Download Interactions between endothelin-1 and the renin–angiotensin

Cardiovascular Research 43 (1999) 300–307
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Interactions between endothelin-1 and the renin–angiotensin–aldosterone
system
Gian Paolo Rossi*, Alfredo Sacchetto, Maurizio Cesari, Achille C. Pessina
Department of Clinical & Experimental Medicine, University of Padova, Padova, Italy
Received 22 December 1998; accepted 26 February 1999
Abstract
The renin–angiotensin–aldosterone (RAA) system and the endothelin (ET) system entail the most potent vasopressor mechanisms
identified to date. Although they were studied in depth in relation to arterial hypertension and cardiovascular diseases, limited information
on their interrelationships in causing hypertension and related target organ damage exists. The identification of consensus sequences for
jun in the regulatory region of the preproendothelin-1 (ppET-1) gene raised the possibility of its transcriptional regulation by angiotensin
II (Ang II). This was confirmed by the finding that stimulation with Ang II of cultured vascular smooth muscle cells (VSMCs) and
endothelial cells (ECs) induced expression of the ppET-1 gene and synthesis of ET-1. Endogenously produced ET-1 was found to
contribute to the hypertrophic response of cardiomyocytes to Ang II and thereby to cardiac hypertrophy. Furthermore, ET-1 exerts
multifaceted effects on the RAA system, such as dose-dependent inhibition of renin synthesis, and stimulation of aldosterone secretion.
The finding of abundant specific ET-1 receptors in the adrenocortical zona glomerulosa (ZG) suggested a direct secretagogue effect of
ET-1. In rats, ET B receptors mediate such an effect, whilst in humans, both ETA and ET B receptor subtypes intervene in regulating the
transcription of the aldosterone synthase gene. In addition, ET-1 stimulates DNA synthesis and proliferation of ZG cells via ETA receptors
and, therefore, might play a role in cell turnover of the normal adrenal cortex and in the onset of adrenal tumours. Studies on the in vivo
interactions between ETs and the RAA system have given conflicting results, insofar as some suggested a participation of ET-1 in the
pressor and cellular effects of exogenously administered Ang II, whereas others did not in the transgenic TGR(Ren 2m)27 rats and in the
two-kidney, one clip.  1999 Elsevier Science B.V. All rights reserved.
Keywords: Angiotensin; Endothelins; Hypertension; Renin–angiotensin system; Receptors
1. Introduction
The renin–angiotensin–aldosterone system (RAAS) and
the endothelin (ET) system are two of the most potent
vasopressor mechanisms identified to date (for a review,
see [1–3]). Therefore, it is not surprising that they have
been investigated extensively in relation to arterial hypertension and related cardiovascular disease. However,
despite this vast body of investigations, only limited
information exists on their reciprocal relationships. Thus,
in this paper, we shall review available knowledge on the
interactions between these two important pressor systems,
*Corresponding author. Tel.: 139-49-821-3304 or 2301; fax: 139-49880-2252.
E-mail address: [email protected] (G.P. Rossi)
with emphasis on the role of endothelin-1 (ET-1) in the
regulation of the RAAS and on in vivo studies supporting
a co-operation of both systems in the regulation of
cardiovascular and adrenocortical function.
2. Potential sites of interaction
Several potential sites of interaction between the RAAS
and ET system, spanning from the molecular level to the in
vivo hormonal and haemodynamic regulation, can be
envisaged. It has been hypothesised that Ang II, the active
peptide of the RAAS, affects the synthesis of ET-1, which,
in turn, can influence the RAAS by acting at different steps
Time for primary review 29 days.
0008-6363 / 99 / $ – see front matter  1999 Elsevier Science B.V. All rights reserved.
PII: S0008-6363( 99 )00110-8
G.P. Rossi et al. / Cardiovascular Research 43 (1999) 300 – 307
301
Fig. 1. Possible mechanisms of ET-1-induced inhibition of renin. ZG, adrenocortical zona glomerulosa cells; JG, juxtaglomerular cells; PLC,
phospholipase C; PKC, protein kinase C; PKA, protein kinase A; TGF-b, transforming growth factor b; AVP, arginine–vasopressin. Plus and minus signs
indicate activation and inhibition, respectively.
(Fig. 1). In keeping with this hypothesis, consensus
sequences for jun were identified in the regulatory regions
of the preproendothelin-1 (ppET-1) gene [4], suggesting
the possibility of transcriptional regulation of this gene by
factors acting through the G-protein–phospholipase C–
protein kinase C pathway (Fig. 2) [5,6].
Of interest, an additional site of interaction between the
RAAS and ET system has recently been identified at the
level of ET-1 biosynthesis. Although the predominant ET
biosynthetic pathway involves the specific cleavage of
pro(big)ET-1 by ECE-1, the possibility that bigETs are
also cleaved by human chymase, the enzyme responsible
for most of the conversion of Ang I to Ang II in the
myocardium [7] (Fig. 2), has been suggested, based on the
observation that the rat chymase was shown to cleave
bigETs at the Try 31 –Gly 32 bond [8], leading to novel 1–31
endothelin isopeptides, ETs(1–31). The latter were shown
in vitro to exert a less potent but slower-developing and a
longer-lasting contraction than ETs(1–21) in porcine coronary artery and rat aorta. Interestingly, at variance with
ET-1, this vasoconstriction of ETs(1–31) was also found
to be inhibited by either the ETA antagonist BQ-485 or the
ET B antagonist BQ-788 and, therefore, these novel peptides might act in a different manner from endothelins [9],
possibly through different receptors.
ET-1 was found to exert multifaceted effects on the
RAAS, such as dose-dependently inhibiting renin production, directly stimulating aldosterone production from
the adrenocortical zona glomerulosa (ZG) [10,11] and
promoting growth of the adrenal cortex. These effects
Fig. 2. Schematic representation of the biosynthetic pathways of the
endothelins showing a role for chymase, the main Ang II-forming enzyme
in the human heart, in ET(1–31) formation.
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G.P. Rossi et al. / Cardiovascular Research 43 (1999) 300 – 307
might be relevant for the regulation of both function and
cell turnover of the adrenal cortex under physiological and
pathophysiological conditions.
3. Effect of the RAAS on endothelin-1
The identification of consensus sequences for regulatory
elements in the regulatory region of both the ppET-1 gene
(Fig. 3) and the endothelin converting enzyme 1 (ECE-1)
gene suggested the possibility that both of these key-genes
involved in ET-1 biosynthesis are regulated by the same
factors. The hypothesis that Ang II can turn on the
transcription of the ppET-1 gene is supported by the in
vitro findings that human and porcine cultured vascular
smooth muscle cells (VSMCs) [12–14] and endothelial
cells (ECs) [15,16] can express the preproET-1 gene and
synthesise immunoreactive (ir) ET-1 upon stimulation with
Ang II. Evidence indicates that Ang II turns on the
transcription of the ppET-1 gene by acting via AT-1
receptors linked to activation of transcription via activator
protein-1 / kinase C-mediated mechanisms [14,15,17,18].
However, the possibility of complex cross-talk between
several signalling pathways that can be activated by a
number of humoral factors, such as insulin, catecholamines, components of the clotting / fibrinolysis cascade,
and cytokines, as depicted in Fig. 3, should be kept in
mind when interpreting results of in vivo studies.
Since Ang II is a well known promoter of cardiac
hypertrophy, the data suggesting an effect of the peptide on
ET-1 transcription raised the possibility that ET-1 might
also intervene in hypertension-related left ventricular hypertrophy and remodelling. This contention is supported by
the observation that endogenously produced ET-1 contributed to the hypertrophic response of cardiomyocytes to
both Ang II and ET-3 [17]. Thus, ET-1 antagonism may
offer an additional weapon for therapeutic interventions
aimed at preventing cardiovascular damage. The demonstration that long-term treatment with ET antagonists not
only greatly improved the survival of rats with chronic
heart failure, but also prevented ventricular remodelling,
i.e., the increase in left ventricular mass and cavity
enlargement [19], as well as the increase in collagen
density [20], strongly supports this view.
4. Effect of ET-1 on the RAAS
Besides its potent haemodynamic effects, the intravenous infusion of ET-1 in animals and humans was found to
deeply affect the RAAS. Renin secretion from juxtaglomerular cells was generally decreased by ET-1 both in
vitro and in vivo, as shown by seven out of eight available
studies [21–28]. Collectively, available evidence is consistent with both a direct and an indirect inhibitory action
of ET-1, through mechanisms that are depicted in Fig. 1.
This inhibition may be relevant in a number of clinical
Fig. 3. Schematic representation of the intracellular signalling mechanisms whereby Ang II can turn on the transcription of the preproET-1 gene via
activation of the phospholipase C and protein kinase C pathways.
G.P. Rossi et al. / Cardiovascular Research 43 (1999) 300 – 307
situations, for instance, in pregnancy-induced hypertension, a vasospastic and volume-reduced disorder where
endothelial cell damage is suspected to play an important
role. Compared to normal pregnancy, pregnancy-induced
hypertension was found to be associated with a two-fold
increase in plasma irET-1 levels, which may be responsible for the inappropriately low plasma renin activity in
relation to the reduced plasma volume [28].
The observation that, despite this inhibitory effect on
renin, ET-1 was found to markedly stimulate aldosterone
secretion both in animals and in humans, suggested a direct
effect of the peptide on the adrenal cortex (for review, see
Ref. [10]). This contention was confirmed by findings of
abundant specific ETA and ET B receptors in the human and
animal adrenal ZG [29–31] as well as by in vitro studies
[32–35], which clearly indicated that, in rats, the ET B
receptor subtype mediates the direct secretagogue effect of
ET-1 on aldosterone [36]. At variance with findings in rats,
available data in humans indicate that both the ETA and
ET B receptors are involved [37] in the transcriptional
regulation of the aldosterone synthase gene, both in
adrenocortical carcinoma and in normal human adrenal
cells [38]. Similar results were recently obtained by
another group working independently [39]. Of interest, in
vitro in dispersed normal human adrenocortical ZG cells,
as well as in Conn’s adenoma cells, ET-1 was found to be
equipotent to Ang II [38], the most important physiological
secretagogue of aldosterone identified so far. Further
experiments from our group provided unequivocal evidence that, in the rat adrenal ZG, by acting via ETA
receptors, ET-1 stimulates both DNA synthesis and cell
proliferation [40]. Since these latter effects were dosedependently blunted by the protein-kinase C inhibitor
Ro31-8220 and by the tyrosine-kinase inhibitor tyrphostin23, they are likely to involve activation of both of these
kinase signalling pathways, but not the protein-kinase A,
cyclooxygenase and lipoxygenase signalling pathways
[40]. Based on these findings, we hypothesised that ET-1
may enhance the growth of the entire adrenal gland by
acting on the ‘cambium’ layer of cells endowed with ETA
receptors, which are mainly located in the ZG. [41].
However, in recent in vivo experiments in rats, it was
found that the administration of the ETA -specific antagonist BQ-123 and the mixed ETA / ET B antagonist bosentan
for four weeks did not affect adrenal gland weight, casting
doubts on the relevance of ET-1 in the maintenance of the
volume of the entire gland in this species (for review, see
Ref. [42]).
Thus, collectively, these data indicate that ET-1 potently
stimulates aldosterone secretion and suggest that it may
affect adrenocortical growth through a direct action on
specific receptors, albeit with differences among species.
These effects of ET-1 are potentially relevant in several
conditions where endothelial damage, hypertension and
hyperaldosteronism coexist, such as congestive heart fail-
303
ure, malignant and severe hypertension, endotoxaemia and
in transplant recipients.
5. In vivo interactions of ET-1 and the RAAS
To investigate whether the aforementioned in vitro
interactions between ET-1 and RAAS have an in vivo
counterpart, a number of studies have been carried out.
Among the original observations stimulating these investigations was the report that subthreshold concentrations of ET-1, i.e., lower than the concentration range
(30–300 pM) needed to elicit a contractile response, were
able to potentiate the vasoconstrictor response to well
known vasoconstrictors, such as serotonin and histamine
[43]. In male HanRen2 / Edin rats derived from crossing
the homozygote transgenic TGR(mREN-2)27 with Edinburgh Sprague-Dawley rats, which show a 73.5% incidence of the malignant phase of hypertension, an increased
ET-1 mRNA content was found in the kidney in the
animals that developed malignant hypertension [44]. Nonetheless, no effect of the mixed ETA / ET B endothelin
antagonist bosentan [45] was seen on blood pressure. At
variance with these findings, bosentan pre-treatment was
capable of blunting the increase in blood pressure, the fall
in cardiac output, and the decrease in arterial conductance
evoked by an infusion of Ang II, both in WKY and in SHR
rats [46]. This blunting was more pronounced in SHR rats,
even thought it was seen in both strains, but it was evident
at the lower (2–10 ng / kg / min) but not at the higher (.30
ng / kg / min) doses of Ang II, thereby suggesting the
possibility of an ET-1 component only in the initial pressor
effect of Ang II. In partial agreement with this contention,
a five-day-infusion of Ang II (0.7 mg / kg / day) to SpragueDawley rats was found to markedly enhance immunostaining for ET-1 in VSMCs; furthermore, administration
of the ETA -selective antagonist PD 155080 abolished the
rise in blood pressure, as did the Ang II AT-1 receptor
antagonist losartan [47]. In 1997, a number of studies
¨
carried out in Dr. Luscher’s
laboratory suggested that ET-1
could play an important role in the structural changes
induced by Ang II infusion. Two weeks of Ang II infusion
(200 ng / kg / min) increased media thickness, the media–
lumen ratio and the cross-sectional area of the mesenteric
and cerebral arterioles, and nearly doubled the content of
ET-1 in the mesenteric tissue, through mechanisms most
likely involving the ETA receptor, inasmuch as the specific
antagonist LU135252 was able to prevent both the development of medial hypertrophy and increased peptide
content in both types of vessels [48]. It was also shown
that a two-week-infusion of a similar dose of Ang II led to
enhanced vascular endothelin converting enzyme activity
and renal ET-1 content in WKY rats [49] and that
LU135252 lowered the Ang II-induced pressure increase
and improved endothelium-dependent relaxation [50]. The
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G.P. Rossi et al. / Cardiovascular Research 43 (1999) 300 – 307
hypothesis that ET-1 might play a role not only in the
haemodynamic effects of Ang II but also in the mechanisms of related cardiovascular damage, is further supported by three sets of observations. First, bosentan
entirely prevented the development of hypertension, the
reduction in renal blood flow and the marked increase in
albuminuria and heart weight induced by a ten-day infusion of Ang II (200 ng / kg / min) [51]. Second, in a canine
model of Page (kidney wrapping) hypertension, bosentan
was found to exert a hypotensive effect in addition to that
of the AT-1 receptor antagonist losartan [52]. This additive
hypotensive effect was found also in a study on rats with
renin-dependent hypertension [53].
An animal model that lends itself to the investigation of
the interactions between the RAA and ET systems in vivo
is the TGR(mREN-2)27 rat. In this model, the introduction
into the rat genome of the mouse Ren-2 gene, encoding for
renin, causes severe hypertension, which is associated with
overexpression of the transgene in several tissues, particularly in the adrenal cortex and the vessel wall, with
ensuing enhanced endogenous production of Ang II in
tissues and low plasma renin activity [54]. A marked
sexual dimorphism of blood pressure changes exists in this
model. In fact, while males develop severe hypertension,
which is fulminant in homozygotes and somehow less
severe in heterozygotes, the female TGR(mREN-2)27 rats
have a milder form of hypertension, which in
heterozygotes peaks at approximately ten weeks of age and
then spontaneously returns to normal values by 35 weeks
of age. Thus, these heterozygote female rats can be
maintained without any antihypertensive treatment. Of
interest, we recently reported that, in these female animals,
the aortic responsiveness to ET-1 followed changes that
closely paralleled those of their systolic blood pressure,
thereby suggesting a role for ET-1 in this form of renindependent hypertension [55], in agreement with previous
reports [56]. However, in contrast with this contention and
in keeping with the aforementioned results in the
HanRen2 / Edin rats cross [44], bosentan did not have
either a blood-pressure-lowering effect or any effectiveness
in preventing left ventricular and vascular hypertrophy in
male heterozygote TGR(mREN-2)27 rats. These findings
were in sharp contrast with the efficacy of the angiotensin
II AT-1 receptor antagonist irbesartan in lowering blood
pressure and preventing left ventricular and arteriolar
hypertrophy in the same model. Thus, it would appear that
in this form of severe hypertension, due to overexpression
of a renin gene, ET-1 does not play any major role. This
conclusion is only partially supported by findings in twokidney one-clip hypertension rats. In this animal model of
renovascular hypertension, the orally active endothelin
antagonist Ro-00203, whilst having no significant effect on
renin secretion and renin gene expression, attenuated the
rise in blood pressure elicited by clipping one renal artery,
although it did not abolish it [57].
The reasons why ET-1 may take part in hypertension
induced by exogenously administered Ang II, but not in
the models with an enhanced endogenous production of
Ang II, are unclear at present. They might depend upon the
different tissue levels attained by Ang II and / or the
different gradients between the bloodstream, endothelium
and VSMCs of the blood vessels’ tunica media, in these
two situations. In fact, it is well documented that, in
heterozygote TGR(mREN-2)27 rats, a high tissue expression of Ang II occurs together with low plasma Ang II,
whilst in the models with exogenous Ang II administra-
Fig. 4. Endothelin-1-dependency of hypertension in different experimental animal models (see Ref. [58] for review) on an arbitrary scale. Regardless of the
initial ET-1 dependency, the pathogenic role of the ET system is deemed to get more and more important once endothelial and target organ damage
supervene.
G.P. Rossi et al. / Cardiovascular Research 43 (1999) 300 – 307
tion, the peptide concentrations are likely to be high in
plasma and lower in tissues.
In contrast with the controversial data on the involvement of ET-1 in renin-dependent forms of hypertension, rather concordant data on the role of the peptide in
mineralocorticoid-dependent forms of hypertension exist
(for a review, see Ref. [58]). Increased levels of irET-1
were found both in plasma and in the arterial wall of rats
with deoxycorticosterone acetate (DOCA)-salt-induced
hypertension [59–61]. Elegant in situ hybridisation studies
by Day et al. [62] showed enhanced expression of the
ppET-1 gene in the vessel wall in the same model.
Treatment with bosentan was quite effective in preventing
vascular hypertrophy in this model. This finding lent
further support to the contention of a direct involvement of
ET-1 in target organ damage in this low-renin form of
hypertension [63]. The contention that ET-1 plays an
important role in salt-dependent forms of hypertension is
further supported by the findings of Barton et al. [64], who
reported that the ETA -specific antagonist LU135252 was
able to partially prevent the development of hypertension
and the structural and functional alterations caused by
chronic salt administration in Dahl salt-sensitive rats. A
role for ET-1 in cardiovascular damage of salt-sensitive
hypertension is suggested also by data obtained in humans
[65].
Fig. 4 summarises available data on the participation of
endothelin in experimental models of hypertension. It must
be pointed out, however, that regardless of the initial ET-1
dependency of hypertension, the pathogenic role of the ET
system is deemed to get more and more important as
endothelial and target organ damage supervene.
6. Therapeutic implications
The identification of interactions at multiple levels
between ET-1 and the RAAS in the pathogenesis of
hypertension and related cardiovascular damage has suggested the potential usefulness of a therapeutic strategy
targeted at both systems.
The potential synergistic / antagonistic effects of a combined inhibition of these two systems on mean arterial
blood pressure (MBP) was investigated by Loffler et al.
[66] in spontaneously hypertensive rats (SHR) [66]. The
endothelin system was inhibited using the ETA -selective
receptor antagonist Ro 61-1790 and / or the mixed
NEP24.11 / ECE inhibitor phosphoramidon, whilst angiotensin I converting enzyme (ACE) was inhibited using
cilazapril. The inhibition of the ET system with maximally
effective doses of either phosphoramidon or Ro 61-1790
similarly decreased MBP by about 230 mmHg potency;
the two agents were equipotent to a maximal ACE
inhibition. Most interestingly, both combined phosphoramidon / cilazapril and phosphoramidon / Ro 61-1790 infusion enhanced the maximal decrease in MBP by 100% to
305
260 mmHg and, thus, almost normalised blood pressure.
Thus, the combined ET / RAAS inhibition may provide an
interesting synergistic potential in terms of blood pressure
reduction. Of further interest, this synergism was found
also in patients with class III New York Heart Association
(NYHA) congestive heart failure, who were haemodynamically stable on ACE inhibitors and diuretics, in whom the
mixed ETA / ET B receptor antagonist bosentan elicited a
clear-cut decrease in systemic and pulmonary vascular
resistance along with an increase in the cardiac index [67].
7. Conclusions and perspectives
The identification of ET-1 by Yanagisawa et al. [68] one
decade ago has added a novel important player to the
‘arena’ of potential mechanisms causing arterial hypertension and related cardiovascular disease. Over the years, it
has been increasingly appreciated that any newly discovered agent cannot be investigated singularly, but rather
should be assessed in the context of all the other known
mechanisms. There are several interactions between the
RAAS and the endothelin system, which may have relevant effects on blood pressure and on hypertensionrelated complications. Experimental research has started to
unravel these interactions, and pilot clinical trials gave
promising results, but the question of whether or not they
are also relevant in humans in the clinical setting and have
therapeutic implications needs to be investigated further.
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