Low Dose Clen Induces Cardiac Apoptosis  

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Nandi
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30/06/2018 7:22 am  

It's been known for some time that clenbuterol at high doses causes cardiac necrosis. This study in animals shows that doses of 1 mcg/kg BW induce apoptosis (programmed cell death) in heart tissue. Humans not uncommonly ingest this much clen. For instance, in a 220 lb (100 kg) bodybuilder this translates to 100 mcg. The CEM store sells clen at a concentration of 200 mcg/ml! Other UG labs sell it at similar concentrations, ranging from 100 to 200 mcg per ml.

J Appl Physiol. 2004 Dec 10; [Epub ahead of print] Related Articles, Links

{beta}2-Adrenergic receptor stimulation in vivo induces apoptosis in the rat heart and soleus muscle.

Burniston JG, Tan LB, Goldspink DF.

Research Institute for Sports and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom.

High doses of the beta2-adrenergic receptor (AR) agonist, clenbuterol, can induce necrotic myocyte death in the heart and slow-twitch skeletal muscle of the rat. However, it is not known if this agent can also induce myocyte apoptosis and whether this would occur at a lower dose than previously reported for myocyte necrosis. Male Wistar rats were given single subcutaneous injections of clenbuterol. Immunohistochemistry was used to detect myocyte specific apoptosis (detected on cryosections using a caspase 3 antibody and confirmed using annexin V, single-strand DNA labelling and TUNEL). Myocyte apoptosis was first detected at 2 h, and peaked 4 h after clenbuterol administration. The lowest dose of clenbuterol to induce cardiomyocyte apoptosis was 1 microg kg(-1), with peak apoptosis (0.35 +/- 0.005 %; P<0.05) occurring in response to 5 mg kg(-1) . In the soleus, peak apoptosis (5.8 +/- 2 %; P<0.05) was induced by the lower dose of 10 microg kg(-1). Cardiomyocyte apoptosis occurred throughout the ventricles, atria and papillary muscles. However, this damage was most abundant in the left ventricular subendocardium at a point 1.6 mm, that is, approximately one-quarter of the way from the apex towards the base. beta-AR antagonism (involving propranolol, bisoprolol or ICI 118,551) or reserpine was used to show that clenbuterol-induced myocardial apoptosis was mediated through neuromodulation of the sympathetic system and the cardiomyocyte beta1-AR, whereas in the soleus direct stimulation of the myocyte beta2-AR was involved. These data show that when administered in vivo, beta2-AR stimulation by clenbuterol is detrimental to cardiac and skeletal muscles even at low doses, by inducing apoptosis through beta1- and beta2-AR, respectively.


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chocolate
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30/06/2018 8:09 am  

70kg and using 140mcg at times (2mcg/kg)... well into the study range... is enough to keep me from ever using it again.

Thank you for this important post Nandi!!!!!


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Nandi
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30/06/2018 8:45 am  

It's ironic that the ban on ephedra containing supplements has likely driven people away from relatively safe thermogenics like the E/C stack to much more toxic agents like clenbuterol. I'm done with clen as well, chocolate, and will stick with things like ephedrine and forskolin/green tea.


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neurotic
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30/06/2018 9:32 am  

clen more toxic than ephedra? hmmm, at least, as far as prostate goes, I think ephedra is much more toxic, don't you think?


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Nandi
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30/06/2018 10:28 am  

If you ask me, the dangers of the possibility of getting BPH pale in comparison with cardiac myocyte cell death! Has anyone ever croaked from BPH, which is easily prevented with anything from Permixon, to Flomax, to Dutasteride? I can adjust the ephedrine dosage so I lose weight and still don't get BPH. And I am prone to BPH, having suffered with it for years, on and off. I value my heart much more than my prostate anyway.

In any case, as I mentioned, if ephedrine is not your cup of tea there are numerous other effective thermogenics like forskolin and green tea that are actually healthful, especially green tea.

I find it hard to find much positive to say about clen.


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jboldman
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30/06/2018 11:15 am  

i have been saying this for some time.

jb


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jhov
 jhov
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30/06/2018 11:53 am  

Thank you!!!!
I am sending this to some friends of mine as we speak!
They chug down clen like it is candy and say that it works like nothing else and that they can be liberal with there diet (moreso then anything else) which makes time on clen shorter and thus safer.

I can not tell you how many times I told them about evidence like this and how faulty their reasoning was especially since clen looses it's effectiveness soo quickly and diet and cardio are the main things to loosing weight in the end. They respect your advice more then anybody else I suppose (much like everyone else on the boards ) so hopefully they listen now Nandi!
peace
J


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liftsiron
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30/06/2018 12:27 pm  
Posted by: Nandi
It's ironic that the ban on ephedra containing supplements has likely driven people away from relatively safe thermogenics like the E/C stack to much more toxic agents like clenbuterol. I'm done with clen as well, chocolate, and will stick with things like ephedrine and forskolin/green tea.

I can't advise anyone in good faith to use clen in the future. Based not solely on this study, but this one reinforces my thinking on the issue.

liftsiron is a fictional character and should be taken as such.


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JGUNS
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30/06/2018 1:04 pm  

This is why Beta blockers are used for congestive heart failure. However,it seems that beta agonists do have their positive benefits and uses in medicine. clenbuterol is used as a treatment for end stage heart failure and this study suggests a beneficial application for clenbuterol. I suppose that in this specific instance, the benefits of clenbuterol would outweigh the long term negatives. The other thing that we should consider is that apoptosis is evident in the final stages of heart failure, but it remains UNKNOWN if it is etiologically linked to the progress of the disease or if it is a concommitant finding related to the progressive disfunction of the heart muscle. In other words it is correlational, but not necessarily causative.

Effects of Chronic Administration of clenbuterol on Function and Metabolism of Adult Rat Cardiac Muscle.

Soppa GK, Smolenski RT, Latif N, Yuen AH, Malik AH, Karbowska J, Kochan Z, Terracciano CM, Yacoub MH.

Harefield Heart Science Centre, Imperial College London, NHLI, Harefield, United Kingdom.

clenbuterol, a beta2 agonist, is known to produce skeletal and myocardial hypertrophy. This compound has recently been used in combination with left ventricular assist devices (LVAD) for the treatment of end-stage heart failure, to reverse or prevent the adverse effects of unloading-induced myocardial atrophy. However, the mechanisms of action of clenbuterol on myocardial cells have not been fully elucidated. In an attempt to clarify this issue we have examined the effects of chronic administration of clenbuterol on Ca(2+) handling and substrate preference in cardiac muscle. Rats were treated with either 2mg/kg/day clenbuterol (clen) or saline (Sal) for 4 weeks using osmotic minipumps. Ventricular myocytes were enzymatically dissociated. Cells were field-stimulated at 0.5 Hz, 1Hz and 2Hz and cytoplasmic Ca(2+) transients monitored using the fluorescent indicator Indo-1-AM. Two-dimensional surface area and action potentials in current-clamp were also measured. We found that in the clen group there was a significant hypertrophy at the organ and cellular level compared with Sal. In clen myocytes the amplitude of the Indo-1 ratio transients was significantly increased. Sarcoplasmic reticulum (SR) Ca(2+) content, estimated by rapid application of 20 mM caffeine, was significantly increased in the clen group. The action potential was prolonged in the clen group compared with Sal. Carbohydrate contribution to the Krebs cycle flux was increased several times in the clen group. This increase was associated with decreased expression of peroxisome proliferator activated receptor alpha (PPARalpha). This study has shown that chronic administration of clenbuterol induces cellular hypertrophy and increases oxidative carbohydrate utilisation together with an increase in SR Ca(2+) content, which results in increased amplitude of the Ca(2+) transients. These effects could be important when clenbuterol is used in conjunction with LVAD treatment.


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JGUNS
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30/06/2018 1:49 pm  

It looks like the cell apoptis may be directly linked to taurine levels. It may be that the clenbuterol is causing a reduction in taurine levels in the areas of the heart, specifically the left ventrical area that may correlate with cell apoptis. I wonder if supplementing with Taurine would have a cardio protective benefit?

Amino Acids. 1998;15(1-2):13-25. Related Articles, Links

The effects of the beta 2-agonist drug clenbuterol on taurine levels in heart and other tissues in the rat.

Doheny MH, Waterfield CJ, Timbrell JA.

Department of Toxicology, School of Pharmacy, University of London, United Kingdom.

The administration of a single subcutaneous dose of clenbuterol to rats altered the level of taurine in certain tissues. Taurine levels in cardiac tissue were significantly decreased 3 h after the administration of 250 micrograms/kg of clenbuterol and remained significantly depressed at 12 h post-dose only returning to control values by 24 h. The level of taurine in the liver increased 3 h after clenbuterol administration but was lower than the control value at 24 h post dose. Lung taurine levels were significantly lower than the control value at 12 hr post dose and remained depressed until 24 h post dose. clenbuterol caused a significant increase in taurine levels in serum and muscle at 3 and 6 hr postdosing respectively but not at other time points. Serum creatine kinase (CK), activity was slightly but significantly raised at the 12 and 24 h time point. The effects of clenbuterol on tissue taurine content were not dose-dependent over the range studied (63-500 micrograms/kg). However taurine levels in the lung were significantly reduced at all doses and in the heart were significantly lower in the treated groups at all except the lowest dose, 12 h post dosing. Liver taurine levels were significantly increased at the highest dose of 500 micrograms/kg. The reduction of taurine concentrations in the heart, caused by clenbuterol, is of concern as taurine has been shown to have protective properties in many tissues especially the heart

It is interesting, because studies also show that clen PREVENTs brain cell apoptosis (neuroprotective qualities) and it also induces fat cell apoptosis. It also seems to have benefits in regards to liver apoptosis as well! 1,2,3

1.J Cereb Blood Flow Metab. 1998 Sep;18(9):1032-9.
Stimulation of beta2-adrenoceptors inhibits apoptosis in rat brain after transient forebrain ischemia.
Zhu Y, Culmsee C, Semkova I, Krieglstein J.
Institut fur Pharmakologie und Toxikologie, Fachbereich Pharmazie und Lebensmittelchemie, Philipps-Universitat, Marburg, Germany.

2.Page KA, Hartzell DL, Li C, Westby AL, Della-Fera MA, Azain MJ, Pringle TD, Baile CA.
beta-Adrenergic receptor agonists increase apoptosis of adipose tissue in mice.
Domest Anim Endocrinol. 2004 Jan;26(1):23-31.

3. Andre C, Couton D, Gaston J, Erraji L, Renia L, Varlet P, Briand P, Guillet JG.
beta2-adrenergic receptor-selective agonist clenbuterol prevents Fas-induced liver apoptosis and death in mice.
Am J Physiol. 1999 Mar;276(3 Pt 1):G647-54.


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JGUNS
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30/06/2018 2:29 pm  

One thing for sure is that the doses that are needed to achieve Cardiac apoptosis (~100 mcgs ED) are doses that bodybuilders typically ramp UP to because they need to in order for clenbuterol to still be effective. This is yet another reason IMHO why Albuterol would look to be a safer choice since there is a shorter elimination time and much less of a need to ramp up to unsafe dosages.


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Nandi
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30/06/2018 3:23 pm  

I got a copy of the entire article, which may not bode well for ephedrine, either. clenbuterol, like ephedrine, causes the release of stored norepinephrine in nerve terminals. After an involved discussion of how they arrived here, the authors concluded that:

Taking all our experimental observations together, the most likely mechanism for clenbuterol induced toxicity on cardiac myocytes appears to be an injurious effect, not directly via the cardiomyocyte beta 2-AR, but indirectly via stimulation of the beta 2-AR of pre-synaptic nerve terminals, which consequently augments the release of norepinephrine.

This is exactly what ephedrine does. Does Albuterol also cause the release of NE? I have not found any research yet to say either way.


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shadymademe
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30/06/2018 4:02 pm  
Posted by: JGUNS
[B]It looks like the cell apoptis may be directly linked to taurine levels. It may be that the clenbuterol is causing a reduction in taurine levels in the areas of the heart, specifically the left ventrical area that may correlate with cell apoptis. I wonder if supplementing with Taurine would have a cardio protective benefit?

If depletion of taurine was the sole purpose for apoptosis, the initial study would not have shown apoptosis of skeletal muscle because clen increases taurine concentrations in said area.

Also remember we are dealing with rats. clen causes apoptosis of adipocytes in rats, but not in humans.

Here is a study concerning Albuterol and subsequent apoptosis via B-1, in vitro.

Beta-adrenergic receptor subtypes differentially affect apoptosis in adult rat ventricular myocytes.

Zaugg M, Xu W, Lucchinetti E, Shafiq SA, Jamali NZ, Siddiqui MA.

Department of Anesthesiology, Health Science Center at Brooklyn, State University of New York, USA.

BACKGROUND-Catecholamine-induced apoptosis is mediated by activation of the beta-adrenergic signaling pathway. We tested the hypothesis that beta(1)- and beta(2)-adrenergic receptor (AR) subtypes differentially affect apoptosis in adult rat ventricular myocytes in vitro. METHODS AND RESULTS-Myocytes were first exposed to norepinephrine (NE) alone (10 mcmol/L) or NE+atenolol (AT) (10 mcmol/L) for 12 hours. AT, a beta(1)-selective AR antagonist, abolished the NE-induced increase in nick end-labeling (TUNEL)-positive cells compared with control (NE, 33+/-3% versus control, 3+/-1%, P<0.0001; NE+AT, 4+/-2% versus control, 3+/-1%, P=0. 98). Annexin V staining, DNA laddering, and caspase activity determinations corroborated these results. Subsequent experiments under prazosin treatment established the apoptosis dose-response curves for the increasingly beta(2)-selective AR agonists isoproterenol (ISO) (beta(1) approximately beta(2)) and Albuterol (ALB) (beta(2)>beta(1)). ISO and ALB induced significantly less apoptosis than NE (beta(1)>beta(2)) at equimolar concentrations as assessed by TUNEL staining [1 mcmol/L: NE (8+/-2%) approximately ISO (7+/-1%)>ALB (2+/-1%); 10 mcmol/L: NE (35+/-2%)>ISO (23+/-1%)>ALB (3+/-1%); 100 mcmol/L: NE (50+/-2%)>ISO (29+/-2%)>ALB (14+/-1%), P<0.0001 except for NE versus ISO at 1 mcmol/L with P=0.62]. ALB-induced apoptosis at 100 mcmol/L was abolished by AT (10 mcmol/L), indicating a beta(1)AR-mediated effect. Importantly, ICI 118551 (0.1 mcmol/L), a highly selective beta(2)AR antagonist, did not decrease the percentage of NE-, ISO-, and ALB-induced apoptosis. Reverse transcription-polymerase chain reaction studies revealed that AT completely reversed the beta-adrenergic signaling-induced changes in the Bcl-2-to-Bax ratio. CONCLUSIONS-These observations provide evidence that beta AR-mediated apoptotic death signaling is largely dissociated from beta(2)ARs and selectively mediated by beta(1)ARs in adult rat ventricular myocytes.

PMID: 10899100 [PubMed - indexed for MEDLINE]
1.


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Alpine
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30/06/2018 4:58 pm  

Wow, I just ran my first 2 week cycle of clen a week ago. It was amazing - I had very noticable results in only two weeks. I hit 120mcg w/ no more sides than a normal ECA stack. Very well tolerated...

I was planning to run 1 more 2 week cycle of it right after Christmas. After reading this I really dont think I should. Obviously using/abusing clen for a long time or over a number of years is very bad. But whats one more cycle for 2 weeks? Im tempted to do it and finish off this clen i bought. The results for me were amazing. Im disappointed in this news.

What do you guys think?

Obviously from this point on I will stick to ECA, Yohimbine/Synephrine & Albuterol thermo stacks.

(Update): After thinking about this I dont see how Albuterol can be much better. From my limited research it basically has the same action as clen but with a shorter half life - correct? Maybe Albuterol is not a good choice either.

I have heard good things about Yohimbine/Synephrine/Ephedrine stacks though. Maybe I will snag some Nutrex Lipo-6 and some Vasopro.


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acecombact1
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30/06/2018 5:33 pm  

did any one notice last sentencr " detrimental to cardiac and skeletal muscles even at low doses"

i thought that clen was anabolic in rats, so how is it detrimental skeletal muscles .

plus these studies done on rats dont apply on humans, people are tying to prove clen is anabolic, but cant because all studies done on humans, so why accept this study if we dont accept anabolic effects of clen!


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