Thread: Clen and the heart
07-13-2004, 11:14 AM #1
Clen and the heart
I keep reading that clen will damage heart skeletal muscle. It seems Muscle Development wrote an article about it. And I also heard taking taurine daily will reverse this. Any mod/vets that can fully clarify this?
07-13-2004, 11:48 AM #2
Scientific Data on Clenbuterol
The use of a high avidity anti-myosin Ab has allowed us to investigate myocyte-specific necrosis. This, in combination with the carefully controlled in vivo protocol, ensured that this technique only identifies those myocytes with a ruptured sarcolemmal membrane, a key indicator of the transition from reversible (oncosis) to irreversible (necrosis) cell death (22, 34). Using this model, we have demonstrated that clenbuterol administration induces necrosis in the heart and soleus muscle of the rat.
The finding that clenbuterol induces myocyte-specific necrosis in the heart is novel. It may be speculated that, in the absence of a functional satellite cell system, all necrosis in the heart will lead to reparative fibrosis. Our acute data may therefore provide etiological support to those of Duncan et al. (11), who showed an increase in collagen infiltration (possibly reparative fibrosis) in the heart after chronic clenbuterol administration. A possible mechanism for clenbuterol's cardiotoxicity is its adverse effect on taurine levels in the heart (9, 36). This amino acid is known to have a protective role in some tissues, particularly in the heart and lungs, with one of its possible roles being the modulation of calcium levels (16). Doheny et al. (9) showed that taurine levels in the heart are depressed in response to a single subcutaneous administration of clenbuterol. Furthermore, the dose of clenbuterol (125 µg/kg body wt) used and the time point (5 h) after clenbuterol administration at which the taurine levels in the heart become significantly depressed almost exactly match those found for the onset of necrosis in the heart in our investigation (Figs. 2A and 3A). Doheny et al. (9) did not investigate taurine levels in the soleus but only in the gastrocnemius muscle, where taurine levels increased 6 h after clenbuterol administration. In light of the present findings, it may also be of interest to investigate changes in the levels of taurine in the soleus after controlled administration of clenbuterol.
This is the first time that myocyte-specific damage has been rigorously investigated and quantified in either the heart or the soleus in response to controlled doses of this 2-AR agonist. Waterfield et al. (36) have previously demonstrated generalized histological damage in the soleus in response to a dose of 2 mg clenbuterol/kg body wt given via drinking water. Although our data clearly support those of Waterfield et al., they further our knowledge by revealing that clenbuterol-induced necrosis occurs in the myocytes and may therefore directly affect muscle function. In addition, by rigorously controlling clenbuterol administrations, we have also been able to advance our knowledge of the dose dependency and time course involved in clenbuterol-induced necrosis.
Throughout our initial investigations (dose dependency, time course, and topographical distribution) of clenbuterol-induced necrosis, clenbuterol was administered parenterally. Many of the previous studies investigating the effects of clenbuterol have administered clenbuterol in the drinking water. Such an approach, although easy to use and effective in inducing anabolism, has several possible shortcomings that cannot always be sufficiently well controlled. Clenbuterol is readily oxidized and needs to be protected from light. The practice of making up fresh solutions on a daily or more often a weekly basis means that the actual dose received by each animal in a communal cage cannot be measured with any precision. This problem is further complicated by the clenbuterol-induced increase in thirst, which we have found to be dependent on the dose administered (unpublished observation). To establish that ingestion of clenbuterol is also myotoxic, we administered a single dose of clenbuterol enterally, the only controllable way to accurately achieve this is by gavage administration. Although this method does not exactly match that of administration via the drinking water, it does replicate the method of administration chosen by most humans, i.e., ingestion of clenbuterol in tablet form. The data (Fig. 5) clearly demonstrate clenbuterol's myotoxic effects when administered enterally. Necrotic damage in the heart was virtually the same whether clenbuterol was administered parenterally or enterally (Fig. 5A). Interestingly, in the soleus, enteral administration of clenbuterol appeared even more damaging than parenteral administration (Fig. 5B). The finding that enteral administration of the saline vehicle control also induced necrosis is presumed to be stress related, although the animals were compliant and apparently relaxed during administration. Hence, we have favored parenteral administration of clenbuterol. This route of administration provides certainty of the dose received by each animal and the time at which the dose was administered. It is quick and achievable under stress-free conditions such that no necrosis is found in the tissues from control animals.
We have shown that cardiomyocyte-specific necrosis in the myocardium is not uniformly distributed. Of the possible factors mediating this heterogeneity, the principal ones may be regional differences in -AR distribution, taurine metabolism, other metabolic requirements, or hemodynamic stresses. Unfortunately, present data relating to the distribution of -ARs and in particular 2-ARs in the heart are scarce. Beau et al. (2) found the transmural distribution of -ARs to be uniform in the nonfailing human heart. Although generally true for the rat heart, in some cases a greater density of -ARs has been found in the papillary muscles and subendocardium (33). This is consistent with the pattern of damage found in the present investigation. However, in contrast, the same group of workers (33) found a homogeneous distribution of -ARs along the longitudinal axis of the heart, which is not consistent with the pattern of damage found in the present investigation (Fig. 4). A possible explanation for this disparity is that Tofukkji et al. (33) only sampled the heart at three points (base, midventricular, and apex). If the same sampling frequency had been applied to the data in Fig. 4, then it is easy to see how important information would have been missed. These data (Fig. 4) serve to reaffirm the dangers of random sampling and the absolute requirement of in-depth topographical knowledge and standardized procedures when quantifying cell death, or anything else, in a complex organ such as the heart.
In support of a possible hemodynamic contribution to the pattern of damage, we consistently found a greater degree of necrosis in the left, rather than right, side of the heart, with damage being most extensive in the left ventricular subendocardium. The inherently higher energy demands of the subendocardium may make this region of the heart more sensitive to hemodynamic perturbations. This compounded with clenbuterol-induced tachycardia and concomitant reductions in diastolic interval, and therefore blood supply, may explain the increased susceptibility of the subendocardium to clenbuterol-induced necrosis.
Also of particular importance within the present investigation is the novel finding that clenbuterol administration induced a significant amount of necrosis in papillary muscles, with possible effects on valve function. It is conceivable that this damage, in combination with the irreversible loss of myocytes from the ventricular walls (and hence a reduction in the pumping capacity of the heart; Refs. 7, 37), may play an etiologic role in the reduction in exercise capacity, and even cardiac failure, seen in clenbuterol-treated animals subjected to exercise (11).
It was found that a significant (P < 0.01) proportion (89%) of clenbuterol-induced necrosis in the soleus was mediated through the 2-AR pathway. Therefore, only a small percentage of clenbuterol-induced necrosis can be attributed to the passage of clenbuterol through the lipid membrane. In contrast, in the heart, both prior 1- or 2-AR antagonism was highly effective in preventing clenbuterol-induced necrosis with little residual damage attributable to any direct intracellular action (Table 1). Because of clenbuterol's greater potency over many other common 2-AR selective agonists, it is difficult to extrapolate the findings of the present study to other agents. However, the finding that clenbuterol-induced myotoxicity is mediated through the 2-AR system suggests that over stimulation of this pathway per se would be toxic.
The finding that clenbuterol induces damage in the heart through both the 1- and 2-AR is not in agreement with our previous findings that the less selective 1- and 2-AR agonist isoproterenol induces necrosis in the myocardium through the 1-AR pathway only (27). This, coupled with the knowledge that NE itself can be cardiotoxic (24), led us to investigate the possibility that clenbuterol may have a neuromodulatory effect over the SNS. Clenbuterol acting on the 2-AR of the sympathetic varicosities could facilitate the release of NE, which could then preferentially act on 1-ARs to induce necrosis through overstimulation of this pathway. Reserpine was administered to block the uptake of NE from the cytosol into the transport vesicles of the sympathetic varicosities. Thus, after a period of basal neuronal activity, the NE-releasing capacity of the neuron is depleted, effectively blocking this pathway. The results (Table 1) support this hypothesis, with the prior administration of reserpine significantly (P < 0.01) preventing clenbuterol-induced necrosis in the heart but not in the soleus. These data clearly show that the myotoxic effects of clenbuterol on the heart (1-AR mediated) can be separated from its anabolic (2-AR mediated) effects on the heart and skeletal musculature. This information may be of great value when proposing clenbuterol administration as a pharmacological aid for the amelioration of muscle wasting in chronically ill patients. The discovery that clenbuterol-induced necrosis in the heart is indirectly mediated through the SNS and 1-ARs, whereas that in the soleus is directly mediated through 2-ARs, may also account for the differences found between the two muscle types in the dose-dependency experiments (Fig. 2). It appears that the heart is not simply less sensitive to clenbuterol, but rather the indirect route of action of clenbuterol on the heart (i.e., 2-AR stimulated NE release, which then acts on cardiomyocyte 1-ARs) requires a higher dose to elicit comparable damage (Fig. 2). In the soleus, the data (Fig. 2B) suggest a threshold response with doses >10 µg/kg body wt possibly inducing receptor desensitisation and, hence, no further increase in the incidence of necrosis.
The present finding that clenbuterol-induced necrosis is mediated through the -AR pathway in vivo lends support to previous work in vitro showing that -AR stimulation reduces the viability of cultured cardiomyocytes (24). Although the intracellular mechanisms of clenbuterol-induced myotoxicity have not been investigated here, the aforementioned work (24) in vitro elegantly demonstrated that loss of cardiomyocyte viability was preceded by an increase in intracellular cAMP followed by an increase in intracellular Ca2+. This is consistent with earlier work demonstrating that an increase in intracellular Ca2+ is a final common pathway in cell death (31), leading to the activation of proteases and phospholipases (18).
The findings of this investigation show that the doses commonly employed to elicit clenbuterol's anabolic properties also induce significant myocyte necrosis in the heart and soleus muscle. It is surprising, therefore, that so little information exists on the myotoxic effects of clenbuterol. A possible explanation for this is that the anabolic effects of clenbuterol have been predominantly investigated in sedentary populations of livestock or caged laboratory animals whose daily activity levels do not make full use of their cardiac functional reserve (7, 37). It is conceivable that cumulative clenbuterol-induced cardiomyocyte necrosis would gradually reduce an animal's cardiac reserve. This could remain asymptomatic until such time when the animal is stressed or required to do work, i.e., vigorous exercise. This could explain the seminal finding of Duncan et al. (11) of a reduction in exercise capacity and a high incidence of sudden cardiac failure in swim endurance-trained rats when receiving clenbuterol. Although the anabolic or hypertrophic effects of clenbuterol have been quite widely demonstrated, studies investigating the functional significance of this anabolism in the form of increased isometric force (5, 20) or exercise capacity (17, 26) in normal populations have been ambiguous. The results from the current investigation could help to resolve this uncertainty, particularly in those studies that have used high doses of clenbuterol (17, 20). It is conceivable that the concomitant loss of myocytes incurred during such administration protocols would reduce the muscles' capacity to do work despite their increased cross-sectional area and wet weight. For example, some of the extra mass could be attributable to reparative fibrosis. Unfortunately, muscle histology was not investigated in these earlier studies (17, 20), and so any possible myocyte damage would have remained undetected.
The present investigation has provided important information on the effects of acutely administered clenbuterol in the rat. In humans, a single dose of clenbuterol is generally self-administered as a 20-µg tablet. This is equivalent to 0.3 µg/kg body wt in a 70-kg male and is comparable to the dose administered in the only clenbuterol investigation using human subjects (23). To compare this with our 300-g rats, the dose needs to be scaled for differences in body weight and metabolic rate between the two species (Kleiber's Law, 0.75 exponent). The relative dose per kilogram in the rat is 60 times that of the human dose, i.e., 17.9 µg clenbuterol/kg body wt. As demonstrated in Fig. 2, this dose is sufficient to induce 3.8 ± 0.49% necrosis in the fibers of the soleus. Such a level of necrosis may appear small, but this is in response to a single administration, and this level of necrosis may underestimate the level induced by enteral administration (Fig. 5B). Individuals abusing clenbuterol often take several tablets and use the side effects of muscle tremors and tachycardia to judge their maximum dose. By using the above calculations, a daily dose of five to six tablets would be sufficient to reach the threshold (100 µg/kg body wt) for inducing damage in the heart and to induce 6.8 ± 1.9% necrosis in the soleus. An important additional factor to be considered is clenbuterol's long half-life within the body (38). Abusers of this substance often administer it by using an "on-off" cycle over several days. An accumulation of nonmetabolized clenbuterol during the on stage of the cycle may lead to chronically elevated plasma levels, which would further impact myocyte loss in both striated muscles. Although the present investigation has not investigated the compound effects of chronic clenbuterol administration, it does demonstrate that, at the very least, damage will be induced at the onset of each cycle of administration.
These data support the conclusion that clenbuterol causes significant myocyte necrosis in the heart and soleus muscle of the rat at doses previously used to demonstrate its anabolic properties. These findings are in good agreement with the indirect evidence from previous investigations into the effects of clenbuterol administration and exercise training, i.e., finding an antagonistic relationship between the two interventions. Furthermore, by scaling these data from our animal model, tentative conclusions can be drawn about the deleterious effects of clenbuterol abuse within the sporting community. This is again supported by accounts of myocardial infarction in bodybuilders taking cocktails of anabolic agents, including clenbuterol (13). Clenbuterol abuse may therefore pose a long-term health risk.
07-13-2004, 12:24 PM #3
Good Post Jbigdog69.
Yes there are effects on the heart. But studies conducted on animals are usually conducted with multiple doses of Clen at doses well above the doses we use for our purposes. Many studies finding really harsh side effect are with doses at 128mcg/kg every 15mins--totally rediculous amounts. With everything there is risk however. I pulled this from one of my text books.
There are four beta-adrenoceptors in the heart, so it is not surptising that aderenrgic stimulaiton from beta2-agonist has major effects on cardiac as well as skeletal muscle (Deshaies et al. 1980; Rothwell & Stock 1985, Palmer et al. 1990). Cardiac adaptations are mediated by the cyclooxygenase metabolite of arachidonic acid meaning that the cardiac hypertrophy should be preventable by adminsitration of fenbufen, a non********* anti-inflammmatory drug that inhibits they cyclooxygenase pathway. This would inhibit the realeaase of prostaglandins and protein syntheses withou inhibiting the skeletal muscle response (Palmer et al. 1990; Duncan 1996)
Tachycardia (rapid heartbeat) is one of the first indications that B2-agonists such as clenbuterol are having an effect. Chronic use of high doses of clenbuterol or slabutanol in rats almost invariably produces cardiac hypertrophy (Cepero et al 1998: Duncan et al. 2000). Clenbuterol treatment in rats has also been shown to increase the size of the adrenal glands due to hyperplasia of adrenocortical cells.
…Shorter periods of clenbuterol administration did not appear to affect cardiac function with low doses (.3-.4 mg/Kg of bodymass)…despite and a 26% increase in left ventricular hypertrophy...
07-13-2004, 12:50 PM #4
Great post guys, thanks.
07-13-2004, 12:53 PM #5Associate Member
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Good post...making it a sticky for me.
07-13-2004, 01:05 PM #6
As shown above i think it was a great post it cleared
up alot for me. And I will still be using clen in the
future. Thanks for helping this newb out.
07-13-2004, 01:16 PM #7
So basically at the amount we are taking there really isnt much concern on any health problems with it. Correct?
07-13-2004, 01:21 PM #8Originally Posted by jmp51483
07-13-2004, 01:39 PM #9Associate Member
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Copied from Jbigdog69's post...
The present investigation has provided important information on the effects of acutely administered clenbuterol in the rat. In humans, a single dose of clenbuterol is generally self-administered as a 20-µg tablet. This is equivalent to 0.3 µg/kg body wt in a 70-kg male and is comparable to the dose administered in the only clenbuterol investigation using human subjects (23). To compare this with our 300-g rats, the dose needs to be scaled for differences in body weight and metabolic rate between the two species (Kleiber's Law, 0.75 exponent). The relative dose per kilogram in the rat is 60 times that of the human dose, i.e., 17.9 µg clenbuterol/kg body wt. As demonstrated in Fig. 2, this dose is sufficient to induce 3.8 ± 0.49% necrosis in the fibers of the soleus. Such a level of necrosis may appear small, but this is in response to a single administration, and this level of necrosis may underestimate the level induced by enteral administration (Fig. 5B).
Interesting...they mention that the dose given to rats was nearly 60 times the relative dose given to a human at 20ug and indicated a 3.8% necrosis in the fibers of the soleus.
Does that mean that I would have to take 1200ug to get the same damaging affects...?
Anybody want to throw in their two cents...?
07-13-2004, 01:42 PM #10Anabolic Member
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technically, anytime you have vary high BP >180/110 for extended continous time it can cause the heart to be damaged . Just to much pressure coming & going. But for clen at 2 wks normal doses Im sure it has no real affect on the heart muscell. Thats good! Im on it now too.. ps good post j dog
07-13-2004, 01:48 PM #11Associate Member
Originally Posted by BeefCakeStew
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07-13-2004, 02:27 PM #12Originally Posted by hatchblack
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