|
| |
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
First published online December 1, 2006
Journal of Experimental Biology 209, 4966-4973 (2006)
Published by The Company of Biologists 2006
doi: 10.1242/jeb.02595
Beta3-Adrenoceptor in the eel (Anguilla anguilla) heart: negative inotropy and NO-cGMP-dependent mechanism
1 Departments of Pharmaco-Biology, University of Calabria, 87030, Arcavacata
di Rende, CS, Italy
2 Departments of Cell Biology, University of Calabria, 87030, Arcavacata di
Rende, CS, Italy
* Author for correspondence at address 2 (e-mail: tota{at}unical.it)
Accepted 16 October 2006
 |
Summary |
|---|
 TOP Summary IntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Using an isolated working heart preparation, we show that a ß3-AR selective agonist BRL37344 (0.1-100 nmol l-1) elicits a dose-dependent negative inotropism in the freshwater eel Anguilla anguilla. This effect was insensitive to the ß1/ß2-AR inhibitor nadolol (10 µmol l-1), but was blocked by the ß3-AR-specific antagonist SR59230 (10 nmol l-1). The analysis of the percentage of stroke work (SW) variations, in terms of EC50 values, induced by BRL37344 alone (10 nmol l-1), and in presence of SR59230 (10 nmol l-1), indicated a competitive antagonism of SR59230. In addition to the classic positive inotropism, the non-specific ß agonist isoproterenol (100 nmol l-1) induced, in 30% of the preparations, a negative inotropic effect that was abrogated by pre-treatment with SR59230, pointing to a ß3-mediated pathway. The BRL37344-induced negative inotropic effect was abolished by exposure to a Gi/o proteins inhibitor pertussis toxin (PTx; 0.01 nmol l-1), suggesting a Gi/o-dependent mechanism. Using L-N5(l-imino-ethyl)ornithine (L-NIO; 10 µmol l-1), as a nitric oxide (NO) synthase (NOS) blocker and haemoglobin (Hb; 1 µmol l-1), as a NO scavenger, we demonstrated that NO signalling is involved in the BRL37344-induced response. Pre-treatment with either an inhibitor of soluble guanylate cyclase (GC) 1H-(1,2,4) oxadiazolo-(4,3-a)quinoxalin-1-one (ODQ; 10 µmol l-1), or an inhibitor of the cGMP-activated protein kinase (PKG) KT5823 (100 nmol l-1), abolished the ß3-dependent negative inotropism, indicating the cGMP-PKG component as a crucial target of NO signalling. Taken together, our findings provide functional evidence for the presence of ß3-like adrenoceptors in the eel Anguilla anguilla heart identifying, for the first time in a working fish heart, the ß3-AR-dependent negative inotropy discovered in mammals.
Key words: catecholamines, teleost, Gi/o proteins, cGMP-dependent protein kinase, autocrine-paracrine regulation, myocardial performance, NOS
|
Introduction |
|---|
|
TOPSummaryIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
;
Brodde et al., 2006).
In 1967, Lands et al. classified the ß-adrenergic receptors
(ß-ARs) into ß1 and ß2 based on the rank order, in different
tissues, of the potency of the two catecholamines, adrenaline and
nor-adrenaline (Lands et al.,
1967). Both ß-ARs have been identified in the mammalian heart
where they are responsible for most of the adrenergic-mediated effects on
cardiac performance, i.e. positive inotropic, chronotropic and lusitropic
responses (Brodde, 1991). To a
large extent these effects result from an elevation of intracellular cAMP
after adenylyl cyclase stimulation through Gs proteins
(Ishikawa and Homcy,
1997).
In various mammalian tissues, including the heart, recent molecular and
pharmacological studies have identified, besides the classic ß1- and
ß2-ARs, a new receptor, called ß3-AR
(Gauthier et al., 1996;
Gauthier et al., 1998;
Varghese et al., 2000;
Tavernier et al., 2003;
Boivin et al., 2006).
ß3-AR, as well as ß1- and ß2-ARs, belongs to the G-protein
coupled receptors characterized by seven transmembrane domains of 22-28 amino
acids showing three intracellular and three extracellular loops. It shares 51%
and 46% identity with ß1- and ß2-AR amino acid sequences,
respectively, and is activated by selective pharmacological agonists
(BRL37344, SR58611, CGP12177), which have
little effect on ß1- and ß2-ARs
(Skeberdis, 2004). Using
synthetic ß3-AR agonists, several studies have shown that ß3-AR
activation induces metabolic and functional processes in many tissues
(Bianchetti and Manara, 1990;
McLaughlin and MacDonald,
1990; Norman and Leathard,
1990; Langin et al.,
1991; Yoshida et al.,
1991; Arch and Kaumann,
1993; Berlan et al.,
1993). In the mammalian heart, functional response to ß3-AR
stimulation differs among species and depends on the anatomical region within
the myocardium (Gauthier et al.,
2000). For example, whereas in human and canine ventricles
ß3-AR stimulation induces negative inotropic effects
(Gauthier et al., 2000); in
human atrium, specific ß3-AR agonists produce positive inotropic actions
(Arch and Kaumann, 1993;
Sennit et al., 1998), as well
as an increase of heart rate under in vivo conditions
(Wheeldon et al., 1994).
However, in human atrial preparations expressing ß3-AR subtype
(Chamberlain et al., 1999), no
cardiac effects could be detected (Kaumann et al., 1997). The
ß3-AR-induced intracellular signal pathways, which operate in cardiac
tissues, have not been completely clarified. However, the negative inotropic
effect has been attributed to an action mechanism that involves
Gi/0 proteins and results from the production of nitric oxide (NO)
by the endothelial isoform of NO synthase (eNOS) with the consequent increase
in intracellular cGMP levels (Gauthier et
al., 1998; Varghese et al.,
2000).
Despite their importance in the vertebrate stress response, knowledge of
ß-ARs in fish is based on relatively few studies centred on a limited
number of species, in which the classic cardiac adrenergic response has been
mainly attributed to ß2-AR stimulation
(Gamperl et al., 1994). In
this context, the presence and role of ß3-ARs have, until now, received
surprisingly little, or no, attention.
The expression of two previously unreported ß-ARs in the teleost
Oncorhynchus mykiss was recently shown
(Nickerson et al., 2003).
These two trout ß-ARs were found to be homologous to the mammalian
ß3-AR and highly expressed in both gills and heart. However, no
physio-pharmacological characterization of ß3-ARs in fish heart or its
subsequent coupling to second messengers has been reported.
The aim of this study was to analyse in the European eel Anguilla
anguilla heart the physiological role of ß3-AR and the downstream
signal transduction mechanism. As in previous studies
(Imbrogno et al., 2001;
Imbrogno et al., 2003;
Imbrogno et al., 2004), we
used juvenile eel hearts with a compact outer ventricular layer and a poorly
developed coronary circulation, which allowed us to analyse the effect of
cardioactive substances without interferences from the coronary vasculature.
We previously reported that in the eel heart the endogenous NO signalling
cascade, through a cGMP-mediated mechanism, transduces the negative inotropic
effects triggered by chemical stimuli such as acetylcholine
(Imbrogno et al., 2001),
angiotensin II (Imbrogno et al.,
2003) and vasostatin I
(Imbrogno et al., 2004). We
now demonstrate that ß3-AR stimulation decreases cardiac mechanical
performance through a PTx-sensitive Gi protein mechanism that
involves a NO-cGMP-cGMP-activated protein kinase (PKG) cascade.
|
Materials and methods |
|---|
|
TOPSummaryIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
), received Ringer's solution from an input reservoir and
pumped against an afterload pressure given by the height of an output
reservoir. The composition of the perfusate (in mmol l-1) was: NaCl
115.17, KCl 2.03, KH2PO4 0.37, MgSO4 2.92,
(NH4)2SO4 50, CaCl2 1.27, glucose
5.55, Na2HPO4 1.90; pH was adjusted to 7.7-7.9 by adding
NaHCO3 (about 1 g l-1)
(Imbrogno et al., 2001). The
Ringer's solution was equilibrated with a mixture of
O2:CO2 at 99.5:0.5%. Experiments were carried out at
room temperature (18-20°C). The controlled non-paced hearts operated at a
frequency of about 50 beats min-1 (see
Imbrogno et al., 2001). Hearts
were stimulated with an LE 12006 stimulator (frequency identical to that of
control, non-paced hearts; pulse width fixed at 0.1 ms; voltage:
1.2±0.1 V; means ± s.e.m.).
Measurements and calculations
Pressure was measured through T-tubes placed immediately before the input
cannula and after the output cannula, and connected to two MP-20D pressure
transducers (Micron Instruments, Simi Valley, CA, USA) in conjunction with a
Unirecord 7050 (Ugo Basile, Comerio, Italy). Pressure measurements (input and
output) were expressed in kilopascals (kPa) and corrected for cannula
resistance. Heart rate (fH) was calculated from pressure
recording curves. Cardiac output (
)
was collected over 1 min and weighed; values were corrected for fluid density
and expressed as volume measurements. The afterload (mean aortic pressure) was
calculated as two-thirds diastolic pressure plus one-third maximum pressure.
Stroke volume (VS; ml kg-1;
fH-1) was used as a
measure of ventricular performance; changes in VS were
considered to be inotropic effects.
and VS were normalised per kilogram of wet body mass.
Ventricular stroke work [WS; mJ g-1;
(afterload-preload) x VS/ventricle mass] served as
an index of systolic functionality.
Experimental protocols
Basal conditions
Isolated perfused hearts were allowed to maintain a spontaneous rhythm for
up to 15-20 min. In all experiments the control conditions were established at
a mean output pressure of about 3 kPa, with a
set to 10 ml min-1
kg-1 body mass by appropriately adjusting the filling pressure.
These values are within the physiological range [for references see Imbrogno
et al. (Imbrogno et al.,
2001)]. Cardiac parameters were simultaneously measured during
experiments. To analyse the inotropic effects distinct from the chronotropic
actions of substances, the preparations were electrically paced. Hearts that
did not stabilise within 20 min from the onset of perfusion were
discarded.
|
The effects of BRL 37344 (10 nmol l-1) were also studied after inhibition of G-proteins by pertussis toxin (PTx); in this case the hearts were pre-incubated for 60 min with PTx.
Since the performance of the in vitro eel heart is stable for
about 2h (see Imbrogno et al.,
2001), our experiments were carried out within this period.
Statistics
Percentage changes were evaluated as means ± s.e.m. of percentage
changes obtained from individual experiments. Because each heart acted as its
own control, a one-way ANOVA test was used for comparisons within groups
(P<0.05). Comparisons between groups were made using a two-way
ANOVA, Duncan's multiple-range test (P<0.05).
The concentration-response curves of the reduction of WS induced by BRL37344 alone and by BRL37344 plus SR59230 were fitted using GraphPad Prism 4.02. This provided the -log of the concentration (in mol l-1) that induced the 50% effect (EC50) of BRL37344 alone and BRL37344 plus SR59230.
Drugs and chemicals
[4-[2-[[2-(3-chlorophenyl)-2-hydroxy-ethyl]amino]propyl]-phenoxy]acetic
acid sodium (BRL37344),
3-(2-ethylphenoxy)-1-[[(1S)-1,2,3,4-tetrahydronaphth-1-yl]amino]-(2S)-2-propanol
oxalate salt (SR59230), isoproterenol (ISO), nadolol, haemoglobin
(Hb), L-N5-(1-iminoethyl)ornitine (L-NIO),
1H-[1,2,4]oxadiazole-[4,3-a]quinoxalin-1-one (ODQ) and pertussis toxin (PTx)
were purchased from Sigma Chemical Company (St Louis, MO, USA).
KT5823 (used in a darkened perfusion apparatus to prevent
degradation) was purchased from Calbiochem (Milan, Italy). All the solutions
were prepared in double-distilled water (ODQ and KT5823 were
prepared in DMSO); dilutions were made in Ringer's solution immediately before
use.
|
Results |
|---|
|
TOPSummaryIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
,
VS and WS that mimic the physiological
values of the in vivo animal [see Imbrogno et al.
(Imbrogno et al., 2001) for
references].
Baseline variables for the resting heart preparations were: output pressure
(kPa) = 2.63±0.53; fH (beats min-1) =
56.47±13.5; (ml
min-1 kg-1) = 10.69±2.18; VS
(ml kg-1) = 0.17±0.02; and WS (mJ
g-1) = 0.57±0.07. Data are expressed as mean ±
s.e.m., N=66.
Effects of ß3-adrenergic stimulation on basal cardiac performance
Concentration-response curves of selective ß3-AR agonist were
generated by exposing the cardiac preparations to increasing concentrations of
BRL37344, since exposure to single repeated doses of
BRL37344 revealed absence of receptor desensitization (data not
shown). The effects of the agonist remained stable for 15 min then gradually
decreased with time. Accordingly, cardiac parameters were measured after 10
min. BRL37344 (0.1-100 nmol l-1) induced a concentration
dependent negative inotropic effect, revealed by a significant reduction of
both VS, starting from the concentration of 1 nmol
l-1, and WS, above 10 nmol l-1
(Fig. 1).
Effects of BRL37344 after treatment with nadolol
To explore putative interactions between
ß1/ß2- and ß3-adrenergic
signalling, hearts were perfused with the ß3-AR agonist
BRL37344 (10 nmol l-1) in presence of a specific
ß1/ß2-ARs inhibitor, nadolol (10 µmol
l-1). Two-way ANOVA test showed no significant differences between
the untreated (with antagonist) and antagonist-treated preparations suggesting
that the negative inotropic effect induced by BRL37344 is not
influenced by ß1/ß2-AR inhibition
(Fig. 2).
|
|
|
Effects of ISO after treatment with SR59230
Isoproterenol (ISO), a non-specific ß-AR agonist, generally produces
positive inotropic and chronotropic effects in the heart
(Brodde, 1991). In our study,
in addition to the classic positive inotropism (data not shown), ISO (100 nmol
l-1) stimulation, in 30% of preparations, induced a negative
inotropic effect that was abolished by pre-treatment with SR59230
(Fig. 4).
G protein interaction
ß3-AR belongs to the guanine nucleotide-binding protein (G
protein)-coupled receptor super family characterized by seven transmembrane
segments (Skeberdis, 2004). To
verify the involvement of G proteins in the ß3-AR-induced inotropic
action, cardiac preparations were perfused with Ringer's solution containing
PTx (0.01 nmol l-1) in presence of BRL37344. In the rat
heart, PTx catalyzes the ADP-ribosylation of the alpha-subunit of
Gi/o and uncouples the interaction between Gi and
several inhibitory receptors, including muscarinic receptors [Angelone et al.
(Angelone et al., 2006) and
references therein]. Whereas PTx alone did not modify basal cardiac
performance (data not shown), its pre-treatment abolished the
BRL37344-dependent negative inotropic effect (i.e.
VS and WS;
Fig. 5), suggesting the
involvement of the Gi/o protein system.
|
;
Imbrogno et al., 2003;
Imbrogno et al., 2004).
|
), and this is known to be the case also in the eel heart
(Imbrogno et al., 2003), we
pretreated the heart with a specific PKG inhibitor (KT5823, 100
nmol l-1). This abrogates the BRL37344-dependent
reduction of VS and WS
(Fig. 6), indicating the
involvement of PKG in the ß3-AR-induced inotropic
response. |
Discussion |
|---|
|
TOPSummaryIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Effects of ß3-AR stimulation
In the eel, ß3-AR stimulation negatively affects cardiac performance.
This conclusion is based on several lines of evidences. Treatment with
BRL37344, a preferential ß3-AR agonist
(Arch and Wilson, 1996;
Balligand, 2000), induces a
dose-dependent negative inotropic effect. As revealed by the analysis of the
percentage of WS variations in terms of EC50
values, this negative inotropism was blocked by the ß3-AR specific
antagonist SR59230 (Trochu et
al., 1999), which in the eel heart acts in a competitive manner.
Inversely, it was not modified by nadolol, a ß1- and ß2-ARs
inhibitor, free of ß3-AR antagonist properties
(Emorine et al., 1989;
Galitzky et al., 1993), ruling
out the involvement of ß1- and ß2-ARs. Moreover, according to the
results obtained in dog (Pelat et al.,
2003) and in human ventricular biopsy
(Gauthier et al., 1996), in
the eel heart, in addition to the classic ISO-dependent positive inotropic
effect (Tota et al., 2004),
non-specific ß-AR stimulation induced, in about 30% of preparations, a
negative inotropism which was abrogated by SR59230 pre-treatment.
No data are currently available regarding the factors that can influence the
sensitivity of the eel heart to isoproterenol stimulation (i.e. specific
agonist concentration, seasonal factors, etc). However, our observations
further support the pharmacological evidence of the ß3-AR functional
expression in the eel heart.
In mammals, the cardiac response to ß3-AR stimulation depends not only
by species-related differences, but also by the organizational level under
study (i.e. in vivo cardiovascular system vs isolated and
denervated working heart) and the functional interactions among its components
[Gauthier et al., (Gauthier et al.,
1996) and references therein]. For example, beyond the negative
inotropism observed in human (Gauthier et
al., 1996), dog (Gauthier et
al., 1999) and guinea pig
(Kitamura et al., 2000)
cardiac preparations, positive inotropic and chronotropic effects have been
reported in in vivo experiments [see Gauthier et al.
(Gauthier et al., 1996) for
references]. However, these in vivo effects were not related to a
direct stimulation of cardiac ß3-AR but to reflex mechanisms
(Tavernier et al., 1992;
Wheeldon et al., 1993;
Wheeldon et al., 1994;
Shen et al., 1996). Thus, the
eel heart preparation used in this study being free of extrinsic nervous and
humoral influences, it is a very appropriate model to analyse the cardiac
effects of ß3-AR. Our data clearly indicate that, as reported in human
(Gauthier et al., 1996), dog
(Gauthier et al., 1999) and
guinea pig (Kitamura et al.,
2000), also in the eel ß3-AR stimulation depresses cardiac
contraction. This effect has been observed beginning from a
BRL37344 concentration of 0.1 nmol l-1, obtaining a
reduction of 27±3.6% for VS and of 27.9±3%
for WS at the higher concentration tested (100 nmol
l-1). Notably, these concentrations are similar to those observed
in mammals, in which the maximum effect was obtained by BRL37344 (1
µmol l-1) in human myocardium, CL316243 (1 µmol
l-1) in guinea-pig, CGP12177 (0.1 µmol
l-1) in dog and BRL37344 (0.1 µmol l-1) in
rat (Gauthier et al., 1999).
Moreover, in light of the classification proposed by Gauthier et al.
(Gauthier et al., 1999) for
mammalian hearts as hyper-responders (human and dog), hypo-responders (rat and
guinea pig) and non-responders (ferret) to ß3-AR agonists stimulation,
the elevated sensitivity of the eel heart to BRL37344, shown by
VS reduction of about 30%, allows it to be classified
within the hyper-responder group. In mammals, the interspecies variability and
the heterogeneous pharmacological profile of ß3-AR agonists were
correlated to cardiac ß3-AR expression. For example, it has been reported
that the negative inotropic effect induced by ß3-AR agonists in human and
dog is associated with the presence of ß3-AR transcripts
(Gauthier et al., 1999). By
contrast, no ß3-AR mRNA was detected in the hypo-responder rat
ventricular myocardium (Gauthier et al.,
1999) and rat right ventricle
(Evans et al., 1996).
Interestingly, Nickerson et al. (Nickerson
et al., 2003) have recently cloned and characterized in the
rainbow trout, Oncorhynchus mykiss, two previously unreported
ß-ARs (i.e. ß3a-AR and ß3b-AR), homologous to the mammalian
ß3-AR. Analysis of tissue expression patterns indicated elevated levels
of ß3a-AR mRNA in both gills and heart and lower levels in red muscle
(Nickerson et al., 2003).
However, the receptor expression level may not be the unique factor governing
the cardiac response to ß3-AR stimulation. In fact, important
interspecies differences in the amino acid sequences of ß3-ARs have been
reported in mammals (Strosberg and
Pietri-Rouxel, 1996; Gros et
al., 1998). These differences concern transmembrane regions that
are considered crucial for ligand binding and G protein interaction
(Strosberg and Pietri-Rouxel,
1996). The presence of ß3-AR transcripts in the heart of
O. mykiss, together with the high functional sensitivity to
BRL37344, that we have documented in A. anguilla,
emphasize the importance of a putative cardiac ß3-AR control in
teleosts.
Transduction mechanism
G-proteins interaction
The mechanisms by which ß3-AR activation induces cardio-depressing
effects are largely unknown. We show here that in the eel heart, the negative
inotropism induced by BRL37344, is abolished by the pre-treatment
with PTx, the toxin which uncouples signal transduction between several
families of receptors and Gi/o proteins [Ai et al.
(Ai et al., 1998) and
references therein]. Accordingly, there is indication that the
ß3-AR-dependent negative inotropy involves PTx-sensitive G proteins. Our
data agree with those obtained in human ventricular biopsies, in which PTx
abolished the effect of ß3-AR stimulation on cardiac contraction
(Gauthier et al., 1996;
Gauthier et al., 1998). In the
heart, PTx-sensitive G proteins, located at the interface between
receptor-response coupling, are involved in various inhibitory transduction
cascades triggered by both chemical and physical stimuli
(Hare et al., 1998). In the
rat heart, ß3-ARs, acting through a Gi protein, mediate the
inhibitory effect of BRL on L-type Ca2+ current
(Zhang et al., 2005).
Moreover, in human heart the PTx-sensitive-ß3-AR-induced negative
inotropic effect was associated with decreased action potential amplitude and
reduced action potential duration
(Gauthier et al., 1996).
Whether in the eel heart the BRL-induced cardio-suppressive effect involves
these or other mechanisms remains to be elucidated.
NO-cGMP-PKG signal transduction pathway
In human ventricle, the ß3-AR-induced negative inotropic action
results from the production of NO by the endothelial isoform of NO synthase
(eNOS) and the consequent increase in intracellular cGMP
(Gauthier et al., 1998;
Varghese et al., 2000). The
role of NO in mediating inotropic effects induced by cardioactive agents has
been extensively demonstrated in the eel by our lab. For example, direct
stimulation of M2 muscarinic acetylcholine receptors
(Imbrogno et al., 2001) and
AT1 angiotensin II receptors
(Imbrogno et al., 2003), or
exposure to vasostatin I (Imbrogno et al.,
2004) decreased contractility through NOS stimulation and a
consequent increased cGMP production. Consistent with the expression of NOS in
the eel heart (Tota et al.,
2005), we have found that the ß3-AR-induced inotropism is
mediated by the NO-cGMP-PKG pathway. This was demonstrated by its abrogation
following pre-treatment with either the NO scavenger (Hb), or NOS (L-NIO), or
soluble GC (ODQ), or PKG inhibitors (KT5823). In the eel heart, an
important intramyocardial target of NO signalling is PKG
(Imbrogno et al., 2003;
Imbrogno et al., 2004). In
isolated mammalian ventricular cardiomyocytes
(Méry et al., 1991),
PKG affects Ca2+ influx and, through phosphorylation of troponin I,
reduces the affinity of troponin C for calcium, thereby negatively regulating
cardiac contractility (Hove-Madsen et al.,
1996).
In conclusion, the present study, for the first time, extends to a working
fish heart the negative inotropic action induced by ß3-AR stimulation
previously reported in mammals. This effect occurs via a
Gi/o-NO-cGMP-PKG signal transduction pathway. The functional
evidence for the presence of ß3-AR in the heart of an ectotherm
vertebrate suggests its ancient evolutionary origin and strongly supports
important functions independent from thermogenic response. In view of the
postulated role of ß3-AR as a homeostatic regulator of the cardiovascular
system, possibly counteracting the excitatory adrenergic influences
(Sterin-Borda et al., 2006),
it is of interest that in the teleost heart, activation of ß3-ARs induces
cardio-suppressive actions. Indeed, the heart of many teleosts, including the
eel, are exposed to stimulatory effects of circulating and intracardiac
catecholamines, particularly under stress conditions [Imbrogno et al.
(Imbrogno et al., 2003) for
references], which may became harmful in the absence of local
counter-regulatory mechanisms. The possibility that in fish ß3-AR could
exert cardio-inhibitory protection versus systemic and/or
intracardiac cascades of excitatory stimuli targeting the heart is a challenge
for future studies.
|
Acknowledgments |
|---|
|
References |
|---|
|
TOPSummaryIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Ai, T., Horie, M., Obayashi, K. and Sasayama, S. (1998). Accentuated antagonism by angiotensin II on guinea-pig cardiac L-type Ca-currents enhanced by beta-adrenergic stimulation. Pflug. Arch. 436,168 -174.[CrossRef][Medline]
Angelone, T., Goumon, Y., Cerra, M. C., Metz-boutigue, M. H.,
Aunis D. and Tota, B. (2006). The emerging cardio-inhibitory
role of the Hippocampal Cholinergic Neurostimulating Peptide (HCNP).
J. Pharmacol. Exp. Ther.
318, 1-9.
Arch, J. and Kaumann, A. (1993). ß3 and atypical ß-adrenoceptors. Med. Res. Rev. 13,663 -729.[CrossRef][Medline]
Arch, J. R. and Wilson, S. (1996). Beta 3-adrenoceptors and the regulation of metabolism in adipose tissues. Biochem. Soc. Trans. 24,412 -418.[Medline]
Balligand, J. L. (2000). The beta 3-adrenoceptor: physiological role and potential therapeutic applications. Acta Clin. Belg. 55,209 -214.[Medline]
Berlan, M., Galitzky, J., Bouquet-Melou, A., Lafontan, M. and Montastruc, J. L. (1993). ß3-adrenoceptor increase in cutaneous blood flow in the dog. J. Pharmacol. Exp. Ther. 268,1444 -1451.
Bianchetti, A. and Manara, L. (1990). In vitro inhibition of intestinal motility by phenylethanolamines: evidence of atypical ß-adrenoceptors in rat colon. Br. J. Pharmocol. 100,831 -839.[Medline]
Boivin, B., Lavoie, C., Vaniotis, G., Baragli, A., Villeneuve,
L-R., Ethier, N., Trieu, P., Allen, B. G. and Hébert, T. E.
(2006). Functional ß-adrenergic receptor signalling on
nuclear membranes in adult rat and mouse ventricular cardiomyocytes.
Cardiovasc. Res. 71,69
-78.
Brodde, O. E. (1991). Pathophysiology of the beta-adrenoceptor system in chronic heart failure: consequences for treatment with agonists, partial agonists or antagonists? Eur. Heart J. 12F,54 -62.[Medline]
Brodde, O. E., Bruck, H. and Leineweber, K. (2006). Cardiac adrenoceptors: physiological and pathophysiological relevance. J. Pharmacol. Sci. 100,323 -337.[CrossRef][Medline]
Chamberlain, P. D., Jennings, K. H. and Paul, F. (1999). The tissue distribution of the human ß3-adrenoceptor studied using a monoclonal antibody: direct evidence of the ß3-adrenergic in human adipose tissue, atrium and skeletal muscle. Int. J. Obes. Relat. Metab. Disord. 10,1057 -1065.
Emorine, L. J., Marullo, S., Briend-Sutren, M. M., Patey, G.,
Tate, K., Delavier-Klutchko, C. and Strosberg, A. D. (1989).
Molecular characterization of the human beta 3-adrenergic receptor.
Science 245,1118
-1121.
Evans, B. A., Papaioannou, M., Bonazzi, V. R. and Summers, R. J. (1996). Expression of beta 3-adrenoceptor mRNA in rat tissues. Br. J. Pharmacol. 117,210 -216.[Medline]
Galitzky, J., Reverte, M., Portillo, M., Carpene, C., Lafontan, M. and Berlan, M. (1993). Coexistence of beta 1-, beta 2-, and beta 3-adrenoceptors in dog fat cells and their differential activation by catecholamines. Am. J. Physiol. 264,403 -412.
Gamperl, A. K., Wilkinson, M. and Boutilier, R. G. (1994). Betaadrenoreceptors in the trout (Oncorhynchus mykiss) heart: characterization, quantification, and effects of repeated catecholamine exposure. Gen. Comp. Endocrinol. 95,259 -272.[CrossRef][Medline]
Gauthier, C., Tavernier, G., Charpentier, F., Langin, D. and Le Marec, H. (1996). Functional ß3-adrenoceptor in the human heart. J. Clin. Invest. 98,556 -562.[Medline]
Gauthier, C., Leblais, V., Trochu, J. N., Balligand, J. L. and Le Marec, H. (1998). The negative inotropic effect of ß3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle. J. Clin. Invest. 102,1377 -1384.[Medline]
Gauthier, C., Tavernier, G., Trochu, J. N., Leblais, V.,
Laurent, K., Langin, D., Escande, D. and Le Marec, H. (1999).
Interspecies differences in the cardiac negative inotropic effects of
ß3-adrenoceptor agonist. J. Pharmacol. Exp.
Ther. 290,687
-693.
Gauthier, C., Langin, D. and Balligand, J.-L. (2000). ß3-Adrenoceptors in the cardiovascular system. J. Clin. Invest. 21,426 -430.
Gros, J., Manning, B. S., Pietri-Rouxel, F., Guillaume, J. L., Drumare, M. F. and Strosberg, A. D. (1998). Site-directed mutagenesis of the human beta3-adrenoceptor-transmembrane residues involved in ligand binding and signal transduction. Eur. J. Biochem. 251,590 -596.[Medline]
Hare, J. M., Givertz, M. M., Creager, M. A. and Colucci, W.
S. (1998). Increased sensitivity to nitric oxide synthase
inhibition in patients with heart failure: potentiation of beta-adrenergic
inotropic responsiveness. Circulation
97,161
-166.
Hove-Madsen, L., Mery, P. F., Jurevicius, J., Skeberdis, A. V. and Fishmeister, R. (1996). Regulation of myocardial calcium channels by cyclic AMP metabolism. Basic Res. Cardiol. 91, 1-8.[CrossRef][Medline]
Imbrogno, S., De Iuri, L., Mazza, R. and Tota, B. (2001). Nitric oxide modulates cardiac performance in the heart of Anguilla anguilla. J. Exp. Biol. 204,1719 -1727.[Abstract]
Imbrogno, S., Cerra, M. C. and Tota, B. (2003).
Angiotensin II-induced inotropism requires an endocardial endothelium-nitric
oxide mechanism in the in-vitro heart of Anguilla anguilla.J. Exp. Biol. 206,2675
-2684.
Imbrogno, S., Angelone, T., Corti, A., Adamo, C., Helle, K. B. and Tota, B. (2004). Influence of vasostatins, the chromogranin A-derived peptides, on the working heart of the eel (Anguilla anguilla): negative inotropy and mechanism of action. Gen. Comp. Endocrinol. 139,20 -28.[CrossRef][Medline]
Ishikawa, Y. and Homcy, C. J. (1997). The
adenylyl cyclases as integrators of transmembrane signal transduction.
Circ. Res. 80,297
-304.
Kaumann, A. J. (1997). Four beta-adrenoceptor subtypes in the mammalian heart. Trends Pharmacol. Sci. 18,70 -76.[CrossRef][Medline]
Kitamura, T., Onishi, K., Dohi, K., Okinaka, T., Isaka, N. and Nakano, T. (2000).The negative inotropic effect of beta3-adrenoceptor stimulation in the beating guinea pig heart. J. Cardiovasc. Pharmacol. 35,786 -790.[CrossRef][Medline]
Lands, A., Arnold, A., Auliff, J. M. and Luduena, F. (1967). Differentiation of receptor systems activated by simpathomimetic amines. Nature 214,597 -598.[CrossRef][Medline]
Langin, D., Portillo, M., Saulnier-Blache, J. and Lafontan, M. (1991). Coexistences of three ß-adrenergic receptors subtypes in white fat cells of various mammalian species. Eur. J. Pharmacol. 199,291 -301.[CrossRef][Medline]
McLaughlin, D. and MacDonald, A. (1990). Evidence for the existence of `atypical' ß-adrenoceptors (ß3-adrenoceptors) mediating relaxation in the rat distal colon. Br. J. Pharmacol. 101,569 -574.[Medline]
Méry, P. F., Lohmann, S. M., Walter, U. and Fischmeister,
R. (1991). Ca2+ current is regulated by
cGMP-dependent protein Kinase in mammalian cardiac myocite. Proc.
Natl. Acad. Sci. USA 88,1197
-1201.
Nickerson, J. G., Dugan, S. G., Drouin, G., Perry, S. F. and Moon, T. W. (2003). Activity of the unique beta-adrenergic Na+/H+ exchanger in trout erythrocytes is controlled by a novel beta3-AR subtype. Am. J. Physiol. 285,R526 -R535.
Norman, B. and Learthard, H. (1990). Evidence that an atypical ß-adrenoceptor mediates the inhibition of spontaneous rhythmical contractions of rabbit isolated jejunum induced by ritodrine and salbutamol. Br. J. Pharmacol. 101, 27-30.[Medline]
Pelat, M., Verwaerde, P., Galitzky, J., Lafontanm, M., Berlan,
M., Senard, J. M. and Montastruc, J. L. (2003). High
isoproterenol doses are required to activate beta3-adrenoceptor-mediated
functions in dogs. J. Pharmacol. Exp. Ther.
304,246
-53.
Sennit, M. V., Kaumann, A. J., Molenaar, P., Beeley, L. J.,
Young, P. W., Kelly, J., Chapman, H., Henson, S. M., Berg, J. M., Dean, D. K.
et al. (1998). The contribution of classical
(ß
-) and atypical ß-adrenoceptor to the
stimulation of human white adipocyte lipolysis and right atrial appendace
contraction by novel ß3-adrenoceptors agonists of differing
selectivities. J. Pharmacol. Exp. Ther.
285,1084
-1095.
Shen, Y. T., Cervoni, P., Claus, T. and Vatner, S. F.
(1996). Differences in beta 3-adrenergic receptor cardiovascular
regulation in conscious primates, rats and dogs. J. Pharmacol. Exp.
Ther. 278,1435
-1443.
Skeberdis, V. A. (2004). Structure and function of ß3-adrenergic receptors. Medicina (Kaunas) 40,407 -412.[Medline]
Sterin-Borda, L., Bernabeo, G., Ganzinelli, S., Joensen, L. and Borda, E. (2006). Role of nitric oxide/cyclic GMP and cyclic AMP in beta3 adrenoceptor-chronotropic response. J. Mol. Cell Cardiol. 40,580 -588.[CrossRef][Medline]
Strosberg, A. D. and Pietri-Rouxel, F. (1996). Function and regulation of the beta 3-adrenoceptor. Trends Pharmacol. Sci. 17,373 -381.[Medline]
Tavernier, G., Galitzky, J., Bousquet-Melon, A., Montastruc, J. L. and Berlan, M. (1992). The positive chronotropic effet induced by BRL37344 and CGP12177, two ß3-adrenergic agonist, does not involve cardiac ß-adrenoceptors but reflex mechanism. J. Pharmacol. Exp. Ther. 91,344 -349.
Tavernier, G., Toumaniantz, G., Erfanian, M., Heymann, M.-F.,
Laurent, K., Langin, D. and Gauthier, C. (2003).
ß3-adrenergic stimulation produces a decrease of cardiac contractility ex
vivo in mice overexpressing the human ß3-adrenergic receptor.
Cardiovasc. Res. 59,288
-296.
Tota, B., Imbrogno, S., Mannarino, C. and Mazza, R. (2004). Vasostatins and negative inotropy uin vertebrate hearts. Curr. Med. Chem. 4,195 -201.
Tota, B., Amelio, D., Pellegrino, D., Ip, Y. K. and Cerra, M. C. (2005). NO modulation of myocardial performance in fish hearts. Comp. Biochem. Physiol. 142A,164 -177.[CrossRef][Medline]
Trochu, J. N., Leblais, V., Rautureau, Y., Beverelli, F., Le Marec, H., Berdeaux, A. and Gauthier, C. (1999). Beta 3-adrenoceptor stimulation induces vasorelaxation mediated essentially by endothelium-derived nitric oxide in rat thoracic aorta. Br. J. Pharmacol. 128,69 -76.[CrossRef][Medline]
Varghese, P., Harrison, R. H., Lofthouse, R. A., Georgakopoulos, D., Berkowitz, D. E. and Hare, M. (2000). ß3-adrenoceptor deficiency blocks nitric oxide-dependent inhibition of myocardial contractility. J. Clin. Invest. 106,697 -703.[Medline]
Wheeldon, N. M., McDevitt, D. G. and Lipworth, B. J. (1993). Investigation of putative cardiac beta 3-adrenoceptors in man. Q. J. Med. 86,255 -261.[Medline]
Wheeldon, N. M., McDevitt, D. G. and Lipworth, B. J. (1994). Cardiac effects of the beta 3-adrenoceptor agonist BRL35135 in man. Br. J. Clin. Pharmacol. 37,363 -369.[Medline]
Xiao, R. P., Cheng, H., Zhou, Y. Y., Kuschel, M. and Lakatta, E.
G. (1999). Recent advances in cardiac ß2-adrenergic
signal transduction. Circ Res.
85,1092
-1100.
Yoshida, T., Hiraoka, N. and Kondo, M. (1991). Effects of a beta 3-adrenoceptor agonist, BRL 26830A, on insulin and glucagon release in mice. Endocrinol. Jpn. 38,641 -646.[Medline]
Zhang, Z. S., Cheng, H. J., Onishi, K., Ohte, N., Wannenburg, T.
and Cheng, C. P. (2005). Enhanced inhibition of L-type
Ca2+ current by beta3-adrenergic stimulation in failing rat heart.
J. Pharmacol. Exp. Ther.
315,1203
-1211.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
P<0.05.
