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.
Kaasjager KA, Koomans HA, Rabelink TJ. Endothelin-1–induced vasopressor responses in essential hypertension. Hypertension. 1997;30:15–21.
Miller WL, Redfield MM, Burnett JC Jr. Integrated cardiac, renal, and endocrine actions of endothelin. J Clin Invest. 1989;83:317–320.
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.
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.
Loutzenhiser R, Epstein M. Effects of calcium antagonists on renal hemodynamics. Am J Physiol. 1985;249:F619–F629.
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.
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.
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.
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.R1 R2 R3 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.R4 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.R5
Vierhapper H, Wagner O, Nowotny P, Waldhausl W. Effect of endothelin in man. Circulation. 1990;81:1415–1418.
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.
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.
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.
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.