(Hypertension. 1998;31:721-722.)
© 1998 American Heart Association, Inc.
Renal Effects of Endothelin-1 in Essential Hypertension
Gian Paolo Rossi;
Emanuela Zilli;
; Achille C. Pessina
Department of Medicina Clinica e Sperimentale,
University of Padova Medical School,
University Hospital,
Padova, Italy
To the Editor:
In their recent article, Dr Kaasjager and
colleagues1 reported important data on the renal
hemodynamic effects of endothelin-1 (ET-1) in 9
subjects with essential hypertension. They showed that ET-1 elicits a
potent vasoconstrictor effect, which was found to be prominent in the
renal vascular bed. The authors also showed that treatment with both
the angiotensin-converting enzyme inhibitor
enalapril and the dihydropyridine calcium channel
blocker nifedipine could prevent the effects of ET-1 on
systemic blood pressure, although only nifedipine seems to
be effective in attenuating the renal constrictor effects of ET-1.
Of interest, the authors measured the ET-1–induced changes of plasma
renin activity (PRA) and plasma aldosterone levels but
failed to detect any significant effect and thereby excluded that these
hormones might account for their renal hemodynamic
findings. In fact, contrary to what Kaasjager et al state, ET-1
infusion did induce a consistent 10% increase of plasma
aldosterone both when administered alone (in the Control
Study) and during enalapril or nifedipine treatment. This
increase was seen even though the peptide was infused for only 180
minutes and at a dosage that produced a peak plasma concentration of
immunoreactive ET-1 (11.6±1.0 pmol/L) which was subthreshold, ie,
lower than the 30 to 300 pmol/L needed to elicit a vasoconstrictor
response in various smooth muscle preparations in
vitro.2
Because ET-1 was shown to enhance aldosterone secretion in
different species, including humans, by acting on specific
receptors3 4 (see Reference 5 for review), in our
opinion this finding deserves careful consideration. From the measure
of spread (SEM) given with the data,1 a wide
dispersion of the values (corresponding to a variation coefficient
ranging between 50% and 60%) is readily evident. This suggests either
a large interindividual variability of the plasma
aldosterone value or a poor measurement reproducibility, or
both. Unfortunately, no information on the method used or on the exact
timing of aldosterone measurements is provided in the
article; therefore, the questions on methodological accuracy and time
course–related variability of plasma aldosterone remain
unanswered. Furthermore, it is our general experience that PRA and
plasma aldosterone levels do not follow a normal
distribution. It is therefore unclear why, although the authors
correctly used a logarithmic transformation of the PRA data, they did
not do the same for plasma aldosterone values.
We suspect that a more accurate measurement of plasma
aldosterone, a larger sample size, and a more appropriate
analysis of the aldosterone data could have
revealed a statistically significant secretagogue effect of ET-1 on
aldosterone. In our view, this is not a trivial issue,
since this secretagogue effect of ET-1 in human adrenocortical cells
involves a calcium-dependent mechanism.6 It is
thus conceivable that the 1.5-fold higher baseline sodium excretion and
the upward shift of the sodium excretion curve in response to ET-1
infusion that were observed during nifedipine treatment
might depend, at least in part, on an inhibition of tonic ET-1–induced
aldosterone secretion.
The authors assumed that the antinatriuretic effect
of ET-1 was exclusively due to renal vasoconstriction and explained
their finding of an enhanced baseline sodium excretion with a
"long-term" effect of nifedipine. We put forward the
alternative hypothesis that this "long-term"
natriuretic effect relies in part on the ability of the
dihydropyridine calcium entry blockers to interfere
with ET-1–mediated aldosterone regulation and thus with
the sodium-retaining action of the steroid at the distal tubule. This
interpretation accords well with the concept that the
natriuretic effect of the
dihydropyridine calcium entry blockers occurs even
without alterations in renal plasma flow and glomerular
filtration rate, ie, through a tubular
mechanism,7 which mainly involves the fractional
distal escape of sodium.8
Of further interest is the fact that the authors failed to observe any
initial vasodilation in response to ET-1 infusion. They suggest that
the ET-1–induced transient vasodilation, which is mainly due to nitric
oxide (NO) release mediated via ETB receptors on
endothelial cells, can be restricted to certain
vascular beds and does not involve the renal vasculature. Although we
cannot rule out this possibility, it is worth mentioning that (1 ) an
impaired endothelium-dependent relaxation has
repeatedly been observed in hypertensive subjects, (2 ) with
immunohistochemistry and reverse transcription–polymerase chain
reaction we recently detected ETB receptors in
vascular smooth muscle cells of the tunica media of human renal
arteries obtained ex vivo,9 and (3 ) these
receptors are likely to mediate for vasoconstriction, at least in
certain vascular beds.10 Thus, it does not seem
unreasonable to assume that an endothelial dysfunction,
which precedes the onset of clinical signs of renal damage and involves
the ETB-mediated NO release, already exists in
the essential hypertensive subjects investigated by Dr Kaasjager and
colleagues, as suggested by their own data with L-arginine
administration. Alternatively, it might be that the direct
ETB-mediated NO release is masked by a direct
vasoconstrictor effect occurring through both ETA
and ETB receptors, which we have found in the
tunica media of the human renal vessels.
References
1.
Kaasjager KA, Koomans HA, Rabelink TJ.
Endothelin-1–induced vasopressor responses in essential hypertension.
Hypertension. 1997;30:15–21.[Abstract/Free Full Text]
2.
Cesari M, Pavan E, Sacchetto A, Rossi GP.
Endothelin-1: a scientist's curiosity, or a real player in
ischemic heart disease? Am Heart J. 1996;132:1236–1243.[Medline]
[Order article via Infotrieve]
3.
Miller WL, Redfield MM, Burnett JC Jr. Integrated
cardiac, renal, and endocrine actions of endothelin. J Clin
Invest. 1989;83:317–320.
4.
Rossi GP, Albertin G, Belloni A, Zanin L, Biasolo MA,
Prayer Galetti T, Bader M, Nussdorfer GG, Palù G, Pessina AC.
Gene expression, localization, and characterization of endothelin A and
B receptors in the human adrenal cortex. J Clin Invest. 1994;94:1226–1234.
5.
Nussdorfer GG, Rossi GP, Belloni AS. The role of
endothelins in the paracrine control of the secretion and growth of the
adrenal cortex. Int Rev Cytol. 1997;171:267–308.[Medline]
[Order article via Infotrieve]
6.
Rossi GP, Albertin G, Bova S, Belloni AS, Fallo F,
Pagotto U, Trevisi L, Palù G, Pessina AC, Nussdorfer GG.
Autocrine-paracrine role of endothelin-1 in the regulation of
aldosterone synthase expression and intracellular
Ca2+ in human adrenocortical carcinoma.
Endocrinology. 1997; 138:4421–4426.
7.
Loutzenhiser R, Epstein M. Effects of calcium
antagonists on renal hemodynamics.
Am J Physiol. 1985;249:F619–F629.
8.
Krusell LR, Jespersen LT, Schmitz A, Thomsen K,
Pedersen OL. Repetitive natriuresis and blood pressure: long-term
calcium entry blockade with isradipine. Hypertension. 1987;10:577–581.[Abstract/Free Full Text]
9.
Rossi GP, Belloni A, Pavan E, Piovan V, Sacchetto A,
Hagiwara H, Nussdorfer GG, Pessina AC. Autoradiographic and
immunochemical detection of endothelin-1 (ET-1) and the
ETA and ETB receptors in
the tunica media of human arteries and veins. Hypertension. 1996;28:698. Abstract.
10.
Teerlink JR, Breu V, Sprecher U, Clozel M, Clozel JP.
Potent vasoconstriction mediated by endothelin
ETB receptors in canine coronary
arteries. Circ Res. 1994;74:105–114.[Abstract/Free Full Text]
Response
Karin A.H. Kaasjager;
Hein A. Koomans;
; Ton J. Rabelink
Department of Nephrology and Hypertension,
University Hospital Utrecht,
Utrecht, The Netherlands
Dr Rossi and colleagues suggest an alternative explanation of
the antinatriuretic effects of ET-1 infusion
through its secretory effects on plasma aldosterone levels.
Their hypothesis is certainly of interest. However, we feel that from
our data this interpretation cannot be supported. First, the difference
in plasma aldosterone, which was measured immediately
before and at the end of the ET-1 infusion, was not significant. If we
use a logarithmic transformation, the increments become even smaller
(270 to 288 pmol/L for control; 256 to 267 pmol/L for enalapril; and
270 to 284 pmol/L for nifedipine). The within-assay
variance coefficient of our assay was 9%, and the between-assay
variance coefficient was 14%. The absence of an effect of
pathophysiological increments in plasma ET-1 on
aldosterone is in agreement with observations from other
groups using similar infusion protocols.1 2 3
Moreover, to really identify the magnitude of a change in plasma
aldosterone from our study, one would need a time-control
study because there are important diurnal changes in the secretion of
the hormone. Second, there was an immediate decrease in sodium
excretion after ET-1 infusion, whereas one would expect a delay in the
onset of the antinatriuretic effect if it were
secondary to aldosterone stimulation. Finally, from our
data there are no indications that effects of ET-1 on
aldosterone can be modulated by calcium channel
blockade.
Rossi et al also offer an alternative explanation for some of our
hemodynamic findings, ie, the absence of initial
vasodilation in response to ET-1 infusion. Although we cannot exclude
that impaired endothelium-dependent relaxation could
contribute to this phenomenon in these hypertensive subjects, we also
did not see this initial vasodilation in previous studies in healthy
volunteers, who are assumed to have normal endothelial
function.4 Moreover, we recently performed a
study in healthy subjects in whom we infused ET-3, a relatively
selective ETB agonist. In this study we did not
see any vasodilation or vasoconstriction in the kidney despite a
threefold increase in plasma ET-3 levels, suggesting that the renal
effects of exogenously administered ET-1 in the human kidney are
predominantly mediated through ETA
receptors.5
References
1.
Vierhapper H, Wagner O, Nowotny P, Waldhausl W.
Effect of endothelin in man. Circulation. 1990;81:1415–1418.[Abstract/Free Full Text]
2.
Sorensen SS, Madsen JK, Pedersen EB. Systemic and
renal effect of intravenous infusion of endothelin-1 in
healthy human volunteers. Am J Physiol. 1994;266:F411–F418.[Abstract/Free Full Text]
3.
Goetz KL, Wang BC, Madwed JB, Zhu JL, Leadley RJ.
Cardiovascular, renal and endocrine responses to
intravenous endothelin in conscious dogs. Am J
Physiol. 1988;255:R1064–R1068.[Abstract/Free Full Text]
4.
Kaasjager HAH, Koomans HA, Rabelink TJ. Effectiveness
of enalapril versus nifedipine to antagonize blood pressure
and the renal response to endothelin in humans.
Hypertension. 1995;25:620–625.[Abstract/Free Full Text]
5.
Kaasjager HAH, Shaw S, Koomans HA, Rabelink TJ. Role
of endothelin receptor subtypes in the systemic and renal responses to
endothelin-1 in humans. J Am Soc Nephrol. 1997;8:32–39.[Abstract]
