Contractile effects of albiglutide in the human and mouse atrium

Albiglutide was developed as a glucagon-like-peptide 1 receptor (GLP-1R) agonist for the treatment of type 2 diabetes. We tested the hypothesis that albiglutide exerts a positive inotropic effect in the human heart via GLP-1R by measuring contractility in paced (1 Hz) human atrial preparations (HAP) from adult patients who underwent surgery for severe coronary heart disease. We observed a time- and concentration-dependent positive inotropic effect of albiglutide in HAP; this effect began at 10 nM albiglutide and increased to 100 nM albiglutide, the highest concentration studied. The positive inotropic effect of albiglutide was accentuated by the phosphodiesterase III inhibitor cilostamide (100 nM) and reduced by 10 µM N-[2-[[(E)-3-(4-bromophenyl)prop-2-enyl]amino]ethyl]isoquinoline-5-sulfonamide, an inhibitor of the 3',5' cyclic adenosine monophosphate-dependent protein kinase. Conversely, the effect was not reversed by 10 µM propranolol, a β-adrenoceptor antagonist, and was less effective than the effect of 1 µM isoprenaline. In the presence of cilostamide, the endogenous agonist GLP-1(7-36)amide at 100 nM augmented the force of contraction in HAP, whereas its precursor, GLP-1(1-36)amide, did not. Contractile force in abligutide-treated (100 nM) HAP in the presence of cilostamide was further enhanced by 100 nM GLP-1(7-36)amide or 10 nM exenatide but was not affected by 100 nM GLP-1(1-36)amide. After the addition of cilostamide, 100 nM albiglutide augmented the rate of tension relaxation and accelerated the time to relaxation in HAP. In contracting HAP, 100 nM albiglutide in the presence of 100 nM cilostamide increased the phosphorylation state of phospholamban and the inhibitory subunit of troponin. In HAP, the positive inotropic effects of albiglutide-both alone and in the presence of 100 nM cilostamide-were attenuated by treatment with 100 nM exendin(9-39), a GLP-1R antagonist. In contrast, 100 nM albiglutide did not increase the force of contraction or the beating rate in isolated left atrial or right atrial preparations from adult mice in the presence and absence of the phosphodiesterase 4 inhibitor rolipram (100 nM). Our data suggest that albiglutide increases the force of contraction via stimulation of GLP-1R and cAMP-dependent phosphorylation in HAP. Albiglutide acts as a partial GLP-1R agonist in HAP. This indicates that any clinical side effects of albiglutide may be less pronounced than those of full GLP-1R agonists.