(Hypertension. 1995;25:620-625.)
© 1995 American Heart Association, Inc.
Articles |
Effectiveness of Enalapril Versus Nifedipine to Antagonize Blood Pressure and the Renal Response to Endothelin in Humans
From the Department of Nephrology and Hypertension, University Hospital Utrecht (the Netherlands).
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Abstract Endothelin-1 infusion into humans to obtain pathophysiological plasma levels causes mild hypertension, strong renal vasoconstriction, and sodium retention. We studied whether oral use of the angiotensin-converting enzyme inhibitor enalapril (20 mg BID) or the calcium channel blocker nifedipine (60 mg OD) could attenuate these effects of endothelin-1 (2.5 ng/kg per minute for 90 minutes) in six healthy volunteers. Endothelin infusion alone increased plasma endothelin from 3.0±0.3 to 8.8±1.0 pmol/L (P<.05). Blood pressure rose by approximately 6 mm Hg (P<.05). Renal function changes were relatively large: Renal blood flow decreased from 941±76 to 729±118 mL/min (P<.05) and glomerular filtration rate from 105±9 to 92±10 mL/min (P<.05); renal vascular resistance increased from 101±7 to 152±20 mm Hg · min/L (P<.05); and sodium excretion decreased from 158±54 to 86±27 µmol/min (P<.05). Enalapril treatment reduced blood pressure from 94±2 to 87±3 mm Hg (P<.05) and prevented the hypertensive response to endothelin. By contrast, despite renal predilatation, endothelin reduced renal blood flow strongly (from 1063±127 to 763±100 mL/min, P<.05), although maximal renal vascular resistance was numerically lower (124±11 mm Hg · min/L) than during endothelin alone (P<.05). Glomerular filtration rate fell from 118±11 to 108±11 mL/min (P<.05). Enalapril did not alter the antinatriuretic effect of endothelin. Nifedipine did not affect blood pressure but prevented the increase caused by endothelin. The endothelin-induced fall in renal blood flow (from 1084±100 to 888±65 mL/min, P<.05) was less than during endothelin infusion alone (P<.05), and maximal renal vascular resistance (111±7 mm Hg · min/L) was lower than in both other experiments (P<.05), whereas glomerular filtration rate was maintained. Nifedipine increased basal sodium excretion (P<.05), which compensated for the decrease observed during superimposed endothelin infusion. In conclusion, both enalapril and nifedipine can counteract the hypertensive effect of endothelin, but nifedipine is more effective in antagonizing the renal effects of endothelin.
Key Words: endothelins • angiotensin-converting enzyme inhibitors • calcium channel blockers • renal circulation
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Introduction |
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We recently reported strong sodium retention and renal vasoconstriction during pathophysiological increments in plasma endothelin after administration of exogenous endothelin.1 2 The reduction in renal perfusion may even occur at endothelin doses that have no effect on systemic blood pressure (BP).1 These observations are relevant, as most conditions with elevated plasma endothelin levels, such as heart failure,3 hepatorenal syndrome,4 and administration of radiocontrast agents5 and cyclosporine,6 are characterized by renal vasoconstriction and sodium retention. Although still subject to debate, endothelin has also been implicated in the pathophysiology of hypertension.7 8 Most patients with severe hypertension and end-organ damage have elevated plasma levels,9 10 and renal vasoconstriction is a hallmark of developing hypertension, even at a stage when BP is still within the normal range.11 In addition, in large conduit arteries of the renovascular bed of the spontaneously hypertensive rat, the constrictor response to endothelin was enhanced.12 These observations support the role of endothelin-induced renal vasoconstriction in the pathophysiology of hypertension and renal disease.
In view of the above, it is important to know whether antihypertensive drugs can antagonize the effects of endothelin. Since the constrictive properties of endothelin depend partly on calcium influx, calcium channel blockers were advanced as possible endothelin antagonists.13 In a preliminary study in humans, we found that short-term infusion of nifedipine caused renal vasodilatation, which compensated for the renal vasoconstrictive effects of endothelin.1 Endothelin may not have only a direct vasoconstrictive effect. Endothelin has been shown to increase renin release in vivo14 15 and to accelerate in a dose-dependent way the formation of angiotensin II (Ang II) by stimulating Ang I–converting enzyme (ACE) activity.16 Moreover, Ang II probably potentiates the vasoconstrictor actions of endothelin.17 These observations suggest that interference with the actions of Ang II may attenuate the vasoconstrictive effects of endothelin. In agreement with this hypothesis, ACE inhibition has been shown to prevent the hypertension caused by long-term endothelin administration in rats.18 In addition, ACE inhibition prevented most of the renal vasoconstriction after short-term endothelin administration in rats.19 20 21 However, this could not be established with Ang II receptor blockade,21 22 suggesting that the antagonism of the endothelin effects was caused by stimulation of bradykinins, nitric oxide, or both.23 Data in humans are not available.
In the present study we therefore investigated whether oral administration of the calcium channel blocker nifedipine and the ACE inhibitor enalapril can attenuate or prevent the renal effects of pathophysiological increments in plasma endothelin in humans. Besides providing basic information on the mechanism by which endothelin exerts its effects, such a comparison may also have clinical implications. To enhance the relevance of such data, we administered maintenance doses used in clinical practice for these medications.
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Methods |
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Studies were carried out in six healthy volunteers (three men and three women). Age ranged from 24 to 36 years. The protocol was approved by the University Hospital Ethics Committee for Study in Humans. After extensive explanation of the protocol, all subjects gave their written informed consent.
All subjects underwent three clearance studies (see below) during which endothelin was infused after 5 days of a diet containing 200 mmol sodium and 100 mmol potassium. Endothelin infusion was repeated after 5 days of treatment with 60 mg nifedipine GITS once daily and after 5 days of treatment with 20 mg BID enalapril during the same diet. The studies were performed with intervals of at least 7 days. The order of the studies was randomized to correct for placebo effects.
Adherence to the diet was controlled by 24-hour urine collections. Subjects took lithium carbonate (400 mg) at 10 PM on the eve 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 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 glomerular filtration rate (GFR), and 2.5% para-aminohippuric acid (PAH), for measurement of estimated renal plasma flow (ERPF), was administered, followed by continuous infusion of this solution throughout the remainder of the study. After at least 1 hour of equilibration, and only when urine osmolality was 70 mOsm/kg or less, 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, infusion of endothelin-1 (ET-1) was started through a separate antecubital vein. ET-1 (Peptide Institute Inc, Scientific Marketing Associates) was dissolved in Haemaccel (Behring Pharma, Hoechst Holland NV) and administered for 15 minutes in a dose of 0.5 ng/kg per minute. When no adverse effects were noticed during this infusion period, endothelin was infused for another 75 minutes in a dose of 2.5 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 45 and 75 minutes after the start of the infusion, and at 45 minutes during recovery. Plasma renin activity (PRA) and atrial natriuretic peptide (ANP) were measured in blood samples drawn at baseline.
BP and heart rate were recorded at 5-minute intervals during the clearance studies with an automatic oscillometer device (Omega 2000, Invivo Research Laboratory Inc). All blood and urine samples were analyzed for sodium (Corning M480 flame photometer), lithium (Perkin-Elmer 3030 atomic absorption spectrophotometer), and inulin and PAH by photometry, as described previously.24 25 PRA and ANP were determined by radioimmunoassay, as described previously.26 Blood samples for determination of immunoreactive endothelin were collected in prechilled potassium-EDTA tubes 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, Millipore Corp). After the cartridges had been 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 washing 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 proET-1 were 52%, 96%, and 7%, respectively. The detection limit of the assay was 0.4 pmol/L.
Calculations and Statistics
Mean arterial BP was calculated as the sum of one third of the
systolic pressure and two thirds of the diastolic pressure. Renal blood
flow (RBF) was calculated by dividing ERPF by (1-packed cell volume),
and renal vascular resistance (RVR) was calculated by dividing mean
arterial pressure by RBF. Values are presented as mean±SEM. PRA
was analyzed after logarithmic transformation. Statistical analysis
was performed by using 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 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 endothelin infusion), Infusion (the final 30-minute
urine collection during infusion, corresponding to the maximal effect),
and Recovery (the second half hour of recovery). Note that the
statistical analysis given in these tables includes all seven
30-minute periods. In the figures, each 30-minute period is
presented separately.
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Results |
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Mean 24-hour urinary sodium excretion on the days before the experiments reasonably matched sodium intake (Table 1). Enalapril treatment decreased BP and increased PRA but had no effect on plasma ANP and endothelin concentrations. Nifedipine treatment had no effect on BP and hormone measurements.
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Effects of ET-1 Infusion During Control Study
ET-1 infusion was well tolerated, and no side effects were
observed. Plasma levels of endothelin increased from 3.0±0.3 to
8.8±1.0 pmol/L at the end of the infusion period (Fig 1). This was associated with an increase in BP of 6.0±1
mm Hg (P<.05), which recovered after the infusion was
stopped (Fig 2). Heart rate did not change (average
values before and during infusion, 58±3 and 56±2 beats per minute,
respectively; Fig 2). RBF also decreased significantly, reaching the
lowest value during the final collection period of endothelin infusion
and showing partial recovery after the infusion was stopped (Fig 2).
Table 2 presents renal hemodynamic data during this
final collection period and the second half hour of recovery. Although
both GFR and ERPF decreased significantly, the fall in ERPF was
relatively greater, and filtration fraction increased. Values measured
in the second half hour of recovery were not significantly different
from baseline. Calculated RVR increased significantly and recovered
incompletely within the 1-hour recovery period. Sodium excretion
decreased progressively during endothelin infusion and recovered
afterward (Fig 3). Fractional sodium excretion decreased
parallel to sodium excretion (Table 3). This was
accompanied by decreases in lithium clearance and maximal urine flow as
well as a tendency toward a lower minimal urinary sodium concentration
(Table 3).
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), during enalapril
(
), and during nifedipine (
). Endothelin was infused for
15 minutes at 0.5 ng/kg per minute followed by 75 minutes at 2.5 ng/kg
per minute.
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Effects of ET-1 Infusion After Pretreatment With Enalapril
In this experiment, ET-1 infusion increased plasma endothelin
concentration from 2.7±0.2 to 9.1±1.8 pmol/L, comparable to increases
found during control experiments (Fig 1). BP, which decreased at
baseline, showed no increase during ET-1 infusion (Fig 2). Heart rate
did not change significantly (Fig 2). Besides lowering BP and
increasing PRA, enalapril pretreatment had effects on baseline renal
hemodynamics, in that GFR and RBF were elevated (Table 2). ERPF was
increased and RVR decreased in all subjects, but these changes did not
reach statistical significance when correction for repeated measures
was applied. In this condition, ET-1 infusion decreased GFR, which was
nonetheless maintained numerically at a significantly higher level than
during the control experiment (Table 2). The relatively large
decrements in ERPF (Table 2) and RBF (Fig 2) after ET-1 infusion
indicate that enalapril did not prevent renal vasoconstriction by
endothelin. Indeed, RVR increased to 124±11 mm Hg · min/L and
recovered incompletely in the 1-hour recovery period. However,
maximal RVR was not as high as found during endothelin infusion alone.
Baseline sodium excretion and endothelin-induced antinatriuresis were
similar to those values in the control study. There was no difference
with regard to the decrease in fractional lithium excretion and urine
flow, whereas minimal urine sodium concentration fell compared with
control ET-1 infusion.
Effects of ET-1 Infusion After Pretreatment With Nifedipine
In this experiment, ET-1 infusion increased plasma endothelin
concentration from 2.6±0.2 to 8.7±1.8 pmol/L, comparable to the
control experiment (Fig 1). Although nifedipine had not decreased basal
BP, it prevented the increase caused by endothelin (Fig 2). Basal heart
rate was increased (P<.05) but did not change during
endothelin infusion (Fig 2). Nifedipine treatment increased RBF and
tended to increase ERPF and decrease RVR. In this situation, the
endothelin infusion had no effect on GFR, and the reductions in ERPF
and RBF were significantly smaller than in the control and enalapril
experiments. RVR also increased to a lesser extent and recovered
completely within the hour after cessation of endothelin. Baseline
sodium excretion was approximately twofold higher compared with the
control and enalapril studies (Fig 3) and decreased during endothelin
infusion. However, sodium excretion remained above control baseline
values throughout the study. Similar to the other studies, the decrease
in sodium excretion was accompanied by a decrease in fractional sodium
excretion, urine flow, and minimal urinary sodium concentration (Table 3), and there was a tendency toward a lower fractional excretion of
lithium.
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Discussion |
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The present study shows that chronic ACE inhibition and calcium channel blockade are equally effective in preventing the hypertensive actions of endothelin in humans. However, ACE inhibition was considerably less effective in preventing endothelin-induced renal vasoconstriction.
Endothelin infusion caused profound renal vasoconstriction and sodium retention in humans: ERPF fell by approximately 25%, and RVR increased by approximately 50%. GFR decreased to a lesser extent, and as a result, filtration fraction increased. These hemodynamic changes were accompanied by only a slight increase in BP of approximately 6 mm Hg. Sodium excretion also fell by approximately 46%, and this antinatriuresis was accompanied by marked reductions in maximal urine flow and fractional excretion of lithium, suggesting that a part of the antinatriuretic effect of endothelin was caused by increased reabsorption in the proximal nephron.27 At the same time, there was a tendency toward a lower minimal urinary sodium concentration, which reached significance in the enalapril and nifedipine studies. Maximal urine flow fell during all three endothelin studies, indicating that endothelin can also increase sodium reabsorption in the diluting segment, that is, distal to the point of isotonicity in the medullary ascending limb of Henle's loop.28 These data are similar to the results of previous studies by us1 2 and others29 30 in which endothelin was infused in healthy humans.
Enalapril pretreatment reduced baseline BP and caused renal vasodilatation. PRA was elevated sevenfold, indicating adequate ingestion of enalapril. Enalapril was effective in preventing the hypertensive effects of endothelin. This may be a specific effect of enalapril, as pharmacological BP reduction by, for instance, clonidine could not prevent the hypertensive action of endothelin.31 In contrast, enalapril could not prevent endothelin-induced renal vasoconstriction. In fact, despite initial renal vasodilatation, endothelin decreased RBF to low values similar to those of the control study. These observations argue against the hypothesis that the effects of endothelin in the human kidney are partially mediated by activation of the Ang II system or that Ang II potentiates the vasoconstrictive action of endothelin. In contrast, the large decrease in RBF during enalapril would rather support observations of Guillon et al32 and Roubert et al,33 who found that endothelin and Ang II may attenuate the vasoconstrictive effects of the other32 by downregulation of their receptors.33
Since enalapril prevented the hypertensive effects of endothelin, maximal RVR after endothelin still remained numerically lower than that obtained in the control study. Similarly, although enalapril could not prevent the decrease in GFR after endothelin, GFR was numerically maintained at a higher level than in the control study. However, this effect is markedly different from that observed in rats and dogs,19 20 21 34 in which ACE inhibition could prevent most of the decrease in RBF and GFR. Since Ang II receptor blockade with saralasin had no effect on the renal vasoconstrictive effects of endothelin, it was hypothesized that this endothelin-antagonizing effect of ACE inhibition was due to decreased catabolism of bradykinin and subsequent nitric oxide stimulation, or stimulation of prostaglandins, rather than to inhibition of Ang II formation.23 Extrapolating this concept to the present observations in humans would imply that stimulation of vasodilator systems by ACE inhibition can counteract endothelin systemically, but not, or much less, in the kidney. In agreement with this notion, we recently demonstrated in healthy volunteers that administration of the substrate for nitric oxide synthase, L-arginine, could not prevent renal vasoconstriction during endothelin doses similar to those used in the present study, although the increase in BP after endothelin was abolished.2
Enalapril did not affect baseline sodium excretion, nor did it modify the antinatriuretic effects and changes in markers of tubular sodium handling caused by endothelin infusion. This suggests that the effects of endothelin in the distal nephron, where Ang II has no effect on sodium handling, are decisive for its effects on sodium excretion. The latter possibility would be in agreement with our previous study,2 in which L-arginine administration could not prevent the antinatriuretic effects of endothelin, although it antagonized the effect of endothelin on the proximal tubule. Alternatively, the lower baseline perfusion pressure in the enalapril-treated subjects may have enhanced the antinatriuretic effects of endothelin. However, note that despite lower baseline BP, the subjects tended to have higher sodium excretion than the control groups (Table 1), which makes this possibility less likely. The present observations are in contrast with studies in rats in which ACE inhibition attenuated endothelin-induced antinatriuresis.19 21 This modulatory effect on sodium excretion in the latter studies may be attributed to pressure natriuresis because, in contrast to the present study, BP increased after endothelin during ACE inhibition in these studies.
Long-term administration of nifedipine was effective in preventing the hypertensive action of endothelin. Endothelin could still reduce RBF, but this reduction was less pronounced compared with control endothelin infusion or endothelin infusion during enalapril, and the increment in RVR was markedly attenuated. In addition, RBF and RVR recovered completely within the first hour after infusion, whereas recovery was incomplete when endothelin was infused in the control study or during enalapril. Finally, note that GFR was maintained at preinfusion levels during endothelin. Sodium excretion decreased similarly as during control endothelin infusion, although the increased basal excretion compensated for this antinatriuretic effect of endothelin (Fig 3). This increased basal sodium excretion is an unusual finding during long-term administration of calcium antagonists35 and may reflect some short-term effect of the morning dose of nifedipine, even though we used the slow-release nifedipine GITS preparation. Overall, the present data are comparable to those obtained in our previous study in which we administered short-term infusions of nifedipine.1
The mechanism by which nifedipine modulates the effects of endothelin is not clear. It was originally suggested that endothelin might act as an endogenous ligand for the voltage-operated calcium channel.13 Although subsequent studies could not confirm such a direct effect of endothelin36 on voltage-operated calcium channels, it seems likely that calcium flux through these channels contributes to the effects of endothelin.37 Blockade of these channels by dihydropyridine-type calcium channel blockers could markedly reduce responses to endothelin in human subcutaneous resistance arteries,38 in the human forearm circulation,39 and in coronary arteries.40 However, the effectiveness of this antagonism may depend on the vascular bed studied: in isolated human omental arteries,38 calcium channel blockade was ineffective in preventing the actions of endothelin. Controversy also exists regarding the interaction of calcium channel blockade and the renal effects of endothelin. Depending on the species studied and the doses of endothelin and calcium channel blocker used, no effect41 42 as well as near-total reversal43 of endothelin-induced renal vasoconstriction has been observed. It is therefore important to notice that the present study in humans demonstrates a potential role of regular maintenance doses of the calcium channel blocker nifedipine as an antagonist of the effects of pathophysiological increments in plasma endothelin. Interestingly, this endothelin-antagonizing effect was present despite the fact that nifedipine causes counterregulatory sympathetic nervous system activation,44 as was also indicated by the tachycardia in our subjects, which probably potentiates the vasoconstrictive effects of endothelin.45 46
The relevance of our data pertains to clinical situations with high levels of plasma endothelin. Most of these conditions, such as heart failure,3 renal failure,47 hepatorenal syndrome,4 severe hypertension,9 10 and administration of radiocontrast agents5 and cyclosporine,6 are associated with renal vasoconstriction and sodium retention. The present study indicates that endothelin can contribute to this renal disturbance. Although both enalapril and nifedipine can counteract the systemic effects of endothelin, nifedipine appears to be more effective in antagonizing the renal effects of endothelin. This concept gains impetus from recent studies demonstrating renoprotective effects from calcium blockers in hypertension48 and administration of radiocontrast agents49 and cyclosporine.50
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Acknowledgments |
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This study was supported by the Dutch Kidney Foundation (grant C93.1322). A.J. Rabelink is supported by a fellowship of the Royal Dutch Academy of Sciences (KNAW).
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Footnotes |
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Reprint requests to A.J. Rabelink, MD, PhD, Department of Nephrology and Hypertension (F03.226), University Hospital Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands.
Received August 1, 1994; first decision October 3, 1994; accepted December 9, 1994.
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