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Selective ET_A Receptor Antagonism with ABT-627 Attenuates All Renal Effects of Endothelin in Humans

MARINA L. H. HONING^*,, MICHEL L. HIJMERING^*,, DAVID E. BALLARD, YONGHONG P. YANG, ROBERT J. PADLEY, PAUL J. MORRISON and TON J. RABELINK^*

^* Department of Vascular Medicine and Diabetes, University Hospital Utrecht, The Netherlands
Clinical Pharmacology Unit, Utrecht, The Netherlands
Abbott Laboratories, Abbott Park, Illinois

Correspondence to Dr. Ton J. Rabelink, Department of Vascular Medicine and Diabetes, University Hospital Utrecht, Room F03.226, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Phone: +31 30 2507329; Fax: +31 30 2543492; E-mail:T.Rabelink{at}digd.azu.nl

	Abstract

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Abstract. Endothelin (ET-1) acts as a potent vasoconstrictor in the human kidney, and this vasoconstriction could contribute to the ischemia seen in acute renal failure. In animal studies, the vasoactive properties of ET-1 are known to be ET_A receptor-and/or ET_B receptor-mediated; however, the receptor subtype involved in the human kidney remains to be defined. In a phase I, single-center, double-blind, randomized, three-period, crossover design, the effects of orally administered ABT-627, a selective ET_A receptor antagonist, on renal hemodynamics during ET-1 infusion were evaluated. Two doses of ABT-627 (5 and 20 mg) were compared with placebo and nifedipine. For each dose level of ABT-627, a cohort of nine subjects was studied. A para-aminohippuric acid/inulin clearance test was performed once at the end of each 7-d treatment period. Infusion of ET-1 significantly decreased effective renal plasma flow, GFR, sodium excretion, and urine flow. Pretreatment with 20 mg of ABT-627 significantly decreased mean arterial pressure. In constrast, 7 d of treatment with both doses of ABT-627 did not affect baseline renal parameters. However, because mean arterial pressure decreased, a tendency toward a reduction of renal vascular resistance could indeed be demonstrated. Compared with placebo, both doses of ABT-627 were equally effective in blocking all renal effects caused by ET-1 infusion. In the model of exogenous ET-1 infusion, ABT-627 had a tendency to prevent ET-1-induced renal changes more effectively compared with nifedipine. The contribution of endogenous ET-1 and the ET_A receptor in maintaining basal renal vascular tone in the human kidney is small. In addition, compared with placebo, selective ET_A receptor antagonism with both doses of ABT-627 completely prevented all renal changes caused by ET-1 infusion.

	Introduction

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Elevated plasma endothelin (ET-1) levels have been reported to play a role in the development of many renal diseases, such as ischemic, cyclosporine, and radiocontrast nephropathies (1,2,3,4,5). Sustained afferent and efferent arteriolar vasoconstriction induced by ET-1 could contribute to ischemia, as observed in acute renal failure (6,7). Besides vasoconstriction, ET-1 stimulates the development of glomerulosclerosis and interstitial fibrosis as exemplified by ET-1 transgenic mice (8). Therefore, ET-1 is an interesting target for therapy aimed at preservation of renal function (9).

ET-1 mediates its biologic effects via binding to two ET receptors: the ET_A and ET_B receptor (10). In animal studies, the constrictive and proliferative actions of ET-1 have been shown to be ET_A receptor- and/or ET_B receptor-mediated (11). In addition, ET_B receptor stimulation has also been shown to be protective, causing vasodilation through release of nitric oxide and prostaglandins, regulating water excretion, and stimulating regeneration of tubular cells after acute ischemic insults (12,13). Unfortunately, there are differences between tissues and species regarding the actions of ET-1 and both ET receptors, and the precise role of the ET_A and ET_B receptor in the human kidney remains to be defined.

The present study was designed to define the role of endogenous ET-1 in human renal physiology by using the orally active selective ET_A receptor antagonist ABT-627. To test the efficacy of ET-1 blockade by ABT-627 and to define the role of receptor subtypes involved in ET-1-induced renal changes, we challenged the human kidney with exogenous ET-1. The effects of ABT-627 will be compared with the calcium channel blocker nifedipine, because recently it was demonstrated that ET-1-induced renal changes could be prevented by nifedipine (14). In addition, previous studies have demonstrated that calcium channel blockers can also prevent cyclosporine- and radiocontrast-induced renal disease (15,16,17).

	Materials and Methods

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Study Design and Measurements
Eighteen healthy, normotensive subjects (9 men and 9 women) ranging in age from 19 to 41 yr participated in the study. The local ethics committee approved the protocol, and written informed consent was obtained from the volunteers before starting any investigation.

The study was designed as a phase I, single-center, double-blind, randomized, three-period, crossover study to evaluate the effects of orally administered ABT-627 on renal hemodynamics during ET-1 (Clinalfa, Läufelfingen, Switzerland) infusion. Two doses of ABT-627 (5 and 20 mg; Abbott Laboratories, Abbott Park, IL; molecular weight 546 g/mol, K_i ET_A = 0.034 nM and K_i ET_B = 63.3 nM) were compared with 60 mg of nifedipine OROS (Oral Osmotic System; Bayer BV, Mijdrecht, The Netherlands) as a positive control, and with placebo. At each dose level of ABT-627, a cohort of nine subjects was studied. The study was divided into three 7-d treatment periods, each separated by a 14-d washout period. During the 7-d treatment period, all subjects maintained a diet containing approximately 200 mmol sodium and 100 mmol potassium per day. Subjects were instructed to regulate their sodium and potassium intake, and certain products were allowed while other products were forbidden, i.e., no standard meals were prescribed. Adherence to the diet was monitored by a 24-h urine collection on day 6.

A para-aminohippuric acid (PAH)/inulin clearance test was performed once at the end of each treatment period. After an overnight fast and with subjects in a supine position, maximal water diuresis was induced by an oral water load of 15 ml/kg body wt, and maintained by subjects drinking amounts of water matching urinary output every half hour. The last study medication of each treatment period was administered 3 h before the start of the PAH/inulin clearance test. A priming dose of a solution containing 2.5% inulin, for measurement of GFR, and 2.5% PAH, for measurement of effective renal plasma flow (ERPF), was administered. Thereafter, this solution was infused continuously throughout the remainder of the study. After at least 1 h of equilibration, two baseline 30-min urine collections were obtained by spontaneous voiding. Blood specimens were drawn at the midpoint of each collection period from the contralateral forearm. Thereafter, infusion of ET-1, dissolved in 0.9% saline (Baxter Healthcare Ltd.), was started through a separate antecubital vein. ET-1 was administered at incremental dosages of 0.5, 1.0, and 2.0 ng/kg per min, each dose for 60 min. The last infusion period was followed by a 60-min recovery period. Throughout the entire clearance study, urine and blood sampling was continued at 30-min intervals. Samples for measurement of plasma endothelin were obtained before ET-1 infusion. Samples for determination of plasma renin and aldosterone were taken before ET-1 infusion, after 165 min of ET-1 infusion and 45 min after stopping ET-1 infusion.

Before start of oral water loading and clearance tests, BP was measured for baseline values, using an automated oscillometer device (Omega 1400, Invivo; Research Laboratory, Inc., Tulsa, OK). During the entire PAH/inulin clearance test, BP and heart rate were recorded at 5-min intervals, also using the automatic oscillometer.

All plasma and urine samples were analyzed for sodium (flame photometry). For determination of plasma and urine inulin levels, inulin was hydrolyzed to fructose and measured by photometry with indolacetic acid (18). Plasma and urine levels of PAH were determined photometrically by a chromaldehyde reaction (19). Plasma immunoreactive endothelin was measured by a modified sandwich enzyme immunoassay, using reagents and a kit from R&D Systems (Minneapolis, MN). The sensitivity of the assay was 0.95 pg/ml immunoreactive endothelin. The assay does not cross-react with ABT-627. Cross-reactivity of the assay with ET-1, ET-2, and ET-3 is 100, 45, and 14%, respectively. Plasma renin and aldosterone levels were analyzed using a specific RIA.

Calculations and Statistical Analyses
ERPF and GFR were estimated based on plasma and urine levels of PAH and inulin, respectively. Furthermore, 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 (MAP) by RBF. The MAP used in the first formula is the sum of one-third of the systolic pressure and two-thirds of the diastolic pressure. All values are presented as mean ± SEM. Values of renin and aldosterone are presented after logarithmic transformation.

Statistical analyses were performed using a crossover ANOVA, using SAS software version 6.12. The ANOVA using a crossover model includes factors for sequence, subjects nested within sequence, period, and treatment. The two active study drugs, ABT-627 and nifedipine, were compared with placebo, and ABT-627 was compared with nifedipine. Statistical significance was set at P < 0.05 (two-tailed).

	Results

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Mean values for 24-h urinary sodium and potassium excretion, body weight, MAP, and heart rate on the days before the experiments are presented in Table 1 for both groups. Treatment for 7 d with 5 mg of ABT-627 (group A) caused only a slight reduction in BP but a significant increase in heart rate. However, selective ET_A receptor antagonism for 7 d with 20 mg of ABT-627 (group B) significantly reduced MAP from 91 to 80 mmHg (P < 0.05), also associated with an increase in heart rate, indicating that endogenous production of ET contributes to the maintenance of systemic vascular constrictor tone.

Compared with placebo, plasma ET-1 levels increased significantly after 7 d of treatment with 5 and 20 mg of ABT-627 (from 2.27 to 3.63 pg/ml after treatment with 5 mg of ABT-627 and from 2.41 to 3.67 pg/ml after treatment with 20 mg of ABT-627) (P < 0.05).

Both dosages of ABT-627 were well tolerated, with headache reported as the most prominent side effect. Also, infusions of ET-1 were well tolerated, and no clinically significant adverse events during ET-1 infusion were reported. Neither treatment with ABT-627 (5 or 20 mg) nor nifedipine influenced plasma renin and aldosterone levels compared with placebo (Tables 2 and 3). In group B, there was one dropout due to noncompliance during the clearance tests.

Effects of ET-1 Infusion on Renal Perfusion after Pretreatment with ABT-627 or Nifedipine Compared with Placebo
In control experiments, infusion of ET-1 decreased ERPF and RBF significantly with a complete recovery after stopping ET-1 infusion. This decrease in renal perfusion was associated with a significant increase in RVR. Pretreatment for 7 d with 5 or 20 mg of ABT-627 did not significantly alter baseline renal parameters. However, compared with placebo, selective ET_A receptor antagonism with both doses of ABT-627 could indeed prevent the vasoconstrictive effects of exogenous ET-1 on renal perfusion (P < 0.05), although 20 mg of ABT-627 was more effective (Tables 2 and 3).

Seven days of treatment with nifedipine showed a tendency toward increased baseline renal perfusion. Because of direct vasodilator effects of nifedipine, the vasoconstrictor effects of ET-1 infusion were attenuated. However, the constrictive effects of ET-1 expressed as a percentage could not be prevented (Figure 1). In this experimental model with exogenous ET-1 infusion, there was a tendency for ABT-627 to prevent ET-1-induced renal changes more effectively when compared with nifedipine.

View larger version (18K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Effect of ABT-627 on effective renal plasma flow (ERPF) (%). Mean percent changes from baseline (average of two 30-min baseline measurements collected before endothelin [ET-1] infusion) in ERPF during ET-1 infusion after 7 d of treatment with ABT-627 (5 or 20 mg), nifedipine, or placebo. Data are shown as mean ± SEM.

Effects of ET-1 Infusion on Renal Filtration and Excretion after Pretreatment with ABT-627 or Nifedipine Compared with Placebo
ET-1 infusion in group A, but not in group B, significantly affected filtration of inulin in the kidney. Pretreatment with either dose of ABT-627 or nifedipine did not alter baseline filtration and did not affect GFR during ET-1 infusion (Tables 2 and 3). In control experiments, the anti-natriuretic effects caused by ET-1 infusion were demonstrated by a significant decrease in sodium excretion, a decrease in urine flow, and a decrease in free water clearance. The urinary osmolality remained stable throughout the experiment.

Pretreatment for 7 d with either 5 or 20 mg of ABT-627 did not significantly alter baseline sodium and water excretion. Compared with placebo, selective ET_A receptor antagonism inhibited the anti-natriuretic response to exogenous ET-1 (P < 0.05). The decrease of urinary sodium excretion and V_max was completely prevented. In addition, the decrease in free water clearance was also inhibited by ABT-627. Both doses of ABT-627 were equally effective in blocking the effects of exogenous ET-1 on natriuresis and diuresis (Tables 2 and 3).

Pretreatment for 7 d with nifedipine tended to increase baseline natriuresis and diuresis, but this difference was not significant. During ET-1 infusion, the natriuresis decreased, but because of a higher baseline, the remaining natriuresis remained in the normal range.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Endothelin infusion in humans caused profound renal vasoconstriction with sodium and water retention. These data are in agreement with the results of previous studies by us and others (7,20,21). Interestingly, although systemic infusion of 2 ng/kg per min of ET-1 had significant effects on renal perfusion, there was no significant increase in MAP during ET-1 infusion. This is in keeping with results from previous studies, indicating that the renal vasculature is more sensitive to small local changes in plasma ET-1 levels than the systemic vasculature (7,20,22).

Seven days of treatment with both doses of ABT-627 did not significantly change baseline renal hemodynamics, i.e., selective ET_A receptor inhibition had no major effects on baseline ERPF, RBF, water, or sodium handling. This finding is in keeping with the effects of acute BQ-123 infusion, a selective ET_A receptor antagonist, on human basal renal function (20). However, 7 d of treatment with the highest dose of ABT-627 did significantly decrease MAP when compared with placebo, a finding that is in agreement with other studies demonstrating that endogenous ET-1 contributes to the maintenance of systemic basal vascular constrictor tone through activation of the ET_A receptor (23,24). If ABT-627 had no effect on renal perfusion but did decrease MAP, then RVR must be lower compared with placebo. Indeed, we could demonstrate a tendency toward a lower RVR after treatment with ABT-627. In agreement with this mild decrease in RVR, some vasodilator response in the human kidney after selective ET_A receptor inhibition must be assumed. This vasodilation could be compatible with blocking the effects of endogenous ET-1 on basal renal vascular tone. It should be noted that the decrease in RVR is relatively mild when compared with the more pronounced renal vasodilator effects of angiotensin-converting enzyme inhibition in the human kidney (14). However, this should not exclude a more prominent effect of ET_A receptor inhibition on renal perfusion in disease states with high ET-1 plasma levels. We can only speculate about the effects of selective ET_A receptor antagonism on the function of the unaffected ET_B receptor. It is demonstrated that in the brachial artery, the ET_B receptor is an important stimulator for the production of the vasodilator nitric oxide (NO); thus, in theory, increased NO release could also have caused the renal and systemic vasodilation (23).

Compared with placebo, baseline plasma endothelin levels increased significantly after 7 d of treatment with both doses of the selective ET_A receptor antagonist. This is an unexpected finding, as it is generally accepted that the ET_B receptor is also an ET-1 clearance receptor (25,26). However, our finding raises the question of whether sufficient plasma levels of ABT-627 were generated such that ET_B blockade occurred. In this study, we did not measure ABT-627 plasma levels. However, in a former study performed by Verhaar et al. (unpublished data), we did measure the C_max after 8 d of treatment with 5 as well as 20 mg of ABT-627 in healthy subjects. These data suggest that it is less likely that the observed increases in circulating endothelin levels are due to antagonist actions at the ET_B receptor, because the drug levels reached are far below the inhibitory concentrations for the ET_B receptor. For example, the C_max after 8 d of treatment with 20 mg of ABT-627 was 58.1 ng/ml (31.7 nM), with 99% being protein bound, leaving 0.3 nM free to bind to the ET_B receptor, whereas the K_i of the ET_B receptor is 63.3 nM. Possible explanations for these increased ET-1 plasma levels include the following: upregulation of ET-1 expression, increased ET-1 production due to inhibition of a negative feedback mechanism, and displacement of ET-1 from its receptor site.

Compared with placebo, 7 d of treatment with both doses of ABT-627 completely prevented the decrease in ERPF and RBF caused by ET-1 infusion, suggesting that the constrictor effects of ET-1 are ET_A receptor-mediated. We were also able to reproduce our previous observations that exogenous ET-1 reduces sodium and water excretion (7). Again, both doses of ABT-627 completely inhibited the decrease in natriuresis and diuresis. Animal studies have demonstrated that ET-1 infusion may increase sodium and water excretion by stimulation of the ET_B receptor (12). However, as we infused ET-1 on top of ET_A receptor blockade, it is of interest that we could not confirm these effects of ET-1 in animals. One explanation could be that there might be a difference between receptor expression and activation in the nondiseased and diseased kidney. Animal studies have demonstrated an upregulation of the ET_B receptor during ischemic renal failure, cirrhosis, and hypertension (27,28,29). Also, maximal water diuresis may have masked any further suppression of anti-diuretic hormone actions caused by ET-1 when infused on top of ABT-627.

In the present study, systemic infusion of ET-1 had no effect on plasma concentrations of renin and aldosterone. In addition, chronic selective ET_A receptor inhibition by ABT-627 had no significant effect on baseline hormone values, despite the significant decreased MAP. In contrast, studies have demonstrated that ET-1 stimulates the production of aldosterone production in the zona glomerulosa of the adrenal gland in rats through activation of the ET_B receptor (30).

Stimulation of the ET receptors activates the phosphoinositol pathway, which consequently increases intracellular calcium through activation of voltage-dependent calcium channels, resulting in vasoconstriction (31). Indeed, it has been demonstrated that calcium channel inhibitors are capable of inhibiting ET-1-induced constriction in the human kidney (32). Our study also demonstrates that 7 d of treatment with nifedipine attenuates the absolute decrease in renal perfusion caused by exogenous ET-1 in the human kidney by increasing the absolute baseline values of ERPF and RBF. In contrast, the effects of ET-1 on renal parameters were not significantly different from placebo when expressed as a percent change from baseline, indicating that the interaction of nifedipine with ET-1 is not specific. In our model of exogenous ET-1 infusion, ABT-627 inhibited renal vasoconstriction and electrolyte excretion more potently than nifedipine (Figure 1).

In conclusion, our study demonstrates that ABT-627 is well tolerated and (compared with placebo) is capable of preventing all renal effects caused by infusion of high doses of ET-1. The vasoconstrictor, anti-natriuretic, and anti-diurectic actions of exogenous ET-1 in the human kidney seem to be ET_A receptor-mediated. High doses of ABT-627 decreased MAP, suggesting an important role for endothelin and the ET_A receptor in maintaining basal systemic vascular tone. In addition, ABT-627 had a tendency to decrease RVR, suggesting mild renal vasodilation that possibly reflects a role for endogenous ET-1 and the ET_A receptor in maintaining basal renal vascular tone. Therefore, ABT-627 could be an effective therapeutic agent in patients with renal diseases associated with increased ET-1 plasma levels.

	References

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