β₂ AR agonists in treatment of chronic heart failure: long path to translation

Abstract

The main clinical manifestations of advanced chronic heart failure (CHF), e.g. in dilated cardiomyopathy (DCM), are reduced systolic and diastolic functions, increased arterial elastance and arterio-ventricular uncoupling, accompanied and exacerbated by an excessive sympathetic activation and extensive abnormalities in the βAR signaling. Loss of cardiomyocytes due to apoptosis is one mechanism that undoubtedly contributes to cardiac remodeling and functional deterioration associated with dilated cardiomyopathy (DCM). Research during the last decade on the single cardiomyocyte level strongly suggested that selective stimulation of β(1) AR activates the proapoptotic signaling pathways, while selective stimulation of β(2) AR is antiapoptotic, but its precise mechanisms remain to be elucidated. Extensive research in the rat model of DCM following induction of myocardial infarction (MI) showed that prolonged treatment with of β(2) AR agonist, fenoterol, in combination with a β(1) AR blocker, metoprolol, is more effective than β(1) AR blocker alone and as effective as β(1) AR blocker with ACE inhibitor with respect to survival and cardiac remodeling. This combined regimen of β(2) AR agonists and a β(1) AR blocker might be considered for clinical testing as alternative or adjunct therapy to currently acceptable CHF arsenal. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."

Figure 1

Subtype-specific G protein coupling and function of β₁ AR and β₂ AR in cardiac myocytes. β₂ AR has dual coupling to Gs and Gi, which activates cell survival signals by the Gs-cAMP-PKA-Akt pathway and the Gi-Gbg-PI3K-Akt pathway, respectively. In contrast, β₁AR couples exclusively to Gs, which activates PKA-independent, CaMKII-mediated apoptotic signaling. (ECC: excitation-contraction coupling).

Figure 2

Kaplan-Meier survival curves after induction of MI in a sham-operated group (Sh), an untreated group (nT), and three different treatment groups. MI was induced by a permanent ligation of the left descending coronary artery. Treatment was started 2 weeks after induction of MI. The number of animals at the beginning of treatment was as follows: SH, 10; and nT, β₁-ACEi, β₁-β2+, and β₁-β₂+ACEi, 27 in each. (Ahmet et al, 2009, J Pharmacol Exp Ther, 331: 178–85).

Figure 3

Average MI size in untreated and treated rats estimated by monthly Echo (left) or on the basis of histological measurements (right) and presented as percentage of LV. Top, all animals; bottom, animals that survived 12 months after the MI induction. Treatment was started 2 weeks after induction of MI. (Ahmet et al, 2009, J Pharmacol Exp Ther, 331: 178–85).

Figure 4

Fenoterol compound has two chiral centers labeled as R (top structure) and S (bottom structure). Fenoterol used as drug is a 50/50 mixture of the 2 enantiomers shown. (Beigi et al, 2006, Chirality, 18: 822–7).