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(Circulation. 1995;92:106-113.)
© 1995 American Heart Association, Inc.

Articles

Role of Endogenous Endothelin-1 in Experimental Renal Hypertension in Dogs

Julian Donckier, MD, PhD; Liviu Stoleru, MD; Wataru Hayashida, MD; Henri Van Mechelen, MS; Philippe Selvais, MD; Laurence Galanti, MD; Jean-Paul Clozel, MD; Jean-Marie Ketelslegers, MD, PhD; Hubert Pouleur, MD, PhD

From the Divisions of Endocrinology and Internal Medicine (J.D., L.G.), University Hospital UCL of Mont-Godinne, Yvoir, Belgium; Departments of Physiology and Cardiology (L.S., W.H., H.V.M., H.P.) and the Unit of Diabetology and Nutrition (P.S., J.-M.K.), University of Louvain, Brussels, Belgium; and the Pharma Division (J.-P.C.), Preclinical Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Correspondence to Julian Donckier, MD, PhD, Endocrinology and Internal Medicine, University Hospital of Mont-Godinne, 5530 Yvoir, Belgium.

	Abstract

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Background Endothelin-1, a vasoconstrictive peptide released by endothelium, may be involved in the pathophysiology of hypertension. The goal of the present study was to evaluate the role of endogenous endothelin-1 in renal hypertension in dogs. The model of hypertension consisted of silk tissue wrapping of the left kidney, which produced hypertension associated with perinephritis after 6 to 8 weeks.

Methods and Results Thirty-two anesthetized open chest dogs were studied randomly: 8 dogs with perinephritic hypertension received the nonpeptidic ET_A-ET_B receptor antagonist bosentan (group 1); 8 other hypertensive dogs received the vehicle solution (group 2); 8 healthy dogs received bosentan (group 3); and 8 healthy dogs received the vehicle solution (group 4). Bosentan was injected as an intravenous bolus (3 mg/kg) followed by a 1-hour infusion at a rate of 7 mg · kg^-1 · h^-1. In hypertensive dogs, bosentan produced a similar decrease (P=.0001) of both left ventricular systolic and mean aortic pressures, which averaged 38 mm Hg (-22% and -24%, respectively). These parameters remained unchanged with the vehicle solution. Left ventricular end-diastolic and left atrial pressures also declined significantly with bosentan (P=.0005 and P<.05, respectively). Left ventricular lengths tended to decrease. The other cardiovascular parameters (heart rate, peak [+]dP/dt, time constant of relaxation, and coronary vascular resistance) did not change significantly. In healthy dogs, bosentan decreased mean aortic pressure by 19 mm Hg (P=.004). Vehicle solution had no effect. Plasma endothelin-1 levels, similar under basal conditions in healthy and hypertensive dogs, increased 30-fold with bosentan (P=.0001).

Conclusions Specific endothelin-1 receptor antagonism markedly lowers blood pressure in experimental hypertension but is less effective on blood pressure of healthy animals. This suggests that endothelin-1 plays a role in the pathophysiology of hypertension but contributes to a lesser extent to the maintenance of normal blood pressure. This role of endothelin-1 is unrelated to its plasma levels. The increase of plasma endothelin-1 with bosentan, due either to a displacement of endothelin-1 from its receptor or to a feedback mechanism, does not prevent this blood pressure reduction.

Key Words: endothelin • hypertension • kidneys

	Introduction

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Endothelin-1, a 21-amino-acid peptide produced by vascular endothelium,¹ is endowed with vasoconstrictive, inotropic, and mitogenic properties.^{1 2 3 4 5} Exogenous administration of endothelin-1 results in a biphasic response characterized by a transient vasodilation followed by a sustained vasoconstriction.⁶ This response has been attributed to stimulation of two subtypes of endothelin receptors: the ET_A receptor, mediating vasoconstriction, and the ET_B receptor, causing endothelium-dependent vasodilation (through a release of endothelium-derived relaxing factor [EDRF] and/or prostacyclin).^{7 8} Under certain experimental conditions with selective agonists, stimulation of ET_B receptor could induce vasoconstriction.⁹ Since the discovery of endothelin-1, research has also focused on the potential roles of this peptide in some pathological states. Although it is clear that endothelin-1 is involved in the pathophysiology of conditions such as myocardial ischemia,^{10 11} cyclosporine nephrotoxicity,^{12 13} and subarachnoid hemorrhage–induced vasospasm,^{14 15} it is questionable whether endothelin-1 would play a role in arterial hypertension. Reports on plasma endothelin-1 concentrations in hypertension have been controversial, as they were found to be either normal or slightly elevated.^{16 17 18} However, because endothelin-1 is secreted in a paracrinal way, polarized toward the smooth muscle layer of the vessel, the value of endothelin-1 measurements in plasma should be taken cautiously. This led for the search for antagonists of endogenous endothelin and, more precisely, for an antagonist of endothelin-1 receptors. Several were discovered, including one that was able to reduce blood pressure in sodium-depleted squirrel monkeys.¹⁹ Furthermore, others have reported an antihypertensive effect of a pure ET_A receptor antagonist, BQ-123, in a model of spontaneously hypertensive rats.²⁰

The present study was conducted to obtain further insight into the potential role of endogenous endothelin-1 in the pathogenesis of hypertension by using the new mixed (ET_A and ET_B) endothelin receptor antagonist, bosentan,²¹ in a model of experimental renal hypertension ("Page kidney"). As previously reported,²¹ bosentan competitively antagonized the specific binding of [¹²⁵I]endothelin-1 to ET_A receptors with an inhibitory constant (K_i) of 4.7 nmol/L and to ET_B receptors with a K_i of 95 nmol/L. Contractions induced by endothelin-1 in rat aorta (ET_A) and by the sarafotoxin S6C in rat trachea (ET_B) were competitively inhibited by bosentan (pA₂=7.2 and 6.0, respectively). The endothelium-dependent relaxation to sarafotoxin S6C in rabbit superior mesenteric artery was also inhibited (pA₂=6.7).²¹

Studies were performed in anesthetized dogs that had been acutely instrumented for cardiovascular and hormonal assessment. Bosentan was also given to healthy dogs to determine whether endothelin contributes to the maintenance of normal blood pressure.

	Methods

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Thirty-two mongrel dogs, weighing 17 to 41 kg, were studied randomly: 8 hypertensive dogs received the endothelin receptor antagonist bosentan (group 1); 8 hypertensive dogs received the vehicle solution (group 2); 8 healthy dogs received bosentan (group 3); and 8 healthy dogs received the vehicle solution (group 4).

Arterial hypertension was produced in the dogs of groups 1 and 2 by wrapping the left kidney with silk tissue. This model, a variant of cellophane wrapping initially described by Page,²² produces persistent hypertension associated with perinephritis. After general anesthesia (induced by 7 mg/kg sodium thiopental IV), intubation, and ventilation (with enflurane 2%), the animals underwent a lumbar incision under sterile conditions. The left kidney was exposed and wrapped tightly with sterile silk tissue. The animals were allowed to recover and were studied after 6 to 8 weeks. At the time of the study, they were afebrile and healthy. Basal plasma urea and creatinine concentrations were normal in hypertensive dogs and were similar to those of the healthy dogs.

Experiment Preparation
The animals were studied while they were under anesthesia (20 mg/kg sodium pentobarbital IV), intubated, and ventilated. A catheter was introduced via the femoral artery into the descending aorta for blood pressure measurement and blood sampling. The animals then underwent thoracotomy. A catheter was implanted in the left atrial appendage for measurement of left atrial pressure (LAP). A micromanometer (JSI-400, Gifila Scientific Instruments) was inserted into the left ventricle through a stab incision of the apex. The left anterior descending coronary artery (LAD) was dissected free near its origin and fitted with a Doppler flow probe (Triton Technology). A pair of piezoelectric crystals was implanted into the ventricular walls to record segment lengths (Sonomicrometer 120, Triton Technology).

Experiment Protocol
The experiment protocol is shown in Fig 1. After completion of the surgical preparation, the animals were allowed to stabilize for 20 minutes. Bosentan (synthesized at F. Hoffmann-La Roche Ltd), dissolved in 50 mL water, was injected as an intravenous bolus (3 mg/kg) followed by a 1-hour infusion at a rate of 7 mg · kg^-1 · h^-1. This dosage was chosen because it was known in preliminary experiments to inhibit all hemodynamic effects of exogenously infused endothelin-1.²³ The specificity of bosentan has been previously established because the binding of 40 other peptides, including the vasoconstrictors angiotensin and neuropeptide tyrosine, was not affected by bosentan.²¹ Electrolyte concentrations and osmolality of bosentan solution were determined (sodium, 8±2 mmol/L; potassium, 0.11±0.03 mmol/L; osmolality, 16±5 mOsm/kg) and reproduced in the vehicle solution (sodium, 8±3 mmol/L; potassium, 0.13±0.05 mmol/L; osmolality, 15±9 mOsm/kg). Hemodynamic parameters were recorded in the basal state and then every 10 minutes throughout the experiment. Arterial blood was obtained immediately after catheter introduction in the aorta, after the 20-minute stabilization period, at the end of the infusion period, and 1 hour after discontinuation of the infusion.

View larger version (15K): [in this window] [in a new window]   Figure 1. Time line of experiment protocol corresponding to hemodynamic data and blood samples.

Data Analysis and Hormonal Measurements
Cardiovascular data were measured and analyzed as previously described.^{6 24 25} The methods for hormonal measurements (endothelin-1, catecholamines) have also been described in detail by our group.^{6 26 27} Briefly, endothelin-1 was measured after plasma extraction on Sep-Pak C₁₈ cartridges (Waters Associates) by radioimmunoassays with specific antibodies and synthetic peptides from Peninsula. A possible interference of the infused bosentan solution (at a concentration of 5 mg/mL) in the radioimmunoassay for endothelin was tested and ruled out. Plasma catecholamine concentrations were measured by high-pressure liquid chromatography with electrochemical detection and a cation exchange analytical column (Bio-Rad) as previously described.²⁸ Concentrations of urea and creatinine were determined with a Dacos Analyzer (Counter Electronics, Inc) and those of electrolytes with an Astra IV System (Beckman Instruments, Inc).

Statistical Analysis
Data were analyzed by two-way ANOVA for repeated measures. Differences between treated and control groups (the grouping factor) were assessed using F tests, and differences between the levels of the trial factor (the within factor) were assessed using conservative Greenhouse-Geisser tests. A detailed contrast analysis is provided in the tables. A value of P<.05 was considered significant. Computations were performed using SAS statistical software. Data are given as mean±SD.

	Results

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Initial Assessment
After anesthesia, intubation, and ventilation, aortic pressure (AOP) was measured in all animals. Mean AOP was significantly higher in all dogs with perinephritis than in the healthy dogs (171±19 versus 113±8 mm Hg; P<.0001).

Cardiovascular Effects of Bosentan
In the hypertensive dogs (groups 1 and 2), before the infusion was started, all cardiovascular parameters remained unchanged during a 10-minute period. Intrave- nous administration of bosentan resulted in pronounced effects on ventricular pressures and AOP. As shown in Figs 2 and 3 and Table 1, left ventricular systolic pressure (LVSP) and mean AOP decreased (P=.0001) by 38±11 (-22%) and 38±9 mm Hg (-24%), respectively, at the end of the infusion period (time 80 minutes minus 20 minutes). This effect, apparent 10 minutes after the start of the infusion, occurred progressively, became maximal 20 minutes after discontinuation of the drug, and persisted until the end of experiment (ie, as long as 60 minutes after the end of infusion). It is noteworthy that LVSP and mean AOP decreased with bosentan but remained unchanged with the vehicle solution (interaction timexdrug on both parameters; P=.0001). Bosentan administration also was associated with a 5 mm Hg decrease (P=.0005) in left ventricular end-diastolic pressure (LVEDP) that remained unchanged during infusion of the vehicle solution (interaction timexdrug on LVEDP; P=.015). Consistent with LVEDP changes, LAP also declined by 3.5 mm Hg (P<.05). With regard to ventricular dimensions, there was a tendency for end-diastolic and end-systolic lengths to decrease (P=.06 and P=.08, respectively), whereas the percent systolic shortening did not change. As indicated in Tables 1 and 2, the other cardiovascular parameters measured in groups 1 and 2 remained unchanged throughout the study.

View larger version (35K): [in this window] [in a new window]   Figure 2. Plots of left ventricular systolic and end-diastolic pressures measured in 16 healthy and 16 hypertensive dogs receiving either bosentan or placebo. Significant differences between bosentan and placebo experiments are indicated.

View larger version (36K): [in this window] [in a new window]   Figure 3. Plots of mean aortic pressure and heart rate measured in 16 healthy and 16 hypertensive dogs receiving either bosentan or placebo. Significant differences between bosentan and placebo experiments are indicated.

View this table: [in this window] [in a new window]   Table 1. Cardiovascular Parameters in Eight Hypertensive Dogs Receiving Bosentan (3 mg/kg IV Bolus Followed by 7 mg · kg-1 · h-1 Infusion) (Group 1)

View this table: [in this window] [in a new window]   Table 2. Cardiovascular Parameters in Eight Hypertensive Dogs Receiving the Vehicle Solution (Group 2)

In healthy dogs (groups 3 and 4), as shown in Figs 2 and 3 and Table 3, administration of bosentan also produced a decrease by 19±7 mm Hg in mean AOP (P=.0044). As in the hypertensive dogs, the mean AOP did not change with the vehicle (interaction timexdrug on mean AOP; P=.0001). This reduction in mean AOP with bosentan was, however, less pronounced in healthy dogs than in hypertensive dogs (interaction timexgroup on mean AOP; P=.0002). There also was a tendency for LVSP to decrease with bosentan (P=.057). As shown in Tables 3 and 4, the other cardiovascular parameters remained unchanged both during bosentan and vehicle solution administration.

View this table: [in this window] [in a new window]   Table 3. Cardiovascular Parameters in Eight Healthy Dogs Receiving Bosentan (3 mg/kg IV Bolus Followed by 7 mg · kg-1 · h-1 Infusion) (Group 3)

View this table: [in this window] [in a new window]   Table 4. Cardiovascular Parameters in Eight Healthy Dogs Receiving the Vehicle Solution (Group 4)

Hormonal Effects of Bosentan
Fig 4 illustrates plasma endothelin-1 concentrations in healthy and hypertensive dogs during administration of either bosentan or vehicle solution. Basal plasma endothelin-1 was detectable in all dogs, but levels were not different between healthy and hypertensive dogs. The surgical procedure did not influence basal levels. No correlation was found between basal endothelin-1 levels and mean AOP. Surprisingly, plasma endothelin-1 concentrations increased approximately 30-fold during bosentan infusion in both healthy and hypertensive dogs (P=.0001). This effect strongly contrasted (P=.0001) with the slight rise (twofold) occurring with the vehicle solution. No correlation was found between the change in plasma endothelin-1 and that of mean AOP during bosentan administration.

View larger version (20K): [in this window] [in a new window]   Figure 4. Plots of plasma endothelin-1 concentrations in 16 healthy and 16 hypertensive dogs receiving either bosentan or placebo. Significant differences between bosentan and placebo experiments are indicated.

Plasma epinephrine and norepinephrine were also measured in the four groups throughout the experiment. No significant differences were found between the groups, and no changes occurred with time. For example, basal levels of plasma epinephrine and norepinephrine were 18±17 and 169±90 pg/mL in healthy dogs and 11±5 and 114±81 pg/mL in hypertensive dogs, respectively. After a 1-hour infusion of bosentan in hypertensive dogs, epinephrine and norepinephrine levels were 76±98 and 102±78 pg/mL, respectively.

	Discussion

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The present study shows that antagonism of endogenous endothelin-1 produces marked decreases in aortic and ventricular systolic pressures in hypertensive dogs. These decreases persist for at least 1 hour after discontinuation of the drug, which could be explained by the 3-hour half-life of bosentan (M. Clozel, personal communication, 1994). Although systemic vascular resistances were not determined, it is likely that these changes resulted from peripheral vasodilation rather than from a depression in myocardial function. A significant decrease in filling pressures, as assessed by LVEDP and LAP, was observed. Both end-diastolic and systolic volumes also tended to decrease. Finally, indexes of cardiac performance, such as peak (+)dP/dt or myocardial segmental shortening, remained unchanged. The decrease in mean AOP in hypertensive dogs, which averaged 38 mm Hg, clearly suggests that endogenous endothelin-1 might play a role in the pathogenesis of renal hypertension. This role of endothelin-1 is even more substantiated by the fact that the magnitude of the decrease in blood pressure with bosentan is greater than that which we observed in another study using an angiotensin-converting enzyme inhibitor or an angiotensin II antagonist (average decrease, 25 mm Hg) (unpublished data). The important contribution of endothelin-1 could be explained by its physiological role as a final effector, acting at the vessel level but stimulated by several factors, such as angiotensin II or epinephrine. In our model of hypertension, angiotensin II at least might be a stimulus for local endothelin production, as demonstrated in cultured vascular endothelial or mesangial cells.^{29 30} In another model of hypertension, the spontaneously hypertensive rat, other authors also underlined the potential role of endothelin in hypertension by demonstrating an antihypertensive effect of an ET_A receptor antagonist, BQ-123.²⁰ In addition to this study, we used a mixed ET_A/ET_B receptor antagonist. This is important since the ET_B receptor may also mediate vasoconstriction under certain conditions.⁹ Although endothelin-1 could have a functional role in hypertension as a vasoconstrictor, it could also be involved by its mitogenic effects in the structural changes in the blood vessel wall associated with hypertension. Indeed, endothelin-1 has been shown to induce proliferation of vascular smooth muscle. Furthermore, it is able to induce hypertrophy of cardiomyocytes.^{5 31} Previously, authors demonstrated increased production of endothelin-1 in hypertrophied rat heart due to pressure overload.³² Others have shown that angiotensin II–induced hypertrophy of cultured rat cardiomyocytes was partially blocked by the endothelin receptor antagonist BQ-123.³³ More recently, the same authors demonstrated in vivo in rats that BQ-123 blocked cardiac hypertrophy provoked by hemodynamic overload.³⁴

Although endothelin appears to be a good candidate for mediating hypertension, the possibility of other changes in endothelial function must be addressed. In animal models of hypertension, there has been evidence that the release of EDRF or nitric oxide could be impaired.³⁵ This point, however, has been controversial, and in contrast with previous reports, a recent study showed preserved endothelium-dependent vasodilation in patients with essential hypertension.³⁶ As recently suggested, it is also possible that dysfunction of the EDRF pathway could be a secondary event rather than an initiator of hypertension.³⁷ The question of a possible influence of anesthesia must be raised. Evidently, anesthesia is known to abolish reflexes, so that can explain the absence of reactive tachycardia or catecholamine release to vasodilation in our experiments.

Furthermore, the hypotensive action of anesthesia may, by itself, trigger compensatory neurohormonal stimulation, including angiotensin II and endothelin-1. Others have shown closely associated changes in plasma endothelin-1 and blood pressure during upright tilting in healthy subjects,³⁸ and the decrease in blood pressure observed in healthy dogs is also consistent with a compensatory role of endothelin-1 in the maintenance of blood pressure during anesthesia and surgery. It therefore cannot be completely ruled out, under our experimental conditions, that the greatest decrease in blood pressure in hypertensive dogs would reflect a more important role of this compensatory mechanism in hypertension rather than reflect the role of endothelin-1 as a primary determinant of the elevated blood pressure.

Another interesting finding of the present study is the observation of similar plasma endothelin concentrations in hypertensive and healthy dogs, under basal conditions. How can these normal plasma endothelin levels in hypertensive dogs be reconciled with a pathophysiological role of endothelin in hypertension? One hypothesis is that endothelin-1 is mainly secreted in a paracrinal way in the subendocardial layer and that the plasma levels, representing only the "spillover," are not indicative of a local overproduction. In this respect, determination of preproendothelin mRNA in tissues would provide a better estimation of a local increase in the peptide production. The possibilities of an upregulation of endothelin receptors or of a postreceptor sensitization must also be addressed. Bosentan induced a marked increase in plasma endothelin-1 that was equal in the hypertensive and normotensive dogs. This increase, which has also been observed in rats,³⁹ could be due to displacement of endothelin from ET_B receptors or to a feedback mechanism whereby receptor antagonism entails increased endothelin secretion. We favor the first hypothesis as endothelin, unlike the atrial natriuretic factor, is not stored in secretory granules but rather is synthesized "de novo."⁴⁰ The possible interference of bosentan in endothelin radioimmunoassay has been tested and ruled out.

In conclusion, the present study shows that specific endothelin antagonism markedly lowers blood pressure in experimental hypertension but is less effective with normal blood pressure. This suggests that endothelin-1 might play a role in the pathophysiology of hypertension. Additional long-term studies, performed in conscious animals and in humans, are required to confirm this effect.

	Acknowledgments

 
This work was supported by grant 3.4577.90 from the Fonds National de la Recherche Scientifique, by a grant from the Bekales Foundation 1994, and by a grant from the Fonds de Développement Scientifique 1993 (UCL), Brussels, Belgium. We thank M. Durant for her expert secretarial help and P. Lison for her technical assistance in the radioimmunoassay laboratory.

Received August 22, 1994; revision received December 8, 1994; accepted December 18, 1994.

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