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Exbm-231-06-34 967.973

Bosentan, Sildenafil, and Their Combination MARTINE CLOZEL,*,1 PATRICK HESS,* MARKUS REY,* MARC IGLARZ,* CHRISTOPH BINKERT,* AND CHANGBIN QIU*,  *Actelion Pharmaceuticals Ltd, CH-4123 Allschwil, Switzerland; and  Department of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China The dual endothelin receptor antagonist, bosentan, and the nary vascular resistance leading to right ventricular (RV) phosphodiesterase inhibitor, sildenafil, are efficacious in ex- failure (1). Two orally available agents have been shown to perimental and clinical pulmonary hypertension (PHT). The be clinically effective. Bosentan, a dual endothelin (ET) effects of bosentan, sildenafil, and their combination wereevaluated in rats with monocrotaline (MCT)-induced PHT. A first ETA/ETB receptor antagonist, improves hemodynamics, group consisted of control rats with no MCT injection. Four increases exercise capacity, and decreases the rate of clinical other groups of rats received MCT subcutaneously and were worsening in patients with World Health Organization Class assigned to receive no treatment, 300 mg/kg/day bosentan as III or IV PAH (2, 3). This is in agreement with a key food admix, 100 mg/kg/day sildenafil in drinking water, or theircombination for 4 weeks. The doses of bosentan and sildenafil pathogenic role of ET in PAH. Sildenafil, which enhances were the maximally effective doses based on a dose-range– nitric oxide (NO) signaling by inhibition of phosphodiester- finding study. Mortality was 0%, 53%, 11%, 11%, and 0%, ase Type 5 (PDE5), was shown to improve hemodynamics respectively, in the five different groups. Bosentan and sildenafil and exercise capacity in patients with PAH, without significantly attenuated the increase in mean pulmonary arterialpressure, and the combination had an additional effect.
significantly affecting the rate of clinical worsening (4).
Similarly, bosentan, sildenafil, and, to a greater extent, their Because bosentan and sildenafil act on different targets, combination significantly reduced right ventricular (RV) hyper- combining these two therapies might provide an added trophy. Bosentan, but not sildenafil, decreased norepinephrine benefit. However, the ET and NO systems interact (5); and BNP plasma concentrations, reduced kidney weight, andnormalized systemic hemodynamics. In conclusion, bosentan therefore, the combination of drugs affecting the two and sildenafil are efficacious in rats with chronic PHT, and their pathways might not be additive. We investigated the effects combination shows an additional effect for decreasing pulmo- of the combination using the rat model of monocrotaline nary arterial pressure, reducing plasma catecholamines, main- (MCT)-induced pulmonary hypertension (PHT).
taining body weight, and reducing mortality. Exp Biol Med231:967–973, 2006 MCT, a pyrrolizidine alkaloid of plant origin (6), Key words: bosentan; endothelin; nitric oxide; pulmonary induces progressive PHT in rats after a single subcutaneous injection (7, 8). Rats exposed to MCT develop acutepulmonary vascular inflammation. Although this model maynot fully reflect the clinical situation of PAH (9), the ET system is associated with the pathogenesis of the disease in Pulmonary arterial hypertension (PAH) is an often-fatal this rat PHT model as well as in human PAH (10–12). Both disease characterized by a progressive increase in pulmo- bosentan (13, 14) and sildenafil (15) have been shown toattenuate the development of PHT in rats treated with MCT.
The objectives of this study were to compare thepharmacologic profiles of bosentan and sildenafil, and to 1 To whom correspondence should be addressed at Actelion Pharmaceuticals Ltd.,Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. Email: martine.clozel@ evaluate the effects of their combination at maximally effective doses on pulmonary arterial pressure, cardiac size,and endothelial function in MCT-induced PHT rats. The Received September 29, 2005.
Accepted November 17, 2005.
effects of the two drugs and their combination on plasmaconcentrations of ET-1, brain natriuretic peptide (BNP; Refs. 16, 17), cGMP (15, 18), and catecholamines (19) were Copyright Ó 2006 by the Society for Experimental Biology and Medicine thermostatically controlled heating table to maintain body Animals. Male Wistar rats were purchased from RCC temperature at 368C–388C. A tracheotomy tube was put in Ltd. (Fu¨llingsdorf, Switzerland) or from the Experimental place and a catheter inserted into the right jugular vein for Animal Center of the Chinese Academy of Sciences measurement of MPAP, using the procedure previously (Shanghai, China), and maintained under identical con- described by Stinger et al. (20). Measurements were ditions in accordance with local guidelines (Basel-Land- recorded for 15 mins using a PowerLab data acquisitionsystem (IOX 1.7.0 Data acquisition; Emka Technologies, schaft cantonal veterinary office or Animal Care and Use Paris, France) connected to a Dell Optiplex GX 270 Committee of the Shanghai Institute of Materia Medica, computer equipped with Datanalyst software (v.1.83.0; Chinese Academy of Sciences). All rats were housed in climate-controlled conditions with a 12:12-hr light:dark Arterial Blood Pressure Measurements in Con- cycle, and had free access to chow and water.
scious, Freely Moving Rats. For measurement of MCT Treatment. MCT (Sigma Chemicals, St. Louis, arterial blood pressure and heart rate, a subset of 25 rats MO) was administered as a single subcutaneous (sc) was surgically implanted with a pressure sensor/transmitter injection (60 mg/kg) in a volume of 3 ml/kg, and control, (model TA11PA-C40; Data Sciences, St. Paul, MN) in the age-matched rats received an equal volume of saline. These peritoneal cavity. The sensing catheter was placed in the animals were randomly assigned into experimental groups, descending aorta below the renal arteries, pointing up- and treatment was initiated immediately after MCT stream. A receiver platform (RPC-1, Data Sciences) injection, for a duration of 4 weeks.
connected the radio signal to digitized input that was then Test Compounds. Test compounds were supplied sent to a dedicated personal computer (Compaq, Deskpro, by Actelion Pharmaceuticals Ltd. (Shanghai, China and Hewlett-Packard, Geneva, Switzerland). Arterial pressures Allschwil, Switzerland). Bosentan was given as food admix, were calibrated using input from an ambient-pressure and sildenafil was given in drinking water.
reference (APR-1; Data Sciences). Two weeks after Experimental Protocols. Dose-Finding Studies implantation of the telemetry device, the rats were for Bosentan and Sildenafil. In the first study, dose- randomized into the five treatment groups (n ¼ 5 per range–finding studies were conducted to determine the group). Arterial blood pressure and heart rate measurements maximally effective doses of bosentan and sildenafil on were collected at 5-min intervals for 4 weeks.
mean pulmonary arterial pressure (MPAP) in MCT-treated ET-1, BNP, cGMP, and Catecholamine Concen- rats. Bosentan (0, 10, 30, 100, or 300 mg/kg/day as food trations. At the end of the hemodynamic experiments in admix; n ¼ 14 or 15 per dose) or sildenafil (0, 3, 10, 30, or anesthetized rats, plasma samples in 5% EDTA were 100 mg/kg/day in drinking water; n ¼ 4 or 5 per dose) was collected for determinations of ET-1, BNP, cGMP, and given for 4 weeks, and MPAP determined in anesthetized catecholamine concentrations. Plasma ET-1 concentration rats, as described below in ‘‘Hemodynamic Study in was measured using a human ET-1 immunoassay kit Anesthetized Rats.’’ Doses of 300 mg/kg/day bosentan (QuantiGlo, QET00; R&D Systems, Minneapolis, MN); and of 100 mg/kg/day sildenafil were chosen for the next BNP was measured using a rat BNP-32 enzyme immuno- study, because they were maximally effective doses, that is, assay (S-1192.001; Bachem, Heidelberg, Germany); cGMP at the plateau of the respective dose-response curves, and was measured using an enzyme immunoassay (DE0600; R&D Systems); and epinephrine and norepinephrine were Comparison and Combination of Bosentan and measured using a CATCOMBI enzyme-linked immuno- Sildenafil. After determination of maximally effective sorbent assay kit (RE58242; IBL, Hamburg, Germany).
doses of bosentan and sildenafil, a second study was Organ Weights. At the end of the study, rats were performed. Male Wistar rats (210–240 g) were randomized sacrificed. Heart, lungs, kidneys, and liver were removed into five groups: Group 1 (control), sc injection of saline and and weighed, and the ratio of organ weight to body weight no treatment (n ¼ 15); Group 2, sc injection of MCT and no (BW) was calculated. The RV and the left ventricle plus treatment (n ¼ 19); Group 3, MCT plus 300 mg/kg/day septum were separated and weighed; the ratio RV/BW was bosentan as food admix (n ¼ 19); Group 4, MCT plus 100 mg/kg/day sildenafil in drinking water (n ¼ 19); and Group Endothelial Function. Ring segments of aorta (one 5, MCT plus 300 mg/kg/day bosentan plus 100 mg/kg/day per rat; n ¼ 8–10 per group), cleaned of fat and connective tissues and 3 mm in length, were mounted between two Hemodynamic Study in Anesthetized Rats. To stainless-steel wires in 10-ml organ baths (Emka Technol- evaluate the effects of bosentan and sildenafil on the ogies). After a 30-min recovery period, stepwise increases in development of PHT in both studies, hemodynamic tension up to 2 g were applied to each segment. Two measurements were performed in anesthetized rats. Four consecutive administrations of 60 mM KCl were performed.
weeks after MCT injection, the rats were anesthetized by Preconstriction of the aortic ring was achieved with a intraperitoneal injection of 100 mg/kg thiobutabarbital-Na concentration of phenylephrine (Sigma) sufficient to reach (Inactin; Byk-Gulden, Konstanz, Germany) and placed on a approximately 70% of the tissue maximum, as determined BOSENTAN AND SILDENAFIL IN PULMONARY HYPERTENSIVE RATS Figure 1. Effect of chronic oral administration of bosentan, sildenafil, and their combination on (A) MPAP in anesthetized rats; and (B) on RVhypertrophy, measured as the ratio of RV weight to BW, 4 weeks after MCT injection. CTR, control; MCT, MCT alone; Bos, bosentan; Sil,sildenafil. þþþP , 0.001 versus control; **P , 0.01 versus MCT alone; ***P , 0.001 versus MCT alone.
with KCl. Then, each segment was tested as follows: (i) bosentan and 100 mg/kg/day sildenafil had similar effects determination of concentration-response curve for 1 nM to and decreased MPAP by 21% (42 6 2 mm Hg and 41 6 3 10 lM acetylcholine (Sigma); and (ii) determination of mm Hg; P , 0.01, respectively). Combination treatment concentration-response curve for 10 pM to 1 lM sodium caused a further decrease and reduced MPAP by 42% (31 6 2 mm Hg; P , 0.001, as compared with untreated rats).
Statistical Analysis. All data are presented as mean Arterial Blood Pressure Measurements in Con- 6 SEM. Statistical analyses were performed by analysis of scious Rats. At baseline, neither mean arterial pressure variance (ANOVA) using Statistica (StatSoft, Berikon, nor heart rate differed among the various groups. Four Switzerland) and Student-Newman-Keuls procedure for weeks after MCT injection, there were no differences in multiple comparisons. The null hypothesis was rejected heart rate between the various groups. Untreated rats when P , 0.05. To avoid a bias due to the death rate showed a significant blood pressure decrease from baseline observed in certain groups, all data missing because of early (D, À9.7 6 2.3 mm Hg), as compared with control rats (D, mortality were imputed using the worst value from each À1.5 6 2.8 mm Hg; P , 0.05). Bosentan, but neither sildenafil nor the combination, significantly prevented thisdecrease (D, À1.6 6 1.6 mm Hg; P , 0.05).
Endothelial Function. MCT-treated rats exhibited a First Study: Dose Finding. PHT had developed in marked endothelial dysfunction, characterized by a de- untreated rats 4 weeks after MCT injection, and chronic oral creased response to acetylcholine (maximal effect ¼ 71.7 6 administration of bosentan and of sildenafil dose-depend- 6.1% in MCT rats vs. 97.2 6 1.6% in controls; P , 0.001; ently reduced the increase in MPAP. The maximally and logEC50 ¼À6.94 6 0.11 in MCT rats vs. À7.44 6 0.03 effective dose of sildenafil, 100 mg/kg/day, reduced MPAP in controls; P , 0.001; Fig. 2A) without any alteration of to the same extent as 300 mg/kg/day bosentan (MPAP, 23.0 the response to sodium nitroprusside (Fig. 2B). Bosentan, 6 3.5 mm Hg and 19.8 6 1.4 mm Hg, respectively). These sildenafil, or the combination increased endothelium- doses were, therefore, chosen for the subsequent study.
dependent relaxation to acetylcholine (Fig. 2A) without modifying the response to sodium nitroprusside (Fig. 2B).
of Bosentan and Sildenafil. Mortality. Because of the ET-1, BNP, cGMP, and Catecholamine Concen- severity of the animal model, mortality was significantly trations. Four weeks after MCT injection, the mean plasma higher in the untreated MCT rats compared with the control ET-1 concentration was significantly increased as compared rats. During the 4-week treatment period and during with control rats (Table 1). Bosentan increased the mean anesthesia at the end of the treatment period, mortality plasma ET-1 concentration by 5-fold as compared with was 0%, 53%, 11%, 11%, and 0%, respectively, in the five untreated MCT rats. In contrast, sildenafil decreased the mean plasma ET-1 concentration by 50% compared with Hemodynamics. Four weeks after MCT injection, untreated MCT rats. The combination of bosentan and untreated rats exhibited higher MPAP as compared with sildenafil increased plasma ET-1 concentration, but to a controls (53 6 3 mm Hg vs. 18 6 1 mm Hg; P , 0.001; lesser extent (93% increase) than with bosentan alone. The Fig. 1). As expected, administration of 300 mg/kg/day plasma BNP concentration increased by 21% and the Figure 2. Effect of chronic oral administration of bosentan, sildenafil, and their combination on endothelium-dependent and independentrelaxation, measured in aortic ring segments isolated from rats 4 weeks after MCT injection. (A) The concentration-response curves in responseto acetylcholine (endothelium-dependent relaxation). (B) The concentration-response curves in response to sodium nitroprusside (endothelium-independent relaxation). CTR, control; MCT, MCT alone; Bos, bosentan; Sil, sildenafil. þþþP , 0.001 versus control; **P , 0.01 versus MCTalone; ***P , 0.001 versus MCT alone.
plasma cGMP concentration increased by 73% in MCT rats injection, the mean BW of untreated animals was 25% less compared with control rats (Table 1); these increases were than that of control rats (267 6 11 g vs. 357 6 9 g; P , significantly inhibited by bosentan. No significant changes 0.001). Bosentan or sildenafil significantly attenuated the in plasma BNP or cGMP concentrations were observed in decrease in BW (297 6 12 g and 304 6 7 g, respectively) rats treated with sildenafil or with sildenafil plus bosentan as and the combination had an additional effect (327 6 7 g; P compared with untreated MCT rats. Catecholamines , 0.001). Right ventricular weight expressed per BW increased in PHT rats, as shown by a 147% increase in increased significantly in MCT rats compared with control plasma epinephrine and a 41% increase in plasma rats (1.50 6 0.1 g vs. 0.48 6 0.02 g; P , 0.001). Bosentan, norepinephrine compared with control rats (Table 1).
sildenafil, or their combination for 4 weeks significantly Bosentan markedly reduced plasma norepinephrine concen- reduced RV/BW by 30%, 33%, and 37%, respectively (P , trations to values even lower than in control rats, and a 0.001 for all vs. no treatment). Similar results were obtained further decrease was observed in MCT rats treated with using the ratio RV/(LV þ septum). The ratio of lung weight bosentan plus sildenafil. There was no effect of sildenafil (LW) to BW significantly increased in MCT rats (7.5 6 0.6 alone on plasma norepinephrine concentration. The increase vs. 4.2 6 0.1; P , 0.001). Bosentan or sildenafil had no in plasma epinephrine was significantly attenuated by statistically significant effect, but the combination signifi- bosentan or the combination, but, again, sildenafil alone cantly decreased the LW (LW/BW ¼ 6.0 6 0.3; P , 0.05 as compared with untreated MCT rats). Liver weight normal- Body and Organ Weights. Baseline BW was similar ized for BW was similar to that of control rats in both in each experimental group. At 4 weeks after MCT untreated MCT rats and bosentan-treated rats. In rats treated Effect of Bosentan, Sildenafil, and Their Combination on Plasma ET-1, BNP, cGMP, and a Data are mean 6 SEM. All missing data were imputed using the worst value from each group.
þþP , 0.01; þþþP , 0.001 versus control.
*P , 0.05; **P , 0.01; ***P , 0.001 versus MCT alone.
BOSENTAN AND SILDENAFIL IN PULMONARY HYPERTENSIVE RATS with sildenafil or the combination, liver weight increased ETA/ETB antagonists (25, 26); this is not the case with (39.0 6 1.1 and 41.6 6 0.6; P , 0.001). The kidney weight selective ETA receptor antagonists (27). In contrast, (KW) to BW ratio increased in MCT-treated rats (6.84 6 sildenafil, similar to PDE5 inhibitors in general, has been 0.21 vs. 6.11 6 0.15; P , 0.01). The increase in KW was shown to stimulate sympathetic activity and increase prevented in part by bosentan (KW/BW ¼ 6.35 6 0.16; P ¼ norepinephrine concentrations (28). Both epinephrine and 0.07), but sildenafil or the combination had no effect on KW norepinephrine were further reduced when bosentan and sildenafil were combined, suggesting a further neuro-hormonal inhibition, which could possibly contribute to the survival benefit brought by the bosentan plus sildenafil The goal of this study was 2-fold: to compare the combination. Bosentan, but not sildenafil, prevented the effects of sildenafil and bosentan, and to evaluate whether decrease in mean arterial blood pressure observed in MCT- the combination of bosentan and sildenafil confers an treated rats, and the effect was partially negated by co- additional benefit for treatment of PHT. Our results show administration of sildenafil. The reductions of KW and that combination therapy may be more effective, particularly plasma BNP concentrations caused by bosentan were also for decreasing MPAP, than either agent given alone at the hindered by sildenafil co-administration. Liver weight was maximally effective dose. Our results also show that increased only in sildenafil-treated rats; this is a known bosentan and sildenafil differ in their profiles, and that species-specific effect of sildenafil (29).
bosentan, but not sildenafil, decreases catecholamines and MCT-induced PHT was associated with a decrease in BNP, reduces KW, and normalizes systemic hemodynam- endothelium-dependent but not endothelium-independent relaxation. This is in contrast with the report by Prie´ et al.
The combination of bosentan and sildenafil had (30) of decreased smooth-muscle responsiveness to NO additive effects on a number of variables, reflecting their with maintained endothelium-dependent vasodilator ca- different mechanism of action: bosentan antagonizes bind- pacity. The study by Prie´ et al., however, was performed in isolated lung preparations, which may explain the A and ETB receptors; sildenafil increases cGMP by PDE5 inhibition. Doses of bosentan and sildenafil that discrepancy. Bosentan and sildenafil had favorable effects moderately lowered MPAP, when given separately, further on endothelial function assessed ex vivo, and their lowered MPAP when given in combination. There was no combination fully normalized endothelium-dependent re- death in the combination group, whereas both bosentan and laxation. ET-1 overexpression causes endothelial dysfunc- sildenafil partially reduced the death rate as compared with tion (31), and bosentan improves endothelium-dependent untreated PHT rats. Although the study was not designed to relaxation in various animal models (32, 33), human vessels be a mortality study, these data suggest that combination (34), and clinical situations (35, 36). Sildenafil increases NO therapy was associated with a maximal survival rate. Both signaling and increases endothelium-dependent relaxation in bosentan and sildenafil inhibited the development of RV hypertrophy, and there was a nonstatistically significant Plasma concentrations of ET-1 increased in MCT rats, trend for an added benefit of combined therapy. Bosentan is consistent with a role of ET in the pathophysiology of PHT.
a potent inhibitor of cardiomyocyte hypertrophy in vitro and They further increased in bosentan-treated rats because of in vivo (21, 22), and sildenafil decreases cardiac hyper- lack of binding of ET-1, in particular to the ETB receptor, trophy by increasing cardiac cGMP content (23).
which is known to contribute to ET-1 clearance (40).
The current data with bosentan in MCT-induced PHT However, the increase in circulating ET-1 by dual receptor are in agreement with previous data obtained with bosentan antagonists is not associated with any negative effects, (13) and with another dual ET receptor antagonist, because both ETA and ETB receptors are blocked. Sildenafil, BSF420627 (14), which were shown to improve survival by enhancing NO sensitivity, may modulate ET-1 production.
and decrease RV hypertrophy in MCT-treated rats. Studies In conclusion, the results of the present study show using PDE5 inhibitors also showed a survival benefit in an additive effects of the combination bosentan plus sildenafil for decreasing MPAP, reducing plasma catecholamines, Neither bosentan nor sildenafil alone significantly maintaining BW, ameliorating lung inflammation, and reduced relative LW; however, a reduction in LW was reducing mortality. These results suggest that combination observed with the combination. The study, however, did not therapy may have added beneficial effects. In the clinical evaluate whether this effect was caused by a reduction in setting, preliminary data indicate that combining bosentan pulmonary edema, or by a decrease in pulmonary vascular and sildenafil in idiopathic PAH patients is safe and hypertrophy. Finally, there was a major effect of the effective (41). Further studies will evaluate whether combination on plasma concentrations of catecholamines, combining sildenafil with bosentan brings additional clinical norepinephrine in particular. Bosentan alone had a major effect on norepinephrine concentration. This decrease incatecholamines has been described previously with dual We thank Daniel Wanner, Hakim Hadana, Pauline Loriette, Virginie Sippel, Shuangshuang Ding, and Josiane Rein for expert technical levels increase in proportion to the extent of right ventricular assistance, and Susan Flores for her editorial support.
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