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(Hypertension. 1997;30:15-21.)
© 1997 American Heart Association, Inc.
Articles |
Endothelin-1–Induced Vasopressor Responses in Essential Hypertension
From the Department of Nephrology and Hypertension, University Hospital Utrecht (The Netherlands).
Correspondence to T.J. Rabelink MD, PhD, Department of Nephrology and Hypertension (F03.226), University Hospital Utrecht, PO Box 85500, 3508 GA Utrecht, Netherlands.
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Abstract |
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Abstract The potential role of endothelin-1 (ET-1) in essential hypertension in humans is still subject to debate. We recently reported strong sodium retention and renal vasoconstriction during pathophysiological increments in plasma ET-1. Apart from this vasoconstrictor action, ET-1 also has mitogenic properties that play a role in the pathophysiology of hypertension. On the other hand, some data refute an important role of ET-1 in hypertension. We therefore investigated in nine subjects with essential hypertension the constrictor actions of ET-1 by challenging these subjects with a systemic infusion of ET-1 (0.5 ng/kg per minute for 60 minutes, then 1.0 ng/kg per minute for 60 minutes, and finally 2.0 ng/kg per minute for 60 minutes). Furthermore, we studied whether these effects of ET-1 could be modulated by oral use of the angiotensin-converting enzyme inhibitor enalapril (20 mg BID) or the calcium channel blocker nifedipine (60 mg OD). ET-1 infusion increased plasma ET-1 levels from 2.5±0.4 to 11.6±1.0 pmol/L (P<.05). Blood pressure rose by approximately 10 mm Hg (P<.05). Cardiac index decreased by 21±2%, whereas calculated systemic vascular resistance increased by 27±6% (P<.05). Renal blood flow decreased from 1051±94 to 707±60 mL/min at the end of the ET-1 infusion (P<.05), and calculated renal vascular resistance increased from 118±19 to 189±19 mm Hg·min/L (P<.05). Sodium excretion decreased from 227±39 to 111±15 µmol/min (P<.05). Both enalapril and nifedipine treatment prevented the systemic effects of ET-1 infusion in these subjects. However, during enalapril treatment, despite renal predilatation, ET-1 reduced renal blood flow (from 1119±132 to 701±75 mL/min, P<.05) and increased renal vascular resistance (from 111±16 to 187±28 mm Hg·min/L, P<.05) to the same levels as during ET-1 infusion alone. Nifedipine pretreatment attenuated the ET-1–induced fall in renal blood flow (from 1088±93 to 907±68 mL/min) and increase in renal vascular resistance (from 105±9 to 133±10 mm Hg·min/L). Although neither drug modulated the antinatriuretic effect of ET-1, nifedipine increased basal sodium excretion (P<.05), which compensated for the decrease during ET-1 infusion. In conclusion, essential hypertensive subjects are sensitive to the vasoconstrictor effects of ET-1. Both enalapril and nifedipine can prevent the systemic effects of ET-1, but nifedipine seems more effective in attenuating the renal constrictor effects of ET-1.
Key Words: endothelin • hypertension, essential • calcium channel blockers • angiotensin-converting enzyme inhibitors
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Introduction |
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The 21–amino acid peptide ET-1 has received a lot of attention over the past years because of its putative role in the pathogenesis of hypertension. For example, ET-1 has been shown to exert a direct vasoconstrictor effect on human resistance arteries.1 2 We recently showed that ET-1 may also cause profound renal vasoconstriction and sodium retention in humans despite elevations in systemic blood pressure, suggesting a shift in the pressure-natriuresis curve.3 ET-1 may play a role in the pathophysiology of hypertension not only by its actions as a constrictor peptide but also by its mitogenic properties.4 Li et al5 have shown that hypertension in the deoxycorticosterone acetate–salt hypertensive rat is accompanied by vascular hypertrophy and increased vascular tissue expression of ET-1. This vascular remodeling could be nearly normalized by specific endothelin receptor blockade.5 ET-1 has also been suggested to play a role in the development of glomerulosclerosis and chronic renal failure, which is an increasingly more frequent complication of hypertension.6 The potential role of ET-1 as a pathophysiological factor in hypertension and its complications gained further support from observations that subjects with usually more severe hypertension, such as malignant hypertension, preeclampsia, hypertension associated with renal transplantation, and hypertension complicated by end-organ damage, have elevated ET-1 plasma levels, which are assumed to reflect spillover of an activated vascular endothelin system.7 8 9 Recently, it was shown that severe hypertension is also accompanied by increased tissue expression of ET-1.10 11 12
However, some data also refute an important role of ET-1 in hypertension. In some experimental models of hypertension, such as the spontaneously hypertensive rat, the vascular ET-1 system is downregulated,13 14 and in agreement, the vascular responsiveness to ET-1 has been shown to be reduced.15 16 17 Importantly, gluteal subcutaneous resistance vessels of essential hypertensive individuals have also been shown to have such a reduced constrictor responsiveness.18 19 Obviously, this would render the endothelin system less useful as a therapeutic target in essential hypertension.
We therefore investigated whether individuals with essential hypertension were sensitive to the constrictor actions of ET-1 by challenging them with a systemic infusion of ET-1. If so, we were interested in finding out whether such an effect of ET-1 could be modulated by commonly used antihypertensive treatment. We therefore repeated these ET-1 infusions after pretreatment with a calcium channel blocker or an ACE inhibitor. Dihydropyridine calcium channel blockers may specifically interfere with the signal transduction pathway of ET-1, which depends for its sustained constrictor effects on the influx of extracellular calcium release.20 ACE inhibitors may inhibit the stimulating effect of angiotensin II on ET-1 expression21 and may counteract ET-1 by stimulating endothelium-dependent vasodilatation, which acts as a counterregulatory system to the constrictor actions of ET-1 and which has been reported to be impaired in essential hypertension.22 23 24
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Methods |
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We carried out studies in nine subjects (three women and six men; age range, 26 to 37 years) with mild to moderate hypertension and no signs of end-organ damage. The protocol was approved by the University Hospital Ethics Committee for Study in Humans. Written informed consent was obtained from each subject.
Ambulatory subjects with essential hypertension were recruited from the outpatient clinics for hypertension and internal medicine of the University Hospital Utrecht. The diagnosis of essential hypertension was established before the study by the absence of any clinical evidence of secondary hypertension and normal serum electrolytes, creatinine, urinalysis, and renal scintiscan. All subjects were nonsmokers.
Before entering the first period (control study), the subject had a drug-free period of 3 weeks. At the end of this period, 24-hour ambulatory blood pressure monitoring was recorded for documentation of essential hypertension. The criteria for acceptance into the study, assessed at the end of the drug-free period, were a mean sitting diastolic pressure greater than 95 and less than 115 mm Hg after 5 minutes of rest assessed during three consecutive measurements with an interval of 2 minutes between each measurement and mean ambulatory diastolic pressure during daytime hours (11 AM to 11 PM) greater than 90 mm Hg.
All subjects underwent three clearance studies (see below) during which ET-1 was infused. The first clearance study was the control study after the drug-free period. ET-1 infusion was repeated after 3 weeks of treatment with 60 mg nifedipine GITS once daily and after 3 weeks of treatment with 20 mg enalapril BID. The two treatment periods were separated by a 2-week washout period. On the last day of each treatment period, a clearance study was performed. The order of the treatment periods was randomized.
Subjects took lithium carbonate (400 mg) at 10 PM on the evening of the clearance studies. The studies were performed after an overnight fast and with subjects in the supine position. Maximal water diuresis was induced by an oral water load of 25 mL/kg body wt and was maintained by subjects drinking amounts of water matching urinary output. At 9 AM, a priming dose of a solution containing 2.5% inulin, for measurement of GFR, and 2.5% para-aminohippuric acid, for measurement of ERPF, was administered, followed by continuous infusion of this solution throughout the remainder of the study. After at least a 1-hour equilibration period, two 30-minute baseline urine collections were obtained by spontaneous voiding. Blood specimens were drawn at the midpoint of each collection period from the contralateral forearm. Then, ET-1 infusion was started, via a separate antecubital vein. ET-1 (Peptide Institute Inc, Scientific Marketing Associates) was dissolved in Haemaccel (Behring Pharma, Hoechst Holland NV) and administered for 60 minutes in a dose of 0.5 ng/kg per minute, followed by an infusion period of 60 minutes in a dose of 1.0 ng/kg per minute and 60 minutes in a dose of 2.0 ng/kg per minute. The infusion period was followed by a 60-minute recovery period. Urine and blood sampling was continued at 30-minute intervals throughout the study. Samples for determination of plasma endothelin were obtained before infusion, at 105 and 165 minutes after the start of the infusion, and at 45 minutes during recovery. PRA and ANP were measured in blood samples drawn at baseline, at 165 minutes after the start of the infusion, and at 45 minutes during recovery.
Blood pressure and heart rate were recorded at 5-minute intervals during the clearance studies with an automatic oscillometer (Omega 2000, Invivo Research Laboratory Inc). Bioimpedance-derived cardiac output, stroke volume, and heart rate were measured continuously (NCCOM3, BoMed Medical Manufacturing Ltd) and recorded automatically at 1-minute intervals. Electrocardiographic monitoring was observed continuously. All blood and urine samples were analyzed for sodium (Corning M480 flame photometry), lithium (Perkin-Elmer 3030 atomic absorption spectrophotometer), and inulin and para-aminohippurate by photometry.25 26 PRA and ANP were determined by radioimmunoassay, as described previously.27 Blood samples for determination of immunoreactive endothelin were collected in prechilled tubes containing potassium-EDTA and centrifuged at 4°C. Plasma was stored at -70°C until the assay and before determination was extracted with Sep-Pak octadecyl solid-phase extraction cartridges (Waters). After the cartridges were conditioned with methanol, deionized water, and 4% acetic acid, duplicate extractions were performed of 1.0 mL plasma acidified with 3 mL of 4% acetic acid. After being washed with 3 mL deionized water and 3 mL of 25% ethanol, the cartridges were eluted with 2 mL of 86% ethanol/glacial acetic acid (96:4, vol/vol). The eluates were dried under nitrogen at room temperature, and the residues were dissolved in 200 µL assay buffer and analyzed by radioimmunoassay (Nichols Institute). ET-1 recovery throughout the extraction was 85%. Reported concentrations (picomoles per liter) are corrected for procedural losses. Cross-reactivities with ET-2, ET-3, and prepro–ET-1 were 52%, 96%, and 7%, respectively. The detection limit of the assay was 0.4 pmol/L.
Calculations and Statistics
Mean arterial pressure was calculated as the sum of
one third of systolic pressure and two thirds of
diastolic pressure. RBF was calculated by dividing ERPF by
(1-Packed Cell Volume). SVR index and RVR were calculated by dividing
mean arterial pressure by cardiac index and RBF,
respectively. Values are presented as mean±SEM. PRA was
analyzed after logarithmic transformation. Statistical
analysis was performed by two-way ANOVA of a randomized block
design, with the ET-1 infusion and the presence of
nifedipine and enalapril as independent variables. The
interaction variance ratios obtained by this method indicate whether
the response to endothelin is different between the two studies. If
treatment variance ratios reached statistical significance, the
differences between the means were analyzed with the least
significant difference test for a value of P<.05.
Data Presentation
To prevent data that would be difficult to survey, we
present the data in the tables as baseline (30-minute urine
collection before the endothelin infusion), infusion (the fourth
and final 30-minute urine collection during infusion, the former
corresponding to the maximal effect), and recovery (the second half
hour of recovery). All urine collections underwent statistical
analysis.
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Results |
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Effects of ET-1 Infusion During the Control Study
ET-1 infusion was well tolerated, and no side effects were observed. ET-1 plasma levels increased from 2.5±0.4 to 11.6±1.0 pmol/L at the end of the infusion period (Fig 1
). This
was associated with an increase in blood pressure of approximately
10 mm Hg (Fig 2). Heart rate did not change
(average values before and at the end of the infusion, 55±2 and 53±3
beats per minute [bpm], respectively). Cardiac index decreased by
21±2% compared with baseline (Fig 3). Calculated SVR
increased 27±6% (P<.05, Fig 3), from 2270±110 to
2890±151 mm Hg·m2/L. RBF decreased from 1051±94
to 886±105 mL/min at 120 minutes of ET-1 infusion. RBF was 707±60
mL/min at 180 minutes of ET-1 infusion (P<.05, Fig 2),
showing partial recovery after the infusion was stopped. GFR decreased
but was accompanied by a proportionally larger decrease in ERPF,
resulting in an increase in filtration fraction (Table 1). Calculated RVR increased from 118±11 to
159±23 mm Hg·min/L at 120 minutes of ET-1 infusion and to
189±19 mm Hg·min/L at 180 minutes and recovered incompletely
(P<.05, Fig 2). Sodium excretion decreased progressively
during endothelin infusion and did not completely recovered afterward
(Fig 4). Fractional sodium excretion, fractional lithium
excretion, and urine flow decreased parallel to sodium excretion (Table 2).
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), during enalapril (
), and during
nifedipine (
). ET-1 was infused for 60 minutes at 0.5
ng/kg per minute, followed by 60 minutes at 1.0 ng/kg per minute and 60
minutes at 2.0 ng/kg per minute. Plasma endothelin levels were
significantly elevated in all three experiments
(P<.05).
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PRA, plasma aldosterone, and ANP levels did not change at the end of the ET-1 infusion (289±117 to 235±110 fmol/L per second, 263±53 to 291±49 pmol/L, and 15±2 to 16±2 pmol/L, respectively).
Effects of ET-1 Infusion After Pretreatment With Enalapril
In this experiment, ET-1 infusion increased plasma ET-1
concentration to values similar to those found during the control study
(Fig 1
). Blood pressure, which decreased at baseline, showed an
increase of approximately 5 mm Hg during ET-1 infusion
(P<.05, Fig 2). Heart rate did not change significantly
from 56±3 to 58±3 bpm at the end of the infusion. During enalapril
treatment, cardiac index and SVR did not change significantly on ET-1
infusion (Fig 3). Besides lowering blood pressure and increasing PRA,
enalapril pretreatment also had effects on baseline renal
hemodynamics: GFR and ERPF were elevated (Table 1). RBF
and RVR were elevated and decreased, respectively (Fig 2). After 180
minutes of ET-1 infusion, GFR decreased to 101±8 mL/min, at a lower
level than that in the control study despite the increased baseline GFR
level (P<.05, Table 1). The same was true for the decrease
in ERPF and RBF (Table 1 and Fig 2, respectively).
Baseline sodium excretion and endothelin-induced antinatriuresis
were similar to values in the control ET-1 infusion study (Fig 4).
Hormone measurements did not change (PRA, plasma
aldosterone, and ANP levels: 1622±320 to 1578±290 fmol/L
per second, 250±45 to 274±53 pmol/L, and 17±3 to 16±2 pmol/L,
respectively).
Effects of ET-1 Infusion After Pretreatment With
Nifedipine
In this experiment, ET-1 infusion increased plasma endothelin
concentrations comparably to the other two experiments (Fig 1).
Nifedipine pretreatment decreased basal blood pressure and
prevented the increase by ET-1 infusion (Fig 2). Heart rate did not
change significantly from 59±2 to 62±3 bpm at the end of ET-1
infusion. Nifedipine pretreatment resulted in a maintained
level of cardiac index and SVR during ET-1 infusion (Fig 3).
Nifedipine treatment increased RBF and ERPF and decreased
RVR (Table 1 and Fig 2). Nifedipine did not prevent
reductions in GFR, ERPF, and RBF. However, the values reached were
significantly higher than those during control ET-1 infusion and those
during ET-1 infusion after enalapril pretreatment (Table 1 and Fig 2).
RVR increased to a lesser extent (P<.05). Baseline sodium
excretion was approximately 1.5 higher than in the control and
enalapril studies (Fig 4) but decreased on ET-1 infusion. Similar to
the changes in renal hemodynamics, the values reached
were above that of control ET-1 infusion.
ET-1 had no effect on hormone measurements during nifedipine pretreatment (PRA, 298±128 to 261±110 fmol/L per second; plasma aldosterone, 270±46 to 297±51 pmol/L; and ANP levels, 17±3 to 15±2 pmol/L).
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Discussion |
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The key findings of our study are that elevations of plasma ET-1 cause large increases in calculated SVR and RVR in hypertensive subjects in a way similar to that previously observed in healthy subjects.28 Both chronic ACE inhibition and calcium channel blockade are effective in counteracting the effects of ET-1 on systemic hemodynamics. However, calcium channel blockade maintained renal perfusion and sodium excretion at a higher level, whereas ACE inhibition did not affect the renal effects of ET-1.
In these hypertensive subjects, a modest increase in plasma ET-1 level caused a further rise in SVR by 27%, indicating that the vascular resistance bed of these hypertensive subjects was sensitive to the constrictor actions of ET-1. Because of a simultaneous decrease in cardiac output, blood pressure rose only by approximately 10 mm Hg. This increase is not different from the one observed in a previous study in healthy volunteers using a similar ET-1 infusion scheme. We have no data on cardiac output in healthy volunteers in that study, but these changes are in agreement with other ET-1 infusion protocols in dogs,29 pigs, and humans,30 in which a decrease in cardiac output invariably was observed. The mechanism of this decrease in cardiac output is not clear but may involve adaptation to the increased afterload as well as a negative inotropic effect secondary to myocardial ischemia.29 31 Notably, none of our subjects experienced any discomfort during the ET-1 infusion, nor were changes in the electrocardiographic monitoring during ET-1 infusion observed.
In contrast to studies reporting the effects of ET-1 in the forearm vascular resistance bed, we did not see an initial vasodilator response,1 nor did we see such a response in our previous studies in healthy volunteers. This may be due to differences in methodology, bioimpedance being less sensitive for detection of such vasodilatation. Alternatively, the initial vasodilatation to ET-1 may not be a generalized phenomenon but restricted to certain vascular beds such as the forearm.
As in our previous studies in healthy normotensive subjects using a similar ET-1 infusion scheme, ET-1 infusion caused profound renal vasoconstriction and sodium retention in essential hypertensive individuals: ERPF fell by approximately 28%, and RVR increased by approximately 60%. GFR decreased to a lesser extent, and as a result, filtration fraction increased. Thus, the renal vasculature seems to be sensitive to the constrictor effects of ET-1 in these individuals with essential hypertension. This renal vasoconstriction has been well recognized as a factor that plays a role in the maintenance of hypertension. This would imply that ET-1 can still act as a hypertensive factor in hypertension. It should be realized that our subjects had plasma ET-1 levels that were in the normal range. Recently, preliminary data showed that subjects with mild hypertension, as was also the case in our study, also have a normal vascular expression of prepro-ET-1.32 From our data, we cannot extrapolate to more severe forms of hypertension, such as malignant hypertension or preeclampsia, in which the vascular ET-1 system probably is activated.7 33 Data on endothelin receptor density/sensitivity on the vascular smooth muscle cell, which would determine the vascular biological effects under such conditions, are not available. Nevertheless, our data would suggest that at certain phases in the development of hypertension, ET-1 may play a role in its pathogenesis, eg, when ET clearance becomes impaired because of renal damage or when drugs such as cyclosporine or erythropoietin, which stimulate endothelial ET-1 production,9 34 35 are administered. Also, enhanced ET-1 gene expression in the endothelium of arteries of humans with severe hypertension has been described.12
The present vascular responsiveness to ET-1 in hypertensive individuals is in contrast to studies in experimental animal hypertension models in which decreased responses have been reported.15 16 17 36 Also, in human isolated resistance vessels, a blunted response to ET-1 was noted.18 19 However, the importance of a reduced vascular sensitivity to ET-1 in isolated blood vessels for the in vivo situation has to be considered cautiously. Indeed, remodeling of the vascular media occurring in hypertension may, particularly in the resistance and microcirculation, considerably amplify vascular responses and result in an exaggerated active pressure development in intact vascular beds, even in the presence of a reduced sensitivity of the isolated blood vessel wall to ET-1.16 37 Interestingly, in hand veins of hypertensive individuals, which are not subject to remodeling, enhanced sensitivity to local ET-1 infusion has been observed.38
In this study, we also extrapolate our previous finding in healthy subjects that chronic pretreatment with antihypertensive drugs is effective in modulating the renal effects in response to ET-1 in subjects with essential hypertension. Although these drugs may interfere with ET-1 through different modes of action, both drugs were effective in preventing systemic actions of ET-1: nifedipine and enalapril reversed systemic vasoconstriction. There was, however, a marked difference in the renal response. Whereas pretreatment with nifedipine prevented the marked increase in RVR, the ET-1–induced renal effects were even stronger after enalapril pretreatment despite initial renal vasodilatation. It is tempting to explain this difference in renal protection against the effects of ET-1 in terms of the modes of action of these drugs. Studies in dogs and rats showed that ACE inhibition attenuated the ET-1–induced changes in renal function, whereas the competitive angiotensin II receptor antagonist saralasin had no effect on either the systemic or renal actions of the peptide.39 These data would suggest that the inhibition of kinin degradation may attenuate the renal actions of ET-1. A consequence of a decreased kinin breakdown is stimulation of endothelium-dependent vasodilatation.24 40 Although this effect could explain the observed prevention of an increase in SVR, these endothelium-dependent vasodilator systems appear to be less effective in the renal circulation. In agreement with this hypothesis is our previous study in healthy volunteers in which the substrate for nitric oxide synthase, L-arginine, was administered. L-Arginine could not prevent renal vasoconstriction during ET-1 infusion, although the increase in blood pressure was abolished.41
During calcium channel blockade, ET-1 infusion could still reduce RBF, but this was less pronounced than during ET-1 infusion alone or ET-1 infusion after pretreatment with an ACE inhibitor despite similar initial vasodilatation, in the latter condition. Consequently, the increment in RVR during calcium channel blockade was markedly attenuated. This suggests that direct interference with the signal transduction pathway of ET-1 is more effective in modulating the renal effects of ET-1. These findings are in agreement with recent observations we made in renal transplant patients with hypertension, a condition that has been associated with both elevated plasma ET-1 levels and increased tissue expression of ET-1.8 42 43 In these patients, treatment with both a dihydropyridine calcium antagonist and an ACE inhibitor could reduce blood pressure. However, only the calcium channel blocker reduced the increased RVR.42
It is assumed that the antinatriuresis following ET-1 is due to renal vasoconstriction.44 In accord, changes in renal sodium excretion following ET-1 infusion show a pattern similar to that of the changes in renal hemodynamics. During enalapril, a very strong sodium retention parallel to the decrease in renal perfusion was observed, reaching the same final values as during the control ET-1 infusion. Baseline sodium excretion during the study was enhanced after calcium channel blockade. This probably reflects the long-term effect of nifedipine on sodium excretion in hypertensive individuals, as has been described by MacGregor et al.45 Calcium channel blockade could not prevent the sodium retention following ET-1 infusion. A more pronounced effect on ET-1–induced sodium retention might have been expected during calcium channel blockade in view of the attenuating effect of these drugs on renal hypoperfusion. On the other hand, a higher overall RBF during ET-1 in the presence of calcium channel blockade does not necessarily represent a higher medullary perfusion, which is the major determinant of perfusion-induced natriuresis. Nevertheless, sodium excretion remained above control ET-1 infusion levels, indicating that the natriuretic action of calcium channel blockers in these hypertensive individuals may partially compensate for the sodium-retaining effects of ET-1.
Limitations of the present study are the mode of ET-1 administration and the doses of the antihypertensive drugs used. The (patho)physiological mode of action of ET-1 is probably a paracrine one.20 Since individuals with essential hypertension usually do not have increased circulating levels of ET-1, as is also the case in the present study, infusion of exogenous ET-1 does not necessarily mimic the in vivo actions of ET-1 in essential hypertension. Nevertheless, the study design does allow conclusions to be drawn regarding possible mechanisms by which ET-1 may contribute to the development of hypertension in these subjects. The second limitation of the study is the enalapril and nifedipine doses used. For both drugs, we used the maximal dose to evaluate whether regular antihypertensive treatment could modify the ET-1–induced pressor response. However, this does not exclude the possibility that higher doses of these drugs may further modify the actions of ET-1.
In conclusion, our data suggest that ET-1 may have a hypertensive action in individuals with essential hypertension. Our data also suggest that when an activated endothelin system is present in hypertension, calcium channel blockers may be more efficacious than ACE inhibitors as they also reduce the renal hypertensive effects of ET-1, such as renal ischemia and sodium retention.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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T.J. Rabelink is supported by a fellowship of the Royal Dutch Academy of Sciences (KNAW).
Received November 20, 1996; first decision December 12, 1996; accepted December 12, 1996.
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