Contractile effects of dulaglutide in the human atrium

Dulaglutide is a glucagon-like peptide 1 receptor (GLP-1R) agonist. Dulaglutide (LY2189265) is a GLP-1(7-37) analogue fused by a linker to a modified immunoglobulin G. GLP-1R agonists like dulaglutide can be used to treat diabetes type 2 and obesity. We tested the hypothesis that dulaglutide directly increased force of contraction in the human heart via GLP-1R. To this end, we conducted contraction experiments in paced (1 Hz) isolated human right atrial muscle preparations (HAP). HAP were obtained during open-heart surgery from adult patients with severe coronary heart disease. We detected a concentration- and time-dependent positive inotropic effect of dulaglutide in HAP. Dulaglutide augmented the rate of tension development, the rate of tension relaxation and accelerated the relaxation time in HAP. Dulaglutide (100 nM) augmented the phosphorylation state of phospholamban at serine 16 and the phosphorylation state of the inhibitory subunit of troponin. The positive inotropic effect of 100 nM dulaglutide in HAP was attenuated by 100 nM exendin (9-39). In contrast, dulaglutide alone or in the presence of phosphodiesterase inhibitor rolipram up to 100 nM failed to exert a positive inotropic effect in isolated electrically paced (1 Hz) mouse left atrial preparations and did not increase the beating rate of spontaneously beating mouse right atrial preparations. Our data suggest that dulaglutide raised force of contraction in the isolated paced human atrium via GLP-1R involving cAMP-dependent protein kinase in HAP.