scholarly journals Effects of clenbuterol on contractility and Ca2+ homeostasis of isolated rat ventricular myocytes

2008 ◽  
Vol 295 (5) ◽  
pp. H1917-H1926 ◽  
Author(s):  
U. Siedlecka ◽  
M. Arora ◽  
T. Kolettis ◽  
G. K. R. Soppa ◽  
J. Lee ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Severe Heart Failure ◽  
Negative Inotropic Effect ◽  
Chronic Administration ◽  
Left Ventricular ◽  
Ventricular Assist Devices ◽  
Inotropic Response ◽  
Left Ventricular Assist Devices ◽  
Acute Effects ◽  
Inotropic Effects

Clenbuterol, a compound classified as a β2-adrenoceptor (AR) agonist, has been employed in combination with left ventricular assist devices (LVADs) to treat patients with severe heart failure. Previous studies have shown that chronic administration of clenbuterol affects cardiac excitation-contraction coupling. However, the acute effects of clenbuterol and the signaling pathway involved remain undefined. We investigated the acute effects of clenbuterol on isolated ventricular myocyte sarcomere shortening, Ca2+ transients, and L-type Ca2+ current and compared these effects to two other clinically used β2-AR agonists: fenoterol and salbutamol. Clenbuterol (30 μM) produced a negative inotropic response, whereas fenoterol showed a positive inotropic response. Salbutamol had no significant effects. Clenbuterol reduced Ca2+ transient amplitude and L-type Ca2+ current. Selective β1-AR blockade did not affect the action of clenbuterol on sarcomere shortening but significantly reduced contractility in the presence of fenoterol and salbutamol ( P < 0.05). Incubation with 2 μg/ml pertussis toxin significantly reduced the negative inotropic effects of 30 μM clenbuterol. In addition, overexpression of inhibitory G protein (Gi) by adenoviral transfection induced a stronger clenbuterol-mediated negative inotropic effect, suggesting the involvement of the Gi protein. We conclude that clenbuterol does not increase and, at high concentrations, significantly depresses contractility of isolated ventricular myocytes, an effect not seen with fenoterol or salbutamol. In its negative inotropism, clenbuterol predominantly acts through Gi, and the consequent downstream signaling pathways activation may explain the beneficial effects observed during chronic administration of clenbuterol in patients treated with LVADs.

Abstract 2492: Clenbuterol, Unlike Other B 2 -Adrenoceptor Agonists, Predominantly Activates the G i Protein in Isolated Rat Ventricular Myocytes

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Urszula Siedlecka ◽  
Monica Arora ◽  
Joon Lee ◽  
Mark A Stagg ◽  
Gopal Soppa ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Ventricular Myocytes ◽  
Severe Heart Failure ◽  
Negative Inotropic Effect ◽  
Inotropic Response ◽  
Acute Effects ◽  
Guanine Nucleotide Binding Protein ◽  
Inotropic Effects ◽  
Rat Ventricular Myocytes ◽  
Isolated Rat

Clenbuterol (CLEN), a β 2 -adrenoceptor (AR) agonist, has been employed in combination with other pharmacological agents and LVADs to treat patients with severe heart failure (HF). Chronic administration of CLEN increases expression of Ca regulatory proteins in isolated cardiac myocytes and improves their contractility. However, the acute effects of CLEN on myocyte contractility compared to other β 2 -AR agonists and the signalling pathway of CLEN remain undefined. Here we compared the acute effects of CLEN to two other β 2 -AR agonists, fenoterol (FEN) and salbutamol (SAL). Isolated rat ventricular myocytes were superfused with β 2 AR agonists and sarcomere shortening was measured. CLEN produced a negative inotropism (30 μM: 65.3 ± 9.7% of control, n=9; p<0.05; 100 μM: 37.9 ± 8.0%, n=9; p<0.01) whereas FEN showed a positive inotropic response (30 μM: 184.8 ± 19.1% of control, n=9; p<0.01; 100 μM: 198.1 ± 20.5%, n=9; p<0.01). SAL had no significant effect. Selective β 1 AR blockade with 300 nM CGP 20712A did not affect CLEN’s action on sarcomere shortening but significantly reduced the contractile response to FEN and SAL (p<0.05). Additional blockade of β 2 AR-Gs with 50 nM ICI 118,551 unveiled a negative inotropic response to FEN (100 μM: 61.5 ± 7.3% of control, n=7; p<0.001) and SAL (100 μM: 67.4 ± 3.6% of control, n=7; p<0.01) and did not alter the response to CLEN. Incubation with 2 μg/ml pertussis toxin (PTX) almost abolished the negative inotropic effects of CLEN: 30 μM (PTX: 95.1 ± 4.9%, n=6 vs control: 73.9 ± 5.5%, n=7; p<0.05) and 100 μM (PTX: 96.2 ± 9.6%, n=6 vs control: 21.7 ± 5.5%, n=7; p<0.001), suggesting the involvement of the inhibitory guanine nucleotide binding protein (G i ). In addition, overexpression of G i by adenoviral (AdV) transfection for 48 hrs induced a stronger negative inotropic effect upon application of CLEN compared with control cultured cells (AdV-Gi: clen 30 μM: 36.8 ± 8.3% of control, n=9; p<0.01; 100 μM: 19.7 ± 6.5%, n=9; p<0.01). In summary, CLEN significantly depresses contractility of ventricular myocytes, an effect not seen with FEN or SAL. CLEN predominantly acts through G i and the consequent downstream signaling pathways activation may explain the beneficial effects observed during administration of CLEN in patients treated with LVADs.

Effects of chronic administration of clenbuterol on function and metabolism of adult rat cardiac muscle

2005 ◽  
Vol 288 (3) ◽  
pp. H1468-H1476 ◽  
Author(s):  
Gopal K. R. Soppa ◽  
Ryszard T. Smolenski ◽  
Najma Latif ◽  
Ada H. Y. Yuen ◽  
Aalya Malik ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Cardiac Muscle ◽  
Chronic Administration ◽  
Left Ventricular ◽  
Ventricular Assist Devices ◽  
Left Ventricular Assist Devices ◽  
Carbohydrate Utilization ◽  
Ventricular Assist ◽  
Assist Devices ◽  
Left Ventricular Assist

Clenbuterol (Clen), a β2-agonist, is known to produce skeletal and myocardial hypertrophy. This compound has recently been used in combination with left ventricular assist devices 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 Clen on myocardial cells have not been fully elucidated. In an attempt to clarify this issue, we examined the effects of chronic administration of Clen on Ca2+ handling and substrate preference in cardiac muscle. Rats were treated with either 2 mg·kg−1·day−1 Clen or saline (Sal) for 4 wk with the use of osmotic minipumps. Ventricular myocytes were enzymatically dissociated. Cells were field stimulated at 0.5, 1, and 2 Hz, and cytoplasmic Ca2+ transients were monitored with the use of the fluorescent indicator indo-1 acetoxymethyl ester. Two-dimensional surface area and action potentials in current clamp were also measured. We found that in the Clen group there was significant hypertrophy at the organ and cellular levels compared with Sal. In Clen myocytes, the amplitude of the indo-1 ratio transients was significantly increased. Sarcoplasmic reticulum Ca2+ 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 tricarboxylic cycle (Krebs cycle) flux was increased several times in the Clen group. This increase was associated with decreased expression of peroxisome proliferator-activated receptor-α. This study shows that chronic administration of Clen induces cellular hypertrophy and increases oxidative carbohydrate utilization together with an increase in sarcoplasmic reticulum Ca2+ content, which results in increased amplitude of the Ca2+ transients. These effects could be important when Clen is used in conjunction with left ventricular assist devices treatment.

Effects of carvedilol and metoprolol on the myocardium during mechanical unloading in a rat heterotopic heart transplantation model

2021 ◽  
pp. 1-6
Author(s):  
Geena Kim ◽  
Hong Ryang Kil ◽  
Cheng Quan ◽  
Sang Su Lee
Keyword(s):  
Heart Transplantation ◽  
Severe Heart Failure ◽  
Left Ventricular ◽  
Ventricular Assist Devices ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Left Ventricular Assist Devices ◽  
Heart Transplants ◽  
Ventricular Assist ◽  
Heterotopic Heart Transplantation ◽  
Mechanical Unloading

Abstract Background and objectives: Left ventricular assist devices enable recovery from severe heart failure and serve as a bridge to heart transplantation. However, chronic mechanical unloading can impair myocardial recovery. We aimed to assess myocyte size, fibrosis, apoptosis, and β-adrenoreceptor levels after rats with left ventricle unloading induced by heterotopic heart transplantation were administered carvedilol and metoprolol. Methods: Thirty rats with heart transplants were divided randomly into control, carvedilol treatment, and metoprolol treatment groups. Follow-up was conducted after 2 and 4 weeks of unloading. Results: Carvedilol and metoprolol treatments did not prevent the decrease in myocyte diameter in unloaded left ventricles. Metoprolol significantly decreased the ratio of the fibrotic area in the unloaded heart, measured using Masson’s trichrome staining after 2 weeks. However, carvedilol and metoprolol did not reduce apoptosis, based on measurements of terminal deoxynucleotidyl-transferase-mediated dUTP nick end-labelling positive cells and the expression of caspase-3 in unloaded hearts after 2 and 4 weeks. Metoprolol treatment did not significantly decrease the mRNA expression of myocardial SERCA2a in the unloaded heart after 2 weeks. Conclusions: Compared to carvedilol treatment, metoprolol treatment improved myocardial fibrosis and SERCA2a expression to a greater extent; however, neither drug prevented myocardial apoptosis.

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