Effects of clenbuterol on contractility and Ca<sup>2+</sup> homeostasis of isolated rat ventricular myocytes

Siedlecka, Urszula; Arora, Monica; Kolettis, Theofilos M.; Soppa, Gopal; Lee, J.; Stagg, Mark A.; Harding, Siân E.; Yacoub, Magdi H.; Terracciano, Cesare

doi:10.1152/ajpheart.00258.2008

Cited by 29 publications

(23 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The absence of a positive inotropic effect in response to selective β 2 -AR stimulation with tulobuterol is consistent with previous reports that show that the positive inotropic effect of β 2 -agonists (e.g. fenoterol) can be blocked by CGP-20712A (GonzalezMuñoz et al, 2009;Siedlecka et al, 2008). This would suggest that the variability in the inotropic effect induced by different β 2 -agonists is, at least in part, mediated by the activation of the β 1 -AR.…”

Section: Discussionsupporting

confidence: 91%

Regulation of contractility and metabolic signaling by the β2-adrenergic receptor in rat ventricular muscle

et al. 2011

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 91%

Regulation of contractility and metabolic signaling by the β2-adrenergic receptor in rat ventricular muscle

et al. 2011

View full text Add to dashboard Cite

“…Thus, mechanical unloading of the failing human ventricles appears to have differential effects on ␤ 2 -AR coupling in LV and RV for an unknown reason. Negative inotropic effects at comparably high concentrations of clenbuterol (Ͼ 10 mole/ liter) were previously also reported by Siedlecka et al, 35 who observed that clenbuterol significantly depressed contraction amplitude and Ca 2ϩ release in rat cardiomyocytes. .…”

Section: Discussionsupporting

confidence: 76%

Regulation of cyclic adenosine monophosphate release by selective β2-adrenergic receptor stimulation in human terminal failing myocardium before and after ventricular assist device support

Kassner

Toischer

Bohms

et al. 2012

The Journal of Heart and Lung Transplantation

View full text Add to dashboard Cite

“…In addition, the possibility of β‐blockers as G i agonists has been advanced (Gong et al ., ) and the combination of β 1 ‐adrenoceptor blockade plus β 2 ‐adrenoceptor‐G i activation has also been advanced as a protective drug design strategy in the setting of mechanical left ventricular assistance for end‐stage HF (Rose et al ., ; Hall et al ., ). In these studies, clenbuterol, a G i ‐biased β 2 ‐adrenoceptor agonist (Siedlecka et al ., ), is added on top of β‐blockers (and sometimes together with ACEI, angiotensin II blockers, digoxin and aldosterone receptor blockers) at a later stage under a mechanical unloading treatment protocol. Therefore, the overall therapeutic effect is likely to be the result of several different factors.…”

Section: Biased Agonism Beyond β‐Blockers In Cardioprotectionmentioning

confidence: 99%

Biased β₂‐adrenoceptor signalling in heart failure: pathophysiology and drug discovery

Woo

Song

Xiao

et al. 2014

British J Pharmacology

View full text Add to dashboard Cite

The body is constantly faced with a dynamic requirement for blood flow. The heart is able to respond to these changing needs by adjusting cardiac output based on cues emitted by circulating catecholamine levels. Cardiac β-adrenoceptors transduce the signal produced by catecholamine stimulation via Gs proteins to their downstream effectors to increase heart contractility. During heart failure, cardiac output is insufficient to meet the needs of the body; catecholamine levels are high and β-adrenoceptors become hyperstimulated. The hyperstimulated β1-adrenoceptors induce a cardiotoxic effect, which could be counteracted by the cardioprotective effect of β2-adrenoceptor-mediated Gi signalling. However, β2-adrenoceptor-Gi signalling negates the stimulatory effect of the Gs signalling on cardiomyocyte contraction and further exacerbates cardiodepression. Here, further to the localization of β1-and β2-adrenoceptors and β2-adrenoceptor-mediated β-arrestin signalling in cardiomyocytes, we discuss features of the dysregulation of β-adrenoceptor subtype signalling in the failing heart, and conclude that Gi-biased β2-adrenoceptor signalling is a pathogenic pathway in heart failure that plays a crucial role in cardiac remodelling. In contrast, β2-adrenoceptor-Gs signalling increases cardiomyocyte contractility without causing cardiotoxicity. Finally, we discuss a novel therapeutic approach for heart failure using a Gs-biased β2-adrenoceptor agonist and a β1-adrenoceptor antagonist in combination. This combination treatment normalizes the β-adrenoceptor subtype signalling in the failing heart and produces therapeutic effects that outperform traditional heart failure therapies in animal models. The present review illustrates how the concept of biased signalling can be applied to increase our understanding of the pathophysiology of diseases and in the development of novel therapies. LINKED ARTICLES IntroductionCardiovascular disease is the number one cause of death globally (World Health Organization, 2011). Coronary artery disease is the most prevalent form of cardiovascular disease and is the cause of heart attack (myocardial infarction), an acute illness with very high mortality and morbidity. Given that adult cardiomyocytes cannot re-enter the cell cycle, the death of cardiomyocytes as a result of the blockade of a major coronary artery will permanently weaken cardiac performance. The workload of the remaining cardiomyocytes has to increase to maintain a sufficient cardiac output. A series of compensatory responses are usually triggered, which in many cases lead to structural changes in the heart itself. The process once started will progress to a serious chronic illness called heart failure (HF). Thus, survivors of heart attacks are predisposed to HF, a potentially fatal condition manifested by a progressive decline of cardiac function. HF is also a common converging point of various late-stage cardiovascular conditions, such as cardiomyopathy, valvular heart disease and hypertension. Age is an important risk factor for ...

show abstract

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

Cited by 29 publications

References 45 publications

Regulation of contractility and metabolic signaling by the β2-adrenergic receptor in rat ventricular muscle

Regulation of contractility and metabolic signaling by the β2-adrenergic receptor in rat ventricular muscle

Regulation of cyclic adenosine monophosphate release by selective β2-adrenergic receptor stimulation in human terminal failing myocardium before and after ventricular assist device support

Biased β₂‐adrenoceptor signalling in heart failure: pathophysiology and drug discovery

Contact Info

Product

Resources

About

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

Cited by 29 publications

References 45 publications

Regulation of contractility and metabolic signaling by the β2-adrenergic receptor in rat ventricular muscle

Regulation of contractility and metabolic signaling by the β2-adrenergic receptor in rat ventricular muscle

Regulation of cyclic adenosine monophosphate release by selective β2-adrenergic receptor stimulation in human terminal failing myocardium before and after ventricular assist device support

Biased β2‐adrenoceptor signalling in heart failure: pathophysiology and drug discovery

Contact Info

Product

Resources

About

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

Biased β₂‐adrenoceptor signalling in heart failure: pathophysiology and drug discovery