β-Adrenoceptor antagonists are commonly used in the therapy of hypertension, coronary heart disease (1), and mainly during the last few years, in the treatment of chronic heart failure (2). However, it is still not clear whether the use of β-adrenoceptor antagonists with intrinsic sympathomimetic activity (ISA) may have any advantages over β-adrenoceptor antagonists without ISA, and which β-adrenoceptor subtype mediates the effects of β-adrenoceptor antagonists with ISA.
Previous studies showed that, in healthy volunteers, long-term use of the nonselective β-adrenoceptor antagonist without ISA propranolol increased lymphocyte β2-adrenoceptor density (3-7); similar effects were obtained with the β2-adrenoceptor selective antagonist ICI 118,551 (8), whereas β1-adrenoceptor-selective antagonists without ISA like bisoprolol (8,9) or atenolol (7) did not affect lymphocyte β2-adrenoceptor density. On the other hand, β-adrenoceptor antagonists with ISA, nonselective (pindolol, mepindolol, bopindolol) or β1-adrenoceptor selective (celiprolol) decreased lymphocyte β2-adrenoceptor density (5,6,9,10), indicating that the ISA of β-adrenoceptor antagonists might be a β2-adrenoceptor agonistic component. However, the β1-adrenoceptor-selective antagonists with ISA, epanolol (ICI 141 292), (11) and xamoterol (12), did not decrease lymphocyte β2-adrenoceptors. In addition, all β-adrenoceptor antagonists with ISA caused positive chronotropic effects in the spontaneously beating right atrium of the reserpinized rat; although both β1- and β2-adrenoceptors coexist in this tissue, predominantly β1-adrenoceptors mediate the positive inotropic and chronotropic effects (13,14), whereas the contribution of β2-adrenoceptors is rather small (15). From these results, therefore, it appears that the ISA of β-adrenoceptor antagonists can be a β1- or β2-adrenoceptor agonistic component, depending on the tissue or species or both.
The human heart contains both β1- and β2-adrenoceptors that can mediate increases in heart rate and contractility both in vitro (for review, see 16) and in vivo (17-20). It is not known whether, in the human heart, β1- or β2- or β1- and β2-adrenoceptors mediate the positive chrono- and inotropic effects of β-adrenoceptor antagonists with ISA. The aim of this study was, therefore, to study the effects of β-adrenoceptor antagonists with ISA on heart rate and contractility in healthy volunteers. For this purpose, we assessed the effects of the β1-adrenoceptor antagonists with ISA celiprolol (that-according to the data from the lymphocyte studies-contains a β2-adrenoceptor ISA) and xamoterol (that-according to the data from the lymphocyte studies-contains a β1-adrenoceptor ISA) on resting heart rate and contractility (assessed a shortening of systolic time intervals (STIs) before and after pretreatment with the highly selective β1-adrenoceptor antagonist bisoprolol (21). Further to characterize the properties of celiprolol, we determined its effect (a) on isoprenaline infusion-induced changes in blood pressure, heart rate, and STIs, and (b) on resting blood pressure, heart rate, and contractility in healthy volunteers whose cardiac β2-adrenoceptors were desensitized by prolonged treatment with the β2-adrenoceptor agonist terbutaline (3 × 5 mg/day for 2 weeks; 22).
Twelve healthy male volunteers (aged 25.7 ± 0.9 years; range, 21-29 years; body weight, 74.1 ± 2.5 kg; range, 69-82 kg) participated in the study after having given informed written consent. All subjects were drug free; they were of average physical fitness and none exercised regularly. Normal health was established by medical history, physical examination, biochemical and hematologic screening, and electrocardiogram to exclude asthma bronchiale, diabetes mellitus, chronic pulmonary disease, hypertension, cardiac disease, and other symptoms pertaining to the cardiovascular system. All volunteers were drug free for ≥6 weeks before entry into the study. The study protocol was approved by the Ethical Committee of the University of Halle-Wittenberg.
We performed this study in two parts: In the first part (Fig. 1), we assessed in a single-blinded, placebo-controlled, cross-over design in six volunteers (mean age, 26 ± 1 years; range, 21-29 years) cardiovascular effects of celiprolol (200, 600, and 1,200 mg, p.o.) or xamoterol (100 and 200 mg, p.o.). The celiprolol experiments (Fig. 1A) lasted for 8 h; cardiovascular effects were assessed in the first 3 h every 30 min, thereafter every 60 min. In the xamoterol experiments (Fig. 1A, lasting also 8 h), cardiovascular effects were assessed in the first 3 h at every 20 min, and thereafter at every 60 min. To study the effects of bisoprolol on celiprolol- or xamoterol-induced cardiovascular effects, volunteers were administered 15 mg bisoprolol 2 h before and 10 mg bisoprolol 1 h after celiprolol (600 mg) or xamoterol (200 mg) intake (Fig. 1B). To study the effects of celiprolol on isoprenaline infusion-induced cardiovascular effects (Fig. 1C), isoprenaline was intravenously infused in doses of 3.5, 7, 17, and 35 ng/kg/min for 10 min each (for details, see 22). One hour after the end of the infusion, volunteers were treated with 600 mg celiprolol; 3 hours after the celiprolol intake, the isoprenaline infusion was repeated. Cardiovascular effects were assessed in the last 5 min of each isoprenaline dose step. Between each study day, there was a ≥8 days washout period for each volunteer.
In the second part of the study, we assessed in an open design in six volunteers (mean age, 25.3 ± 0.7 years; range, 23-29 years), the cardiovascular effects of celiprolol (600 mg) before and after 2 weeks' treatment of the volunteers with 3 × 5 mg/day (7 a.m., 2 and 9 p.m.) terbutaline, p.o. First terbutaline intake was in the evening (9 p.m.) after the celiprolol experiments; last terbutaline intake was on day 15 at 7 a.m. (i.e., 1 h before celiprolol administration). The time schedule for assessment of cardiovascular effects was identical to that in the first part of the study.
All experiments were performed with the subjects in supine position in a quiet air-conditioned room and after an almost identical time schedule: after arrival in the clinical laboratory at 7:15 a.m. and after affixment of the instruments, indwelling polythene catheters were positioned in an antecubital vein of the right arm (for blood samples) and-in the isoprenaline experiments-of the left arm (for infusion). After ≥30 min of rest baseline hemodynamic values (for blood pressure, heart rate, and STIs) were determined. In all studies lasting for 8 h, a small meal was given to the volunteers 3 and 5 h after first drug application.
Systolic and diastolic blood pressure was measured with a standard mercury sphygmomanometer (Erkameter; Richard Kallmeyer, Bad Tälz, Germany). Baseline recordings of blood pressure (five recordings) and STIs (five cardiac cycles) were performed after 30 min of complete supine rest. STIs were obtained noninvasively according to standard techniques (23) from simultaneous recordings of an electrocardiographic (ECG) lead, a phonocardiogram and a carotid pulse tracing at a high paper speed of 100 mm/s by using a 6/12 electrocardiograph BIOSET 8000 (Hörmann Medizintechnik, Zwönitz, Germany). The following parameters were measured: RR intervals (ms) of the ECG from which heart rate (beats/min) was calculated; duration of the electromechanical systole (QS2, ms) from the beginning of the Q wave of the ECG to the first high-frequency vibrations of the second heart sound; duration of the left ventricular ejection time (LVET, ms) from the rapid upstroke to the trough of the incisural notch of the carotid pulse tracing; and duration of preejection period (PEP, ms) derived mathematically by subtracting LVET from QS2. For further details, especially for correction of QS2 for changes in heart rate (19,24,25). The QS2 corrected for heart rate is herein referred to as QS2c. Throughout the text, only data for QS2c are shown because this is the most sensitive parameter of STIs (26).
Blood samples for assessment of plasma catecholamines levels and drug plasma concentrations were withdrawn through the indwelling forearm venous catheter and were collected in ice-cold EDTA-tubes. Samples were centrifuged with 600 g for 10 min at 4°C, the plasma was removed and quickly frozen at −80°C. Plasma catecholamines were assessed by high-pressure liquid chromatography (HPLC) with fluorometric detection (for details, see 25). Xamoterol plasma levels were assessed by HPLC with fluorometric detection according to previously described methods (27). Celiprolol plasma levels were determined after liquid-liquid extraction by HPLC with UV detection; atenolol was used as internal standard. Bisoprolol plasma levels were assessed after solid-phase extraction by HPLC with fluorometric detection; metoprolol was used as internal standard.
In both study parts, the drugs used were well tolerated, and only minor adverse effects were reported. Both after 100 and 200 mg xamoterol, volunteers complained about palpitation. Sometimes the highest dose of celiprolol induced a marked finger tremor. Prolonged treatment with terbutaline induced a finger tremor as well, but the intensity decreased with the duration of intake. During isoprenaline infusion, some volunteers complained about palpitation.
For statistical analysis of differences in the baseline hemodynamic values and plasma catecholamine levels, unpaired two-tailed Student's t test was used. Celiprolol- and xamoterol-induced changes from placebo, the influence of bisoprolol on celiprolol- and xamoterol-induced alterations in cardiovascular effects, the effects of celiprolol on isoprenaline-mediated cardiac effects, and the influence of a prolonged treatment with terbutaline on celiprolol-mediated cardiovascular effects were tested for significance by an analysis of variance (ANOVA) for repeated measures (Friedman Nonparametric Repeated-Measure Test). A p value <0.05 was considered to be significant. Experimental data are expressed as the mean ± SEM of six experiments. Statistical calculations were performed by using the InSTAT program (GraphPAD software, San Diego, CA, U.S.A.).
Celiprolol tablets (Selectol) were kindly supplied by Upjohn (Heppenheim/Germany). Xamoterol tablets (Corwin) were obtained from Stuart Pharmaceuticals Ltd. (Wilmslow, Cheshire, U.K.), isoprenaline sulfate (Aleudrina) for infusion from Boehringer (Ingelheim, Germany), bisoprolol tablets (Concor) from Merck (Darmstadt, Germany) and terbutaline tablets (Bricanyl) from Astra Pharmastern (Wedel, Germany). Placebo tablets were kindly produced by our hospital pharmacy.
Cardiovascular effects of celiprolol
A single oral dose of celiprolol (200, 600, and 1,200 mg) to six healthy volunteers caused the following hemodynamic changes: an increase in heart rate (Fig. 2A), a decrease in diastolic blood pressure (Table 1), and a shortening of QS2c (Fig. 3A). Most effects could be observed within the first 3 h of the experiments and lasted throughout the study. Systolic blood pressure, however, was only minimally increased (Table 1).
Although celiprolol (200 mg) did not significantly affect plasma noradrenaline levels (153 ± 29 pg/ml vs. 155 ± 37 pg/ml, measured 3 h after drug intake; Table 2), 600 mg celiprolol increased plasma noradrenaline by 48 ± 21 pg/ml (measured 3 h after celiprolol intake; Table 2); this increase was even more pronounced after 1,200 mg celiprolol (87 ± 20 pg/ml 3 h and 73 ± 14 pg/ml 6 h after celiprolol intake; Table 2).
Celiprolol plasma levels 1 h after intake of the 200-mg dose were 0.03 ± 0.01 μg/ml; 3 h after application, 0.28 ± 0.15 μg/ml; and 6 h after application, 0.36 ± 0.04 μg/ml; for 600 mg celiprolol, plasma levels were 0.21 ± 0.13, 1.53 ± 0.48, and 1.20 ± 0.14 μg/ml; and for 1,200 mg, 2.23 ± 1.21, 3.66 ± 0.79, and 2.51 ± 0.17 μg/ml.
We next studied which β-adrenoceptor subtype might be involved in the celiprolol effects. For this purpose, we assessed the influence of the highly selective β1-adrenoceptor antagonist bisoprolol on cardiovascular effects evoked by 600 mg celiprolol. To ascertain that bisoprolol concentrations are sufficient to block completely β1-adrenoceptors throughout the experiments, we gave 15 mg orally 2 h before, and an additional 10 mg 1 h after the dose of 600 mg celiprolol; under these conditions, plasma levels of bisoprolol 3 h after celiprolol intake (i.e., a time when most celiprolol effects were maximal) were 83.5 ± 10.2 ng/ml (corresponding to a β1-adrenoceptor occupancy of >80% and a β2-adrenoceptor occupancy <5%; 21). Under these conditions, bisoprolol did not attenuate the effects of celiprolol on diastolic blood pressure (Table 1), heart rate (Fig. 2B), or shortening of QS2c (Fig. 3B); bisoprolol, however, significantly enhanced the effects of celiprolol on systolic blood pressure (Table 1) and heart rate (Fig. 2B).
Cardiovascular effects of xamoterol
A single oral dose of xamoterol (100 and 200 mg) caused a significant increase in systolic blood pressure (Table 3), a transient decrease in diastolic blood pressure (Table 3), a significant increase in heart rate (Fig. 4A), and a significant shortening of QS2c (Fig. 5A). Most effects could be observed within the first 1-2 h of the experiments and lasted-with the exception of changes in diastolic blood pressure-throughout the study.
Xamoterol plasma levels after administration of the 100-mg dose were 17.5 ± 4.7 ng/ml after 2 h, 15.7 ± 4.3 ng/ml after 3 h, and 12.2 ± 3.0 ng/ml after 4 h; for the 200-mg dose, plasma levels were 25.9 ± 6.0, 26.8 ± 4.6, and 29.8 ± 5.0 ng/ml. Xamoterol did not significantly affect plasma noradrenaline or adrenaline levels (data not shown).
Pretreatment of the volunteers with bisoprolol (15 mg, 2 h before and 10 mg 1 h after 200 mg xamoterol) significantly attenuated the xamoterol-induced increase in systolic blood pressure (Table 3), the transient decrease in diastolic blood pressure (Table 3), the xamoterol-induced increase in heart rate (Fig. 4B), and shortening of QS2c (Fig. 5B).
Effects of celiprolol on isoprenaline-induced cardiovascular changes
To find out whether celiprolol can also exert β1- or β2-adrenoceptor antagonistic properties (or both), we studied the effects of 600 mg celiprolol (i.e., a dose that caused significant increases in heart rate and contractility (see Figs. 2 and 3) on hemodynamic effects induced by the β-adrenoceptor agonist isoprenaline. Isoprenaline (3.5-35 ng/kg/min) caused dose-dependent increases in systolic blood pressure and heart rate, decreases in diastolic blood pressure, and shortening of QS2c (Fig. 6). In addition, isoprenaline significantly increased plasma noradrenaline levels [at the highest dose investigated (35 ng/kg/min), the increase was 79 ± 25 pg/ml; Table 2]. After pretreatment of the volunteers with 600 mg celiprolol, these isoprenaline effects on systolic and diastolic blood pressure, heart rate, and QS2c were completely suppressed (Fig. 6). In addition, in the presence of celiprolol, isoprenaline did not significantly affect plasma noradrenaline levels (changes from baseline, 24 ± 25 pg/ml; Table 2).
Cardiac effects of celiprolol before and after prolonged dosing of healthy volunteers with terbutaline.
In a final set of experiments, we studied the effects of celiprolol on blood pressure, heart rate, and contractility in six healthy volunteers whose cardiac β2-adrenoceptors were desensitized by prolonged treatment with the β2-adrenoceptor agonist terbutaline (3 × 5 mg/day for 2 weeks; 22). When celiprolol (600 mg) was administered to the volunteers before the terbutaline treatment, this resulted-very similar to the data described (see Table 1 and Figs. 2 and 3)-in an increase in systolic blood pressure, a decrease in diastolic blood pressure, an increase in heart rate and a shortening of the QS2c (Fig. 7). Immediately after the last terbutaline intake (day 15, 7 p.m.) the volunteers exhibited an increased resting systolic blood pressure and heart rate and a decreased resting QS2c (see legend to Fig. 7); under these conditions, celiprolol (600 mg) decreased systolic blood pressure and heart rate and did not significantly affect diastolic blood pressure and QS2c (Fig. 7). Moreover, before terbutaline treatment, celiprolol increased plasma noradrenaline levels (by 62 ± 37 pg/ml 3 h and by 51 ± 25 pg/ml 6 h after drug intake; Table 2); after the terbutaline treatment, this effect was completely abolished (changes from baseline 3 h after celiprolol, −34 ± 32 pg/ml; 6 h after celiprolol, −31 ± 30 pg/ml; Table 2).
In this study, in healthy male volunteers, the β1-adrenoceptor antagonists with ISA, celiprolol (28) and xamoterol (29), increased resting heart rate and shortened resting QS2c. Physiologically a shortening of QS2c induced by adrenergic drugs reflects a positive inotropic effect (23,26,30). Thus our data indicate that both drugs can exert in humans positive inotropic and chronotropic effects in accordance with previously reported data (31-37).
In this study we used the highly selective β1-adrenoceptor antagonist bisoprolol to subclassify the (cardiac) β-adrenoceptor subtype involved in the effects of xamoterol and celiprolol. A bisoprolol-sensitive effect is very likely due to β1-adrenoceptor stimulation, and a bisoprolol-insensitive effect is very likely due to β2-adrenoceptor stimulation (21). The results of the bisoprolol studies revealed that the (cardiac) β-adrenoceptor subtype involved differs between celiprolol and xamoterol. Bisoprolol significantly attenuated the increase in heart rate and shortening of QS2c induced by xamoterol, indicating that, at the concentrations used in this study, xamoterol is, under resting conditions, a (weak) agonist at (cardiac) β1-adrenoceptors. However, we recently showed that, in healthy volunteers, during bicycle exercise or i.v. infusion of isoprenaline, xamoterol behaves like a β1-adrenoceptor antagonist [i.e., it shifted the dose-response curves for increases in heart rate or shortening of QS2c to the right (38)], in accordance with data from the literature (34-37,39). Thus these results are in favor of the idea that the ISA of xamoterol is a β1-adrenoceptor-selective component, and this holds true also for the human heart.
In contrast to its effects on xamoterol-induced hemodynamic changes, bisoprolol did not attenuate but rather increased celiprolol-induced increases in heart rate and shortening of QS2c. We do not know the reason for this surprising bisoprolol-evoked enhancement of celiprolol effects on heart rate and QS2c; it is, however, interesting to note that DeMey et al. (32) described a similar phenomenon in healthy volunteers; these authors used 1,200 mg celiprolol and 20 mg bisoprolol and found that bisoprolol did not attenuate but rather tended to increase celiprolol-induced heart-rate increases and shortening of QS2. Nevertheless, the fact that bisoprolol-in contrast to its effect on xamoterol effects (see earlier)-did not attenuate celiprolol effects on heart rate and contractility favors the idea that-under resting conditions-celiprolol is a (weak) agonist at (cardiac) β2-adrenoceptors. Thus it may be concluded that the ISA of celiprolol is a β2-adrenoceptor agonistic component, and this holds true also for the human heart.
On the other hand, celiprolol [600 mg [i.e., the dose that caused significant increases in heart rate and contractility via (cardiac) β2-adrenoceptors] significantly antagonized i.v. isoprenaline infusion-induced increases in heart rate and shortening of QS2c. Several studies showed that the effect of isoprenaline on heart rate is mediated by β1- and β2-adrenoceptor stimulation to about the same extent (for reviews, see 16,40), whereas isoprenaline-induced increases in contractility appear to be mediated predominantly via β1-adrenoceptor stimulation (19). We cannot decide from our experiments whether celiprolol blocks β1- and β2- or selectively only β1-adrenoceptors. However, the fact that the shift to the right of the dose-response curves for increases in heart rate and shortening of QS2c were similar might favor the idea that in this dose (600 mg), the selective β1-adrenoceptor antagonist celiprolol might exert some additional β2-adrenoceptor antagonistic effects. This idea is further supported by the fact that celiprolol nearly completely abolished the increase in plasma noradrenaline levels induced by isoprenaline infusion-an effect that is entirely mediated by (presynaptic) β2-adrenoceptor stimulation (8,41-43). Furthermore, a weak β2-adrenoceptor-antagonistic property for celiprolol was also described in animal studies (44,45).
Further to characterize the ISA of celiprolol, we studied its effect before and after 2-week oral treatment of healthy volunteers with the β2-adrenoceptor agonist terbutaline. We previously showed that, in healthy volunteers, this treatment caused a subtype-selective β2-adrenoceptor desensitization: thus, after the terbutaline p.o. treatment, β2-adrenoceptor-mediated effects (as assessed by terbutaline infusion-induced increases in heart rate, shortening of QS2c, decreases in diastolic blood pressure, and increases in plasma noradrenaline) were significantly diminished (22,46). On the other hand, this terbutaline p.o. treatment did not or only marginally affect β1-adrenoceptor-mediated effects [as assessed by isoprenaline infusion-induced increases in systolic blood pressure or exercise-induced increases in heart rate (22,46)]. In this study, as shown in Fig. 7, the increase in heart rate and shortening of QS2c induced by 600 mg celiprolol had completely disappeared after the 2 weeks treatment of the volunteers with terbutaline. Moreover, under these conditions, celiprolol failed to increase plasma noradrenaline levels. One possible explanation for the lack of effect of celiprolol could be that the effects of a partial agonist are strongly dependent on the number of available functional receptors (47). Because terbutaline treatment desensitizes β2-adrenoceptors (see earlier), the number of functional β2-adrenoceptors decreases, which should lead to an attenuated effect of celiprolol. However, according to our experimental design, celiprolol was given to the volunteers 1 h after the intake of the last terbutaline tablet; under these conditions, resting heart rate was increased and resting QS2c was shortened. Thus celiprolol was given to an already activated β2-adrenergic receptor system; under these conditions, partial agonists should behave like antagonists. In fact, in this study, celiprolol decreased (the previously increased) heart rate to basal levels, which is compatible with the view that it acts as an antagonist.
In conclusion, under resting conditions, in healthy volunteers, β-adrenoceptor antagonists with ISA can exert increases in heart rate and contractility that are mediated by either (cardiac) β1-adrenoceptor (xamoterol) or (cardiac) β2-adrenoceptor (celiprolol) stimulation. Thus in the human heart, the ISA of β-adrenoceptor antagonists can be a β1- or β2-adrenoceptor agonistic component.
Acknowledgment: This work was supported by grants of the Deutsche Forschungsgemeinschaft (DFG Br 526/3-3) and Pharmacia & Upjohn Gmbh (Erlangen, Germany).
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