Abstract
Purpose
A salutary effect of β2 adrenergic receptor (AR) agonist, fenoterol has been demonstrated in a rat model of post-myocardial infarction (MI) dilated cardiomyopathy (DCM). Recent reports on single cardiomyocyte experiments suggested that out of two enantiomers, RR and SS, that constitute a racemic mixture of fenoterol, only RR-enantiomer is an active component that might be a promising new drug for treatment of chronic heart failure. The objective of this study was to compare the efficacy of the RR enantiomer of fenoterol with efficacy of racemic fenoterol, and SS, an inactive enantiomer, in whole animal experimental models of DCM.
Methods
Two weeks after induction of MI by permanent ligation of the anterior descending coronary artery early cardiac remodeling and MI size were assessed via echocardiography and rats were divided into treatment groups. Treatment (placebo, racemic fenoterol, RR- or SS-enantiomers of fenoterol) continued for 6 months while progression of DCM was followed by serial echocardiography.
Results
Compared with untreated rats, rats treated with racemic fenoterol demonstrated previously described attenuation of LV remodeling, functional decline and the arrest of the MI expansion during the first 2 months of treatment. On the contrary, the treatment with either RR-, or with SS-enantiomers of fenoterol was completely ineffective.
Conclusion
The conclusion drawn on the basis of previous experiments with single cardiomyocytes that RR-enantiomer of fenoterol represents an active component of racemic fenoterol and can be further investigated as a new drug for treatment of chronic heart failure was not confirmed in the whole animal model of DCM.
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References
Xu J, Kochanek KD, Murphy SL, Tejada-Vera B. Deaths: final data for 2007. NVSR. 2010;58:1–135.
Ahmet I, Lakatta EG, Talan MI. Pharmacological stimulation of beta2-adrenergic receptors (beta2AR) enhances therapeutic effectiveness of beta1AR blockade in rodent dilated ischemic cardiomyopathy. Heart Fail Rev. 2005;10:289–96.
Ahmet I, Krawczyk M, Zhu W, Woo AY, Morrell C, Poosala S, et al. Cardioprotective and survival benefits of long-term combined therapy with beta2 adrenoreceptor (AR) agonist and beta1 AR blocker in dilated cardiomyopathy postmyocardial infarction. J Pharmacol Exp Ther. 2008;325:491–9.
Ahmet I, Morrell C, Lakatta EG, Talan MI. Therapeutic efficacy of a combination of a beta1-adrenoreceptor (AR) blocker and beta2-AR agonist in a rat model of postmyocardial infarction dilated heart failure exceeds that of a beta1-AR blocker plus angiotensin-converting enzyme inhibitor. J Pharmacol Exp Ther. 2009;331:178–85.
Talan MI, Ahmet I, Xiao RP, Lakatta EG. β(2) AR agonists in treatment of chronic heart failure: long path to translation. J Mol Cell Cardiol. 2011;51:529–31.
Chesley A, Ohtani S, Asai T, Xiao RP, Lunberg MS, Lakatta EG, et al. β2-adrenergic receptor delivers an anti-apoptotic signal to cardiac myocytes through Gi-dependent signaling pathways. Circ Res. 2000;87:1172–9.
Zhu WZ, Zheng M, Lefkowitz RJ, Koch WJ, Kobilka B, Xiao RP. Dual modulation of cardiac cell survival and cell death by β2-adrenergic signaling in adult mouse heart cells. Proc Natl Acad Sci USA. 2001;98:1607–12.
Zhu WZ, Wang SQ, Chakir K, Kolbilka BK, Cheng H, Xiao RP. Linkage of β1-adrenergic stimulation to apoptotic heart cell death through protein kinase A-independent activation of Ca2+/Calmodulin Kinase II. J Clin Invest. 2003;111:617–25.
Zheng M, Zhu W, Han Q, Xiao RP. Emerging concepts and therapeutic implications of β-adrenergic receptor subtype signaling. Pharmacol Ther. 2005;509:109–15.
Jozwiak K, Khalid C, Tanga MJ, Berzetei-Gurske I, Jimenez L, Kozocas JA, et al. Comparative molecular field analysis of the binding of the stereoisomers of fenoterol and fenoterol derivatives to the beta2 adrenergic receptor. J Med Chem. 2007;50:2903–15.
Beigi F, Bertucci C, Zhu W, Chakir K, Wainer IW, Xiao RP, et al. Enantioselective separation and online affinity chromatographic characterization of R, R- and S, S-fenoterol. Chirality. 2006;18:822–7.
Woo AY, Wang TB, Zeng X, Zhu W, Abernethy DR, Wainer IW, et al. Stereochemistry of an agonist determines coupling preference of beta2-adrenoceptor to different G proteins in cardiomyocytes. Mol Pharmacol. 2009;75:158–65.
Kim HS, Siluk D, Wainer IW. Quantitative determination of fenoterol and fenoterol derivatives in rat plasma using on-line immunoextraction and liquid chromotography/mass spectrometry. J Chromatogr A. 2009;1216:3526–32.
Ahmet I, Krawczyk M, Heller P, Moon C, Lakatta EG, Talan MI. Beneficial effects of chronic pharmacological manipulation of beta-adrenoreceptor subtype signaling in rodent dilated ischemic cardiomyopathy. Circulation. 2004;110:1083–90.
Xiao RP, Ji X, Lakatta EG. Functional coupling of the β2-adrenoceptor to a pertussis toxin-sensitive G protein in cardiac myocytes. Mol Pharmacol. 1995;47:322–9.
Xiao RP, Avdonin P, Zhou YY, Cheng H, Akhter SA, Eschenhagen T, et al. Coupling of β2-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes. Circ Res. 1999;84:43–52.
Xiao RP, Zhang SJ, Chakir K, Avdonin P, Zhu W, Bond RA, et al. Enhanced Gi signaling mediates the diminution of β2-adrenergic contractile response in failing spontaneous hypertensive rat heart. Circulation. 2003;108:1633–9.
Acknowledgment
This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging.
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Ahmet, I., Turner, T., Lakatta, E.G. et al. Fenoterol Enantiomers Do Not Possess Beneficial Therapeutic Properties of Their Racemic Mixture in the Rat Model of Post Myocardial Infarction Dilated Cardiomyopathy. Cardiovasc Drugs Ther 26, 101–108 (2012). https://doi.org/10.1007/s10557-011-6366-9
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DOI: https://doi.org/10.1007/s10557-011-6366-9