Original Paper Kidney Blood Press Res 2006;29:351–359 DOI: 10.1159/000097625
Received: September 18, 2006 Accepted: October 27, 2006 Published online: November 30, 2006
Vasopeptidase Inhibition Normalizes Blood Pressure and Restores Endothelial Function in Renovascular Hypertension Thomas Quaschning a Berthold Hocher b Sabine Rühl c Annette Kraemer-Guth a Johannes Tilgner d Christoph Wanner c Jan Galle c a
Department of Nephrology, University Hospital of Freiburg, Freiburg, b Center for Cardiovascular Research, Institute of Pharmacology, Berlin, c Department of Nephrology, University Hospital of Würzburg, Würzburg, and d University Hospital of Heidelberg, Heidelberg, Germany
Key Words Vasopeptidase inhibitor ACE inhibitor Renovascular hypertension Nitric oxide Endothelium Relaxation Vasoconstriction
Abstract Background/Aims: Vasopeptidase inhibitors by definition inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), therefore they may exceed the effect of ACE inhibitors in the treatment of hypertension. The present study investigated the effect of the vasopeptidase inhibitor AVE7688 in comparison to the ACE inhibitor ramipril on systolic blood pressure (SBP) and endothelial function in renovascular hypertension. Methods: Wistar-Kyoto rats with renovascular hypertension (two-kidney one-clamp-model) were randomized 2 weeks after unilateral clamping of the right renal artery for 3 weeks’ oral treatment with either AVE7688 (30 mg/kg/day), ramipril (1 mg/kg/day) or placebo. SBP was measured by the tail-cuff method and endothelium-dependent and -independent vascular function was assessed in isolated preconstricted (norepinephrine 10 –7 mol/l) aortic rings as relaxation to acetylcholine (10 –10 – 10 –4 mol/l) and sodium nitroprusside (10 –10 –10 –4 mol/l), respectively. Results: Two weeks after clamping, SBP was significantly elevated (196 8 16 vs. 145 8 8 mm Hg for
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sham-operated rats; p ! 0.01) and further increased in placebo-treated animals to 208 8 19 mm Hg. Treatment with AVE7688 and ramipril had a similar blood pressure-lowering effect (119 8 8 and 124 8 10 mm Hg, respectively; p ! 0.01 vs. placebo). Maximum endothelium-dependent relaxation was reduced in hypertensive rats (72 8 6 vs. 99 8 7% in control rats; p ! 0.05). Endothelium-dependent relaxation was restored by AVE7688 (101 8 6%) and ramipril (94 8 8%), respectively, whereas endothelium-independent relaxation was comparable in all groups. Conclusion: In renovascular hypertension the vasopeptidase inhibitor AVE7688 exhibited similar blood pressure-lowering and endothelial protective properties as compared to the ACE inhibitor ramipril. Therefore, in high renin models of hypertension, vasopeptidase inhibition may be considered an alternative treatment option to ACE inhibition. Copyright © 2006 S. Karger AG, Basel
Introduction
The beneficial effect of angiotensin-converting enzyme (ACE) inhibition has been documented in many large randomized trials for the treatment of hypertension [1, 2], after myocardial infarction [3–5] and in heart failure [6]. The HOPE (Heart Outcomes Prevention Evalua-
PD Dr. Thomas Quaschning Department of Nephrology, University Hospital of Freiburg Hugstetter Strasse 55 DE–79106 Freiburg (Germany) Tel. +49 761 130 3240, Fax +49 7664 613 196, E-Mail
[email protected]
tion) study confirmed that ACE inhibitors are vascular protective independent of their effects on blood pressure and remodeling [7]. The mechanisms involved may be related to their inhibitory effects on angiotensin formation and/or on activation of bradykinin-related effects [8]. ACE inhibitors not only prevent the formation of a potent vasoconstrictor with proliferative properties but also increase the local concentration of bradykinin and, in turn, the production of nitric oxide (NO) [9] and prostacyclin [10], which may contribute to the vascular protective effects of the ACE inhibitors. The synergistic effect of combined neutral endopeptidase (NEP) and ACE inhibition is based on the simultaneous blockade of the angiotensin II synthesis and the degradation of several vasoactive peptides including bradykinin and natriuretic peptides, which contributes to vasodilatation, diuresis and improvement of myocardial function. Thus, the development of combined vasopeptidase inhibitors represents an attractive therapeutic strategy for the treatment of cardiovascular disease, such as hypertension [11–14]. Vasopeptidase inhibition has been shown to lower blood pressure under various experimental conditions including renovascular hypertension [15], spontaneous hypertension [16, 17], deoxycorticosterone acetate-induced hypertension [17], as well as salt-sensitive hypertension [18–20]. Therefore, its beneficial effects seem to be independent of the activity of the renin-angiotensin system or the degree of salt retention [11, 21]. In spontaneously hypertensive rats, vasopeptidase inhibition significantly lowered blood pressure even when combined with experimental diabetes [16]. Correspondingly, significant reduction of blood pressure in low, normal, and high renin models of hypertension was revealed by treatment with omapatrilat, the vasopeptidase inhibitor with most preclinical and clinical data available at present [17]. Since antihypertensive effects of combined ACE/NEP inhibition exceeded those of ACE inhibition alone [22–25], vasopeptidase inhibition may advance as a promising novel option for the treatment of various forms of hypertension [26]. In salt-sensitive Dahl rats, omapatrilat, as compared with equipotent doses of the ACE inhibitor captopril, restored the impaired NO system by increasing protein levels of endothelial NO synthase and vascular nitrate levels, and normalized endothelium-dependent relaxations [18]. Since endothelial dysfunction is not only the result but also a promoter of cardiovascular disease, vasopeptidase inhibition may be beneficial in interrupting the vicious cycle of altered endothelial function. Correspondingly, in spontaneously hypertensive rats, omapa352
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trilat not only lowered blood pressure, but also improved systemic hemodynamic parameters [27]. Therefore, we designed the present study to evaluate the effect of the vasopeptidase inhibitor AVE7688 in comparison to the ACE inhibitor ramipril on endothelial function and vascular reactivity in renovascular hypertension.
Methods Animals and Study Design Three-month-old, male Wistar-Kyoto rats were kept under controlled environmental conditions with respect to temperature (20 ° C), humidity (64%) and a 12-hour night-day light cycle. Animals were fed on standard breeding rodent chow and water ad libitum. Wistar-Kyoto rats were randomly assigned to either unilateral clamping of the renal artery according to the two-kidney one-clamp (2K1C) model or sham operation (sham). Unilateral clamping of the right renal artery was performed in 60% of the animals as described [28, 29], whereas 40% underwent sham operation. For clamping of the right renal artery, a U-shaped silver clip (0.24 mm internal diameter) was placed around the right renal artery under intraperitoneal anesthesia with pentobarbital (40 mg/kg). Blood pressure was measured by the tail-cuff method [30] on day 14 after operation and animals with systolic blood pressure (SBP) of 180 mm Hg and above were included in the study. Wistar-Kyoto rats exhibiting renovascular hypertension were randomized on day 14 after unilateral clamping for 3 weeks of antihypertensive treatment. AVE7688 (30 mg/kg/day), ramipril (1 mg/kg/day) or vehicle was administered with chow for 3 weeks. In preliminary experiments, doses of AVE7688 and ramipril have been selected to lower blood pressure equipotent in this model. On day 21 of treatment (day 35 after operation), rats were euthanized and tissue harvesting was performed to evaluate vascular reaction in the organ bath as described below. Experimental protocols were conducted according to the local institutional guidelines for the care and use of laboratory animals and are in accordance with international guidelines for research animal use. Blood Pressure and Heart Rate Blood pressure and heart rate were measured by the tail-cuff method (Blood Pressure Monitor BMN-1756, Föhr Medical Instruments GmbH, Seeheim, Germany) in unanesthetized rats that underwent 4 days of extensive training to get used to this procedure [30]. For every data point, five measurements were performed and mean values of five subsequent measurements were calculated. Blood pressure and heart rate were measured on day 0 (prior to operation), 7, 14 (prior to beginning of treatment), 21, 28, and on day 35 (prior to tissue harvesting). Tissue Harvesting Rats were anesthetized with pentobarbital (40 mg/kg b.w., i.p.) and were euthanized by cervical dislocation. The aorta was isolated using a no-touch technique as described [31], removed and
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Organ Chamber Experiments Aortic rings were suspended to fine tungsten stir-ups (diameter 50 m), placed in an organ bath filled with 10 ml Krebs solution and were connected to force transducers (Föhr Medical Instruments GmbH) for isometric tension recording as described before [32]. After an equilibration period of 60 min, aortic rings were progressively stretched to their optimal passive tension (2.0 8 0.2 g) as assessed by the response to 100 mmol/l KCl in modified Krebs solution [33]. Rings were preconstricted with norepinephrine (approx. 70% of KCl 100 mmol/l) and relaxations to acetylcholine (ACH; 10 –10 –10 –5 mol/l) or sodium nitroprusside (SNP; 10 –11–10 –5 mol/l) were acquired. In additional experiments, cumulative concentration-response curves to endothelin-1 (ET-1; 10 –10 –10 –7 mol/l) were obtained. All chemical substances and drugs used in this study were purchased from Sigma Aldrich Chemical Co. (Munich, Germany) apart from ET-1 which was purchased from Calbiochem (La Jolla, Calif., USA). Calculations and Statistical Analysis Relaxations to agonists in isolated vessels are given as percent precontraction in rings precontracted with norepinephrine to about 70% of contraction induced by KCl (100 mmol/l). The contractions were expressed as a percentage of 100 mmol/l KCl-induced contractions, which were obtained at the beginning of every experiment. Results are presented as mean 8 SEM. In all experiments, n equals the number of mice per experiment. For statistical analysis, the sensitivity of the vessels to the drugs was expressed as the negative logarithm of the concentration that caused half-maximal relaxation or contraction (pD2). Maximal relaxation (expressed as a percentage of precontraction) or contraction was determined for each individual concentration-response curve by non-linear regression analysis with the use of MatLab software (Math Works Inc., Natick, Mass., USA). For comparison between two values, the unpaired Student’s t test or the non-parametric Mann-Whitney test was used when appropriate. For multiple comparisons, results were analyzed by ANOVA followed by Bonferroni’s correction [34]. Pearson’s correlation coefficients were calculated by linear regression where appropriate. A value of p ! 0.05 was considered significant.
Results
Systolic Blood Pressure SBP increased during 14 days after clamping of the right renal artery (2K1C). On day 14, animals which exhibited SBP of 180 mm Hg and above were randomly assigned to receive 30 mg/kg/day AVE7688 (2K1C + AVE7688; SBP 199 8 12 mm Hg), 1 mg/kg/day ramipril Vasopeptidase Inhibition in Renovascular Hypertension
21-Day treatment period
Operation 240 Systolic blood pressure (mm Hg)
placed immediately into cold (4 ° C) modified Krebs-Ringer bicarbonate solution (in mmol/l): NaCl 118.6, KCl 4.7, CaCl2 2.5, MgSO4 1.2, KH2PO4 1.2, NaHCO3 25.1, EDTA 0.026, and glucose 10.1. Under a microscope, vessels were rinsed with a cannula to remove residual blood cells, cleaned of adherent tissue and cut into rings 3 mm long.
*
220 200 180 160 140 120 100 0
7
14
21
28
35
Time (days) Sham + placebo Sham + AVE7688
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Fig. 1. Systolic blood pressure (tail-cuff measurements) of Wistar-
Kyoto rats after unilateral clamping of the renal artery or sham operation, respectively, at day 0. Rats were treated with either AVE7688 (30 mg/kg/day p.o.), ramipril (1 mg/kg/day p.o.), or placebo on days 14–35. Results are given as mean 8 SEM of 6 rats/ group. * p ! 0.01 vs. all other groups on days 21–35.
(2K1C + ramipril; SBP 188 8 11 mm Hg), or placebo (2K1C + placebo; SBP 196 8 16 mm Hg; fig. 1). Animals that underwent sham operation (sham) were randomized on day 14 to receive either 30 mg/kg/day AVE7688 or placebo; their SBP was not elevated on day 14 (145 8 8 mm Hg for sham + placebo vs. 139 8 9 mm Hg for sham + AVE7688; p ! 0.01 vs. 2K1C animals of any group). In contrast to sham-operated rats on placebo treatment, in 2K1C animals on placebo treatment SBP increased to 208 8 19 mm Hg on day 35 (vs. 140 8 11 mm Hg for sham + placebo; p ! 0.01; fig. 1). Treatment with ramipril or AVE7688 lowered SBP in 2K1C rats significantly and to a comparable extent (124 8 10 and 119 8 8 mm Hg respectively on day 35; p ! 0.01 vs. 2K1C + placebo for both). Treatment with AVE7688 in sham-operated animals further lowered blood pressure in normotensive animals slightly but not significantly (111 8 8 mm Hg on day 35; n.s. vs. 2K1C + AVE6788; fig. 1).
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Operation
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Fig. 2. Heart rate of Wistar-Kyoto rats after unilateral clamping
of the right renal artery or sham operation, respectively, at day 0. Rats were treated with either AVE7688 (30 mg/kg/day p.o.), ramipril (1 mg/kg/day p.o.), or placebo on days 14–35. Results are given as mean 8 SEM of 6 rats/group.
Heart Rate Heart rate did not differ significantly among the study groups (fig. 2). It was neither significantly influenced by the clamping/sham operation nor by the treatment and did not significantly vary during the 35 days of observation. Endothelium-Dependent Relaxation In rats with clamping of the right renal artery on placebo treatment (2K1C + placebo), maximum endothelium-dependent relaxation of preconstricted aortic rings to SBP was significantly reduced in comparison to shamoperated animals (72 8 6 vs. 99 8 7% of preconstriction with norepinephrine; p ! 0.05; fig. 3). Treatment with ramipril and AVE7688 completely restored endotheliumdependent relaxation (maximum relaxation 94 8 8% (2K1C + ramipril) and 101 8 6% (2K1C + AVE7688) of preconstriction with norepinephrine; p ! 0.05 vs. 2K1C + placebo; fig. 3). In sham-operated, AVE7688-treated animals, maximum endothelium-dependent relaxation did not differ significantly from sham-operated, placebotreated animals (103 8 5% of preconstriction with norepinephrine; n.s. vs. sham + placebo).
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Fig. 3. Endothelium-dependent relaxation to acetylcholine in aortic segments of Wistar-Kyoto rats after unilateral clamping of the renal artery or sham operation, respectively, at day 0. Rats were treated with either AVE7688 (30 mg/kg/day p.o.), ramipril (1 mg/ kg/day p.o.), or placebo on days 14–35. Results are given as mean 8 SEM of 6 rats/group. * p ! 0.05 vs. all other groups.
Preincubation with indomethacin did not significantly alter endothelium-dependent relaxation in any of the groups (fig. 4). Preincubation with 10–5 mmol/l L-NAME completely blunted endothelium-dependent relaxation in all groups (fig. 5). Endothelium-Independent Relaxation In contrast to endothelium-dependent relaxation, maximal endothelium-independent relaxation to the NO donor SNP was comparable in all groups (fig. 6), thus indicating that the NO-dependent intracellular signal transduction pathway was not affected in this model. Concentration-Dependent Contraction to Endothelin-1 Maximum contraction to ET-1 was similar among all groups (114 8 8% for sham + placebo, 124 + 9% for sham + AVE7688, 120 8 8% for 2K1C + placebo, 126 8 11% for 2K1C + AVE7688, 124 8 10% for 2K1C + ramipril; fig. 7). Preincubation with 10–5 mmol/l L-NAME did slightly increase contractile response to ET-1 but did not lead to differences in vasoreactivity among the groups (fig. 8). Quaschning /Hocher /Rühl / Kraemer-Guth /Tilgner /Wanner /Galle
Indomethacin 10–5 mol/l
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20 40 60 Sham + placebo 80
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Relaxation, % of contraction to norepinephrine (3 × 10–7 mol/l)
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Fig. 4. Endothelium-dependent relaxation to acetylcholine in aortic segments of Wistar-Kyoto rats after unilateral clamping of the renal artery or sham operation, respectively, at day 0. Rats were treated with either AVE7688 (30 mg/kg/day p.o.), ramipril (1 mg/ kg/day p.o.), or placebo on days 14–35. Results are given as mean 8 SEM of 6 rats/group. Aortic rings were preincubated with indomethacin 10 –5 mol/l for 30 min. * p ! 0.05 vs. all other groups.
Contraction, % of contraction to norepinephrine (3 × 10–7 mol/l)
Relaxation, % of contraction to norepinephrine (3 × 10–7 mol/l)
20 40 Sham + placebo Sham + AVE7688 2K1C + placebo
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prusside in aortic segments of Wistar-Kyoto rats after unilateral clamping of the renal artery or sham operation, respectively, at day 0. Rats were treated with either AVE7688 (30 mg/kg/day p.o.), ramipril (1 mg/kg/day p.o.), or placebo on days 14–35. Results are given as mean 8 SEM of 6 rats/group.
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Endothelin (–log mol/l)
Fig. 5. Endothelium-dependent relaxation to acetylcholine in aor-
Fig. 7. Dose-dependent contractions to endothelin-1 in aortic seg-
tic segments of Wistar-Kyoto rats after unilateral clamping of the renal artery or sham operation, respectively, at day 0. Rats were treated with either AVE7688 (30 mg/kg/day p.o.), ramipril (1 mg/ kg/day p.o.), or placebo on days 14–35. Results are given as mean 8 SEM of 6 rats/group. Aortic rings were preincubated with L-NAME 10 –5 mol/l for 30 min.
ments of Wistar-Kyoto rats after unilateral clamping of the renal artery or sham operation, respectively, at day 0. Rats were treated with either AVE7688 (30 mg/kg/day p.o.), ramipril (1 mg/kg/day p.o.), or placebo on days 14–35. Results are given as mean 8 SEM of 6 rats/group.
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L-NAME 10–5 mol/l
Contraction, % of contraction to norepinephrine (3 × 10–7 mol/l)
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0 10
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Endothelin (–log mol/l)
Fig. 8. Dose-dependent contractions to endothelin-1 in aortic segments of Wistar-Kyoto rats after unilateral clamping of the renal artery or sham operation, respectively, at day 0. Rats were treated with either AVE7688 (30 mg/kg/day p.o.), ramipril (1 mg/kg/day p.o.), or placebo on days 14–35. Results are given as mean 8 SEM of 6 rats/group. Aortic rings were preincubated with L-NAME 10 –5 mol/l for 30 min.
Discussion
Vasopeptidase inhibition is a novel treatment approach in cardiovascular disease such as hypertension and heart failure. Since the inhibition of the ACE turned out to represent a very successful principle in the treatment of hypertension in numerous large-scale clinical studies [e.g. 1, 2], their results encouraged attempts to inhibit other key enzymes in the regulation of vascular tone as well – such as NEP. Similar to ACE, NEP is an endothelial cell surface metalloproteinase, which is involved in the degradation of several regulatory peptides including the natriuretic peptides [35]. Simultaneous inhibition of ACE and NEP, vasopeptidase inhibition, has been shown to effectively lower blood pressure under various experimental [15–20] and clinical conditions [36–41]. We demonstrate for the first time that in renovascular hypertension, the vasopeptidase inhibitor AVE7688 lowers blood pressure and restores endothelial function comparable to the effect of ACE inhibition with ramipril. In Wistar-Kyoto rats with renovascular hypertension, AVE7688 completely normalizes endothelium-dependent relaxation. It furthermore does not affect vascular response to ET-1. 356
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The latter is remarkable, since NEP is involved in the enzymatic conversion of big endothelin-1 to its active form, the vasoconstrictor peptide ET-1 [42] and therefore probably may interfere with the contractile response of the vasculature to ET-1. In addition, certain NEP inhibitors are capable of inhibiting the endothelin-converting enzyme (ECE) [43] and the vasopeptidase inhibitor omapatrilat has been shown to improve reduced vascular ECE levels in a model of salt-sensitive hypertension [44], thus leading to normalization of ECE activity in this model. Interestingly, the treatment of hypertensive patients with the selective NEP inhibitor candoxatril led only to a minimal reduction of the blood pressure, whereas its combination with an ACE inhibitor caused a marked reduction [45]. These findings are in line with the data of the present study demonstrating that the dual inhibition of ACE and NEP does not exhibit effects which go beyond the endothelial benefits of ACE inhibition alone. Moreover, endothelial function seems mainly to be dependent on blood pressure since improvement of endothelium-dependent relaxation was paralleled by a similar decrease in blood pressure on treatment with either ramipril or AVE7688. Furthermore, vasopeptidase inhibition in normotensive, sham-operated animals did not substantially alter vasoreactivity (even though blood pressure was slightly lower) as compared to placebo-treated animals. Therefore, in this model, AVE7688 has benefits comparable to ramipril in respect to the improvement of endothelial function and completely normalized endothelium-dependent relaxation. This is in line with findings of beneficial endothelial effects of AVE7688 in atherosclerotic rabbits [46]. As omapatrilat before [15], AVE7688 has proven to be an effective blood pressure-lowering agent in renovascular hypertension in the present study. Since vasopeptidase inhibition may exhibit significant beneficial effects on renovascular hemodynamics and renal function [47–50] and slow progression of renal disease [51, 52], the kidney may be considered a main target organ for protective effects of vasopeptidase inhibitors. In particular AVE7688 – which has proven a favorable pharmacodynamic profile as compared with other inhibitors of the renin-angiotensin system [53] – has been demonstrated to ameliorate [54] and even prevent diabetic nephropathy [55]. AVE7688 contributed to nephroprotection by antifibrotic and anti-inflammatory effects [56] – parameters which were not evaluated in the present study. Therefore, in a variety of conditions associated with cardiovascular disease, vasopeptidase inhibition may be Quaschning /Hocher /Rühl / Kraemer-Guth /Tilgner /Wanner /Galle
an alternative treatment option to ACE inhibition. Nevertheless, to replace or extend traditional treatment concepts, novel cardiovascular drugs will have to come up with an excellent profile of beneficial effects and/or minimized side effects. Vasopeptidase inhibition has been demonstrated to be beneficial in diabetes [16], endothelial dysfunction [18], and renal failure [57], which are common conditions among cardiovascular patients. The encouraging experimental and clinical results obtained with this broad-spectrum and potent cardiovascularly active agent warrant further clinical investigation. Clinical trials on vasopeptidase inhibition in hypertension have demonstrated efficient lowering of blood pressure by this novel therapeutic principle [36–38, 57– 59]. However, on vasopeptidase inhibition, severe side effects occurred, such as a higher incidence of angioedema
as compared to ACE inhibitor treatment [41, 60]. Serious known side effects are obviously directly bound to the mechanism of vasopeptidase inhibition [60]. They therefore may hardly be avoided and may substantially limit the benefit of this therapeutic principle. Therefore, the relation of efficacy and safety will have to be evaluated carefully in large-scale clinical studies. Their future results will help to better assess whether there is a place for vasopeptidase inhibition in the treatment of cardiovascular disease. Acknowledgements AVE7688 and ramipril were provided by Aventis Deutschland GmbH. This work has been supported by a grant from Aventis Deutschland GmbH.
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