral biological activities of NC are similar to those exerted by opioids.1 In particular, both NC and endomorphins induce hypotension and bradycardia and reduce peripheral resistance.2 3 4 5 6 However, the opioid receptor antagonist naloxone does not alter the effect of NC, thus suggesting that the latter peptide activates receptors different from those of opioids.2
The cardiovascular effects of NC have been
characterized mainly in rats.1 2 3 4 5 6 Similar to
opioids, NC causes hypotension without reflex tachycardia;
instead, bradycardia occurs after acute intravenous
injection.6 The role, if any, of endogenous NC
and related peptides in the regulation of
cardiovascular function remains unknown, mainly because
of the lack of potent and selective receptor antagonists.
Recently, this limitation has been overcome, at least partially, by the
discovery of
[Phe1(CH2-NH)Gly2]NC(1–13)NH2
([F/G]NC(1–13)NH2). This compound has been
shown to act as a selective antagonist in
peripheral NC-sensitive preparations such as the guinea pig
ileum and mouse vas deferens.7 We exploited the
availability of new technologies for measuring
hemodynamic parameters in the
mouse8 9 to design a series of experiments aimed to
characterize the cardiovascular action of exogenous NC
and NC-related peptides. In addition, we tested the
antagonistic property of
[F/G]NC(1–13)NH2 in vivo to investigate the
role of endogenous NC in the regulation of
cardiovascular function.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Animals
Male Swiss Morini mice (28 to 35 g body wt), purchased from Morini (Reggio Emilia, Italy), were housed at constant room temperature (24±1°C) and humidity (60±3%) with a 12-hour light/dark cycle. All experimental protocols complied with standards for the care and use of animal subjects as stated in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and were approved by the local Animal Care and Use Committee.
Substances
[F/G]NC(1–13)NH2 was prepared as
described by Guerrini et al.7 All other peptides used in
this study were prepared by solid-phase synthesis and purified by
high-performance liquid chromatography, as
described previously.10 Bradykinin;
DL-thiorphan
(DL-3-mercapto-2-benzylpropanoyl-glycine); leu-enkephalin;
U504885; 2,2,2-tribromoethanol; and tert-amyl alcohol were purchased
from Sigma-Aldrich. Verapamil was a gift from
Knoll.
Experimental Protocol
For measurement of mean blood pressure (MBP),8 a
polyethylene catheter (PE-10 soldered to a PE-50, Clay Adams) was
inserted into the left carotid artery and pushed into the thoracic
aorta of mice anesthetized with 2,2,2-tribromoethanol (88
nmol/100 g body wt IP) dissolved in tert-amyl alcohol. Another catheter
was inserted into the left jugular vein for drug injection. Both
catheters (filled with 5% heparinized saline solution) were tunneled
under the skin and exteriorized at the back of the neck. The animals
were then allowed to recover for 5 hours. Intra-arterial
MBP was measured with a Statham transducer connected to the carotid
catheter, and heart rate (HR) was measured with a counter triggered by
the pressure waveform.
In a set of experiments, aortic blood flow (ABF) was measured with a pulsed Doppler flowmeter (Pulse-Doppler, University of Iowa). With mice anesthetized, a Doppler probe (0.8 mm internal diameter, Crystal Biotech) was implanted and secured with 6-0 ophthalmic silk around the abdominal aorta just below the origin of the left renal artery. The electronic zero, established by turning off the ultrasound signal, was equal to zero flow obtained by a short-lasting occlusion of the aorta. Then the probe wires were tunneled out of the back of the neck, and the animals were allowed to regain consciousness. Experiments were performed 5 hours after implantation of the probe.
During basal and experimental periods, hemodynamic parameters were continuously recorded in unanesthetized, free-moving mice using a Quartet polygraph (Ugo Basile Biological Apparatus). A 50-µL syringe (Hamilton) was used for drug injection. Injection volume was 30 µL, followed by 10 µL saline to flush the jugular catheter.
Experiment 1: Effect of NC and NC-Related Peptides on MBP and
HR
After 15 minutes of stabilization, basal
hemodynamic measurements were obtained and mice were
given NC at 1, 10, or 100 nmol/kg body wt (n=5, 5, and 7,
respectively). MBP and HR were recorded continuously for the
following 10 minutes.
In additional experiments, the effects induced by intravenous injection of 100 nmol/kg NC(1–17)NH2, NC(1–13)NH2, NC(1–13)OH, NC(1–9)NH2, or [F/G]NC(1–13)NH2 were evaluated in unanesthetized mice (n=5 each group).
Experiment 2: Effect of Thiorphan on Hemodynamic
Changes Induced by NC or NC Fragments
Mice received thiorphan at 2.5 mg/kg body wt (n=5 each group) or
vehicle intravenously (n=4 each group) and then were
injected with NC, NC(1–13)NH2, or NC(1–13)OH at
100 nmol/kg. MBP and HR were recorded continuously for additional
10 minutes. In preliminary experiments, we found that the dose of
thiorphan used in the present study enhanced the MBP-lowering
effect of exogenous bradykinin (38±3 versus 25±3 mm Hg in
controls, P<0.01), whereas it does not alter the
hypotension evoked by verapamil, a compound not metabolized
by neutral endopeptidase (NEP) 24.11 (27±2 versus
25±2 mm Hg in controls, P=NS).
Experiment 3: Effect of [F/G]NC(1–13)NH2 on
NC-Evoked Changes in MBP, HR, and ABF
After stabilization, [F/G]NC(1–13)NH2
(at 1, 10, or 100 nmol/kg body wt) or vehicle was injected in
unanesthetized mice. Five minutes later, NC (1, 10, or 100
nmol/kg body wt) was administered intravenously. Each
animal received a single dose of agonist and antagonist
(n=5 each group). MBP and HR were recorded continuously for 10
minutes after NC injection. In a subgroup of animals, ABF was also
measured.
Experiment 4: Selectivity of [F/G]NC(1–13)NH2
To test the selectivity of the antagonist, we
pretreated mice with [F/G]NC(1–13)NH2 (100
nmol/kg body wt) or vehicle. Five minutes later, NC (10 nmol/kg body
wt), bradykinin (20 nmol/kg body wt), endomorphin-1 (100 nmol/kg body
wt), leu-enkephalin (100 nmol/kg body wt), or U504885 (100 nmol/kg body
wt) was given (n=5 each group). Hemodynamic
measurements were obtained for an additional 10 minutes.
Statistical Analysis
All data are expressed as mean±SEM.
Multivariate repeated-measures ANOVA was performed to
test for interaction between time and grouping factor.
Univariate ANOVA then was used among groups and over time.
Differences within and between groups were determined using paired or
unpaired Student's t test, respectively. A value of
P<0.05 was considered significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Experiment 1: Effect of NC and NC-Related Peptides on MBP and HR
No difference was detected between groups given vehicle or NC (1, 10, or 100 nmol kg) in basal MBP (112±4, 112±3, 110±5, and 114±3 mm Hg, respectively; P=NS) or HR values (551±46, 556±44, 585±51, and 542±43 beats/min, respectively; P=NS).
Intravenous bolus injection of NC decreased the MBP of Swiss Morini mice (Figure 1, left). The hypotensive response to 10 nmol/kg lasted <10 minutes, whereas a more prolonged hypotension was evoked by 100 nmol/kg (from 114±3 to 97±2 mm Hg at 10 minutes, P<0.01). No incremental MBP effect was observed with higher doses (data not shown). As also shown in Figure 1 (right), 100 nmol/kg NC reduced HR from 542±43 to 479±31 beats/min (P<0.05). A similar effect was observed with 10 nmol/kg NC. No change in MBP and HR was observed after administration of vehicle.
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, n=5) or nociceptin at 1 (
, n=5), 10 (
, n=5),
and 100 (
, n=7) nmol/kg body wt was given at time 0. Values are
mean±SEM. *P<0.05, **P<0.01 versus
basal; §P<0.05, §§P<0.01 versus
vehicle.As shown in Figure 2, 100 nmol/kg NC(1–17)NH2 or NC(1–13)NH2 caused hypotension and bradycardia similar to that caused by NC. By contrast, the same dose of NC(1–13)OH, NC(1–9)NH2, or [F/G]NC(1–13)NH2 did not alter MBP or HR. A tendency of HR to increase following NC(1–9)NH2 was observed but did not reach statistical significance.
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Experiment 2: Effect of Thiorphan on Hemodynamic
Changes Induced by NC or NC Fragments
Thiorphan, an inhibitor of NEP 24.11, reduced MBP by
10±1 mm Hg (from 112±2 to 102±1 mm Hg,
P<0.05), whereas no effect was observed in vehicle-treated
mice (111±3 to 110±3 mm Hg, P=NS). As shown in
Figure 3, pretreatment with thiorphan
enhanced the MBP- and HR-lowering effects of
NC(1–13)NH2 and revealed the ability of
NC(1–13)OH to evoke hypotension and bradycardia. The decreases in MBP
and HR induced by NC(1–13)OH after thiorphan were similar to that
evoked by the naturally occurring agonist NC.
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Experiment 3: Effect of [F/G]NC(1–13)NH2 on
NC-Evoked Changes in MBP, HR, and ABF
As shown in Figure 4, the
dose-response curves to NC were shifted to the right by
[F/G]NC(1–13)NH2. Complete blockade of
NC-induced hemodynamic effects was observed with a 10:1
antagonist/agonist stochiometric ratio.
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)
nmol/kg body wt (n=5 each dose). Values are mean±SEM.
*P<0.05, **P<0.01 versus vehicle.As shown in Figure 5, NC-induced hypotension was associated with an increase in ABF, with this response also being prevented by [F/G]NC(1–13)NH2.
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Experiment 4: Selectivity of [F/G]NC(1–13)NH2
Although preventing the hypotension and bradycardia evoked by NC,
[F/G]NC(1–13)NH2 did not alter the MBP effect
induced by bradykinin (-22±2 versus -20±1 mm Hg in controls,
P=NS) or by the µ-receptor agonist endomorphin-1 (-10±1
versus -11±2 mm Hg in controls, P=NS). No
significant MBP change occurred after leu-enkephalin or U504885 in mice
given the NC antagonist or its vehicle (data not shown).
Leu-enkephalin and U504885 induced bradycardia (-35±3 and -43±7
beats/min, respectively), with these changes being unaltered by
[F/G]NC(1–13)NH2 (-38±5 and -44±5
beats/min, respectively).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The cardiovascular effects of NC, a novel opioid peptide that has received a great deal of attention from the neuroscience community, have now been investigated. The present study describes the hemodynamic action of NC, NC fragments, and the putative antagonist for the ORL1 receptor in conscious mice. Moreover, the role of NEP in the inactivation of the peptides was evaluated.
As far as we know, this is the first report indicating that NC exerts hypotensive and bradycardic effects in mice. The range of doses showing pharmacological activity and the duration of the hemodynamic effects were similar to those already reported in rats.2 6 At variance with most vasodilators, NC-induced hypotension is associated with a decrease in HR. In rats, this bradycardia is significantly reduced by bilateral vagotomy and abolished by the combination of this maneuver with guanethidine. These findings suggest that the bradycardic effect of NC is mediated by a concomitant inhibition and activation, respectively, of the sympathetic and parasympathetic outflows to the heart.6
Characterization of the cardiovascular effects of NC fragments revealed that NC(1–13)NH2 retains a potent agonistic activity in mice, whereas NC(1–9)NH2 is ineffective. These results are consistent with in vitro studies showing that NC(1–13)NH2 is the smallest peptide maintaining the same efficacy and potency as the natural peptide.11 12 Interestingly, the fragment NC(1–13)OH does not exert any cardiovascular effect. This could be due to a high susceptibility to enzymatic degradation and/or to a low affinity for the receptor. The former possibility is favored by the observation that the protease inhibitor thiorphan significantly enhances the hypotensive and bradycardic effect induced by NC(1–13)OH. Once again, these data are consistent with those obtained in the mouse vas deferens: In fact, pretreating this tissue with thiorphan caused a 10-fold increase in NC(1–13)OH potency, whereas the potency of NC(1–13)NH2 was not significantly modified.13 Altogether, these findings suggest that NEP 24.11 plays an important role in the peripheral degradation of NC and NC-related peptides. NEP 24.11 appears to be less important in the brain, where aminopeptidase N and endopeptidase 24.15 have been indicated as the main enzymes responsible for NC degradation.14 15 We found that the fragment NC(1–9)NH2, which does not alter MBP, tends to induce tachycardia, an effect opposite to that evoked by NC. Further studies are necessary to determine whether this action is due to interaction of NC(1–9)NH2 with unrelated receptors or to other unforeseen properties of the fragment.
Hemodynamic effects similar to those exerted by NC have been reported with the µ-opioid receptor ligands endomorphin-1 and -2. Despite the structural similarity of NC and its receptor with the opioid peptides and receptors, the cardiovascular effects mediated by NC are not modified by naloxone.4 Thus, the two systems (NC and opioids) appear to exert a similar depressant action on the cardiovascular system by activating distinct receptors. Only recently, the lack of selective antagonists has been overcome by the discovery that [F/G]NC(1–13)NH2, an analogue designed to be resistant to degradation by aminopeptidases, is instead a fairly potent NC receptor antagonist in various preparations in vitro.7 Actually, the putative ORL1 antagonist has been found to exert residual agonistic activity in Chinese hamster ovary cells transfected with the human ORL1,16 with this property being directly proportional to receptor expression.17 However, we found that in vivo [F/G]NC(1–13)NH2 is devoid of any residual agonistic activity at doses from 1 to 100 nmol/kg. In addition, the same range of doses was able to antagonize NC-induced cardiovascular effects.
Selectivity of [F/G]NC(1–13)NH2 is
indicated by the failure of the ORL1 antagonist to
interfere with the hypotensive action of a structurally unrelated
peptide, such as bradykinin, and more importantly, with the hypotension
induced by endomorphin-1, a µ-receptor agonist. In addition,
[F/G]NC(1–13)NH2 did not alter the bradycardia
evoked by leu-enkephalin or by the synthetic
-receptor agonist U504885. These results are
consistent with those showing the selectivity of the
antagonist in vitro.7
The observation that [F/G]NC(1–13)NH2 does not affect basal systemic hemodynamics does not favor a major role of endogenous NC in the regulation of cardiovascular function under normal conditions. NC acts as a modulator of pain perception at the level of the central nervous system and peripheral neuronal endings. Therefore, the vasodilator property of NC could become evident under pathological conditions characterized by nociception in association with hypotension. It is hoped that this possibility will be addressed by the use of the antagonist [F/G]NC(1–13)NH2.
The present study deals with the acute pharmacological effects of NC on cardiovascular function. Recent evidence indicates that NC exerts diuretic and antinatriuretic responses in rats.18 It would be interesting to evaluate whether NC antagonism is able to alter sodium homeostasis, thus producing long-term effects on blood pressure.
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Acknowledgments |
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This work was supported by 60% and 40% grants (No. F07C/1997: Il cuore insufficiente) from the Italian Ministry of the University (MURST).
Received September 17, 1998; first decision October 30, 1998; accepted November 24, 1998.
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References |
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