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1 Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Webster Street, Liverpool L3 2ET, UK 2 Academic Unit of Molecular Vascular Medicine, University of Leeds, Leeds LS2 9JT, UK
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(Received 13 July 2006;
accepted after revision 4 September 2006; first published online 14 September 2006)
Corresponding author J. G. Burniston: Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Webster Street, Liverpool L3 2ET, UK. Email: j.burniston{at}ljmu.ac.uk
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s) and induce cardiomyocyte apoptosis via cAMP and Ca2+ entry-dependent mechanisms, whereas, ß2-AR couple with both Gs and the pertussis toxin (PTX)-sensitive inhibitory G protein (Gi) and do not induce cardiomyocyte apoptosis in vitro (Communal & Colucci, 2005). For the most part, the observations in vitro are substantiated by studies using genetically manipulated animals, confirming that elevated ß1-AR signalling (15-fold overexpression of the ß1-AR) induces cardiomyopathy (Engelhardt et al. 1999), whereas, 60-fold overexpression of the ß2-AR is not detrimental (Liggett et al. 2000). Based on this body of evidence, there is growing interest in the therapeutic potential of ß2-AR agonists for the treatment of heart failure. For example, in addition to their more well-established anabolic effects (Yacoub, 2001; Soppa et al. 2005), ß2-agonists have been proposed as a potential anti-apoptotic therapy (Ahmet et al. 2004; Xydas et al. 2006) and a means of providing inotropic support to the failing heart (Xiao et al. 2003). It is important to recognize, however, that studies in vitro and transgenic models are not analogous to the proposed therapeutic use, in which exogenous ß2-AR agonists would be given in vivo. We have shown that administration of the ß2-agonist clenbuterol in vivo induces myocyte death in cardiac and skeletal muscle (Burniston et al. 2002; Burniston et al. 2005e). Our findings do not contradict those of studies in vitro. In fact, our work using wild-type animals confirms that apoptosis is induced by stimulation of the cardiomyocyte ß1-AR. When clenbuterol is given in vivo, however, its stimulation of ß2-AR of the peripheral vasculature and sympathetic nervous system potentiates noradrenaline release from the sympathetic varicosities, and this is sufficient to stimulate cardiomyocyte ß1-AR and induce apoptosis (Burniston et al. 2005e). Therefore, the use of exogenous ß2-agonists as a therapy for heart failure, or other chronic diseases, needs to be considered carefully.
Recently, clenbuterol (Xydas et al. 2006) and another commonly investigated ß2-AR agonist, fenoterol (Ahmet et al. 2004), have each been shown to have beneficial effects on the myocardium of animals subjected to coronary artery ligation. Since fenoterol has been reported to be a more potent anabolic agent than clenbuterol (Ryall et al. 2002), fenoterol may be the preferred therapeutic option. However, fenoterol stimulates the ß1-AR as well as the ß2-AR (Hoffmann et al. 2004), and its stimulation of the ß2-AR is selectively mediated via the Gs pathway (Xiao et al. 2003), which is similar to the pro-apoptotic ß1-AR signalling pathway. Therefore, we hypothesized that, when given to whole animals in vivo, fenoterol will be more myotoxic and have less favourable haemodynamic effects than clenbuterol. To test this hypothesis, we first measured the incidence of myocyte apoptosis in the heart and soleus muscle of animals administered equimolar doses of fenoterol, clenbuterol or isoprenaline. Then, in a second group of animals, implanted with telemetric blood pressure transducers, we measured the effects on blood pressure and heart rate of equimolar doses of fenoterol and clenbuterol.
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All experimental procedures were conducted in accordance with the Animals (Scientific Procedures) Act 1986 and according to UK Home Office guidelines. Male Wistar rats (289 ± 19 g) were bred in-house in a conventional colony, housed in controlled conditions of 20°C, 45% relative humidity and a 12 h light (06.00–18.00 h) and 12 h dark cycle, with water and food available ad libitum.
ß-Agonist-induced myocyte apoptosis
The dose dependency of ß-agonist-induced apoptosis was investigated from 0.003 to 3 mmol kg–1. Independent groups of rats (n = 6 in each group) were given single subcutaneous injections of either ß-agonist (fenoterol, clenbuterol or isoprenaline) or saline vehicle and were killed 4 h later. To investigate the ß-AR subtype mediating myocyte apoptosis, animals (n = 6–8 in each group) were given single subcutaneous injections of either 10 mg kg–1 bisoprolol (ß1-AR selective antagonist) or 10 mg kg–1 ICI 118 551 (ß2-AR selective antagonist) 1 h before injection of the most damaging dose (3 mmol kg–1) of ß-agonist. Previous experiments using this model (Tan et al. 2003; Burniston et al. 2005e) have shown that such administrations provide selective ß1- or ß2-AR antagonism, respectively.
At the end of each experiment, the rats were concussed and killed by cervical dislocation, and their heart and soleus muscles isolated. The heart was mounted apex uppermost on a cork disc, and a segment of the mid-belly of each soleus was mounted in transverse section. Muscles were snap-frozen in super-cooled isopentane and stored at –80°C, prior to cryo-sectioning (5 µm thick). Apoptosis was detected on cryosections in vitro using an anti-caspase 3 antibody (R&D Systems, Minneapolis, MN, USA) as previously described (Goldspink et al. 2004; Burniston et al. 2005c,d,e, 2006). Our previous work (Goldspink et al. 2004) and that of others (De Angelis et al. 2002) has shown that caspase 3 activity colocalizes with dUTP nick-end labelling on cryosections in vitro, and with annexin V–biotin detection of phosphatidylserine externalization in vivo (Burniston et al. 2005e), validating this method of detecting apoptosis.
The incidence of ß-agonist-induced myocyte death in the heart and soleus muscles was quantified from cryosections stained with caspase 3. Cardiomyocyte death was measured in the left ventricular subendocardium. For each heart, six to eight fields of view (x100 magnification), encompassing the entire subendocardial region (approximately 104 cells), were digitized. Positive staining (apoptosis) was differentiated from the Haematoxylin background, and the incidence of myocyte death expressed as percentage area relative to each field of view. To quantify myocyte death in the soleus, three random fields of view (x100 magnification) across each transverse section were digitized. Both injured and viable fibres were counted (> 700 fibres), and the number of damaged fibres expressed as a percentage of the total.
The haemodynamic effects of ß-agonist (fenoterol or clenbuterol) administration were investigated in a separate group of animals surgically implanted with telemetric blood pressure transducers.
Surgical procedures
Prophylactic antibiotic (2 mg kg–1 Baytril, Enrofloxacin, Bayer Healthcare, Monheim, Germany) was administered 2 h prior to surgery. Anaesthesia was induced in a chamber using 4% isoflurane in medical oxygen, and the animals were intubated (18 gauge catheter) and mechanically ventilated (
60 breaths min–1, 300 ms inspiration time) with 1.5% isoflurane. The animal's heart rate and arterial O2 saturation were monitored via pulse oximetry and their body temperature was monitored via a rectal probe and maintained using a heated mat. The abdomen was prepared, a laparotomy performed and the intestine parted and held in place with a retractor and surgical gauze. A section of the aorta (10 mm length) was isolated immediately distal to the renal bifurcation, and two lengths of suture passed underneath to allow proximal and distal occlusion. The catheter probe of the telemetric blood pressure transducer (TA11 PA-C40; Data Sciences International, St Paul, MN, USA) was introduced cranial to the distal occlusion and advanced proximally into the vessel. A small amount of tissue adhesive and a cellulose patch were used to cover the site of the catheter insertion, and the patency of the vessel and performance of the transducer verified using the telemetric receiver. The transducer body was placed in the abdominal cavity, and the incision closed in two layers, incorporating the suture rib of the transducer in the muscular wall of the abdomen. Anaesthesia was withdrawn, and each animal received fluid therapy (1.5 ml sterile saline I.P.) and was allowed immediate access to food and water. Analgesia (0.05 mg kg–1 buprenorphine, Alstoe animal health, York, UK) was given (I.M.) peri-operatively and at 12 h intervals for 48 h postoperatively.
Measurement of blood pressure and heart rate
The output from the animal's blood pressure transducer was monitored via radiotelemetry by placing the receiver underneath the animal's cage. Throughout data collection, the animals were conscious and able to move freely around their cage. The blood pressure waveform, displayed in real time, was analysed using AcqKnowledge software (Biopac systems Inc., Goleta, CA, USA) to give systolic and diastolic blood pressures and heart rate. Seven days after implanting the transducer, the animal's heart rate and blood pressure responses to different doses (0.003–3 mmol kg–1) of ß-agonist or saline were measured using a randomized cross-over design. Animals (n = 4) were given a bolus injection (I.P.) of either clenbuterol or fenoterol, and their blood pressure and heart rate responses recorded for 24 h; a 2 day wash out period was allowed before the next administration. The muscles of these animals were not harvested. At the end of each experiment, the rats were concussed and killed by cervical dislocation, and their heart and soleus muscles isolated.
Statistical analyses
Data were analysed by two-way analysis of variance, employing either an unrelated factorial design to investigate differences in the incidence of myocyte apoptosis or a repeated measures design to investigate differences in the magnitude of the haemodynamic response. In all cases, differences were considered statistically significant if P < 0.05.
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s signalling pathway (Xiao et al. 2003). These findings are in agreement with previous studies in vitro (Hoffmann et al. 2004) and clinical data (Burgess et al. 1991) that have each suggested that fenoterol stimulates both ß1- and ß2-AR. In light of this evidence, we should reappraise our classification of fenoterol as a selective ß2-AR agonist. Indeed, fenoterol-induced cardiomyocyte apoptosis (Fig. 1) may underlie the previously observed myocardial scaring after intravenous infusion of this agent (Pack et al. 1994), and it could be speculated that the similar cardiotoxicity of isoprenaline and fenoterol might also link their respective associations with the asthma mortalities of the 1960s and 1980s (Sears & Taylor, 1994; Beasley et al. 1999). In agreement with the myotoxicity data, the poorer selectivity of fenoterol for the ß2-AR was also evident in its effects on heart rate and blood pressure (Fig. 6). Fenoterol had a greater positive chronotropic effect than clenbuterol, but our data do not provide evidence for a causal link between raised heart rate and myocyte death. Studies conducted in vitro (Communal & Colucci, 2005) and our previous work in vivo (Burniston et al. 2005b,e) have each demonstrated that the myotoxic effects of ß-agonists are mediated by overstimulation of the ß1-AR and its downstream signalling cascade. The haemodynamic changes caused by clenbuterol (Fig. 6) agree well with previous data from anaesthetized rats (Jones et al. 2004) and, as opposed to fenoterol, conform to the expected paradigm for a ß2-AR selective agonist. Jones et al. (2004) also investigated the ß2-agonist pro-drug BRL-47672, reporting that it had a lesser effect on heart rate and mean arterial pressure than clenbuterol. Muscle anabolism induced by BRL-47672 (Jones et al. 2004) may be similar to that induced by clenbuterol (Rajab et al. 2000) and therefore BRL-47672 may represent a more acceptable means of inducing muscle growth. However, caution should still be advocated because BRL-47672 is metabolized to a ß2-AR agonist (Sillence et al. 1995), and the potential myotoxicity of this metabolite is unknown.
In support of previous work from our laboratory (Burniston et al. 2002, 2005a,e; Ng et al. 2002; Tan et al. 2003; Goldspink et al. 2004), skeletal myofibre death was mediated only via the ß2-AR, irrespective of the agonist administered (Fig. 3B). When the hearts from these animals were investigated, however, the effect of ß1- or ß2-AR selective antagonism was different depending on which agonist was used (Fig. 3A). Clenbuterol-induced cardiomyocyte apoptosis could be prevented by either ß1-AR or ß2-AR blockade, whereas only ß1-AR selective blockade prevented fenoterol- or isoprenaline-induced cardiomyocyte death. Previously, we have shown that clenbuterol induces cardiomyocyte death in vivo by modulating the sympathetic nervous system (Burniston et al. 2002, 2005e). Because of this, the cardiotoxicity of ß2-AR selective agonists, such as clenbuterol (Fig. 2A) or salbutamol (Pack et al. 1994), is less than that of agonists, such as fenoterol and isoprenaline, that also stimulate the cardiomyocyte ß1-AR and, thereby, directly induce cardiomyocyte death. The cardiotoxicity of isoprenaline and fenoterol was decreased, rather than increased, after ß2-AR antagonism (Fig. 3A). This effect, which is contrary to expectations from studies in vitro showing an anti-apoptotic effect of ß2-AR agonism, exemplifies the need to conduct studies, such as the present work, that replicate the intended use of these agents in vivo.
Owing to differences in body size and pharmacobiodynamics, it is not possible to extrapolate doses used here for rats to likely doses in humans. However, our haemodynamic data can be used to identify doses that induced changes within the animals' physiological range. Administration of either fenoterol or clenbuterol at doses of 0.3 mmol kg–1 or greater induced maximal increases in heart rate (563.5 ± 8.6 beats min–1; Fig. 6A), which represent the upper limit of the animals' physiological range. At the lesser dose of 0.03 mmol kg–1, fenoterol increased the animals' heart rate to 78% and clenbuterol to 42% of their heart rate reserve (maximum heart rate minus resting heart rate). At this dose, fenoterol and clenbuterol each induced significant myocyte apoptosis in the soleus muscle (Fig. 2B), while the incidence of apoptosis in the heart failed to reach statistical significance (Fig. 2A). These findings show the potential of these agents to induce myocyte death at ‘physiological’ doses and are especially worrisome with regard the illicit use of these agents. The pseudoscience associated with the abuse of ß2-agonists for promoting muscle growth suggests that the user increase the dose until the side-effects, which include muscle tremors and elevated heart rate, can no longer be tolerated (Duchanie, 1992). This form of prescription could be responsible for the reported cases of myocardial infarction in body builders abusing clenbuterol (Goldstein et al. 1998; Kierzkowska et al. 2005). Whether endogenous catecholamine release could also cause myocyte death at levels eliciting submaximal changes in heart rate cannot be extrapolated from these findings using synthetic agents but is worthy of investigation.
Our finding that fenoterol and clenbuterol cause cardiomyocyte apoptosis in healthy animals does not contradict recent work by Ahmet et al. (2004) and Xydas et al. (2006) reporting that these agents reduce cardiomyocyte apoptosis in a model of myocardial infarction induced by coronary artery ligation. When administered to normal healthy animals in vivo, ß2-agonists induce cardiomyocyte death by neuromodulation of the sympathetic nervous system and stimulation of the cardiomyocyte ß1-AR. The apparent disparity between the findings of the present work and those of Ahmet et al. (2004) and Xydas et al. (2006) is explained by the desensitization of the ß1-AR signalling pathway that is associated with this model of cardiac damage (Anthonio et al. 2000). In agreement with this, each of these studies (Ahmet et al. 2004; Xydas et al. 2006) reported that the antiapoptotic effect of ß1-AR antagonism was less than that of ß2-agonism and that there was no synergistic effect when the two interventions (ß1-AR antagonism and ß2-agonism) were combined. Similarly, the finding that clenbuterol administration is therapeutic and augments recovery of the unloaded myocardium (Yacoub, 2001; Hon & Yacoub, 2003) can be reconciled with the present findings by appreciating that these patients also receive ‘combination therapy’ that includes ß1-AR blockade. However, it is important to note that these protective mechanisms (selective desensitization of ß1-AR or co-administration of a ß1-AR antagonist) are unlikely to be present in other chronic diseases, such as cancer cachexia or sarcopenia, for which ß2-AR agonist therapy is also being considered. In each of these situations, the myotoxic effects of ß2-AR stimulation on the skeletal muscle will not have been ablated. However, we have recently discovered that the hypertrophic effects of clenbuterol can be separated from its myotoxic effects in the heart and skeletal muscle by carefully controlling the dose administered (Burniston et al. 2006).
In conclusion, comparison of the dose-dependent myotoxic and haemodynamic effects of fenoterol and clenbuterol revealed that each of these agents induced significant skeletal myocyte death and considerable cardiomyocyte death at a dose (0.03 mmol kg–1) eliciting a less than maximal change in heart rate. At this dose, fenoterol induced a greater increase in heart rate, whereas clenbuterol had a greater hypotensive effect. The cardiotoxic effects of these agents in vivo contrast with the effects predicted from studies in vitro and highlight the dangers of arbitrarily translating findings in vitro to whole animal models.
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P < 0.05, significantly different from an equimolar dose of fenoterol or isoprenaline. Also shown are dose–response relationships for myocyte apoptosis in the heart (C) and soleus muscle (D) after administration of ß-agonists (fenoterol, clenbuterol or isoprenaline). Data are presented as percentages relative to the most myotoxic dose: 3 mmol kg–1 fenoterol, in the heart; and 0.03 mmol kg–1 clenbuterol, in the soleus.
