The dual incretin-based agonist survodutide (BI 456906) can activate both glucagon receptors (GCGR) and glucagon-like peptide-1 receptors (GLP-1R) and is currently being evaluated in clinical trials for use in humans. The stimulation of both receptors should lead to the activation of adenylyl cyclases, followed by an increase in cyclic adenosine monophosphate. In the present study, it was hypothesized that survodutide, like the GLP-1R agonist semaglutide, enhances force of contraction in human right atrial preparations (HAP) via GCGR and/or GLP-1R. Additionally, the effect on the sinus node was examined in spontaneously beating mouse right atria.
The force of contraction was measured in isolated, electrically stimulated (1 Hz) preparations of HAP from adult patients undergoing open-heart surgery due to of severe coronary heart disease in Tyrode's solution (37°C). Finally, the preparations were freeze clamped and used for Western blotting. Spontaneously beating right atrial preparations (RA) from adult wild-type mice were isolated and analyzed using the same experimental setup as for human preparations, but without electrical stimulation.
It was observed that survodutide, in the presence of the phosphodiesterase III inhibitor cilostamide, raised the force of contraction in HAP in a concentration- and time-dependent manner starting at 3 nM (p < 0.05, n = 9). Moreover, the positive inotropic effect of survodutide could be reduced by the GLP-1R antagonist exendin (100 nM) and, to a lesser extent, by the GCGR antagonist adomeglivant (10 µM). Survodutide was less effective and less potent than isoprenaline in increasing the force of contraction in HAP. Furthermore, in contrast to the effects of isoprenaline, survodutide did not significantly shorten the time to relaxation. Consequently, the phosphorylation of phospholamban was increased by isoprenaline but hardly at all by survodutide. These data suggest that survodutide also increases contractile force via a cAMP-independent pathway. In spontaneously beating mouse right atrial preparations, survodutide exerted positive chronotropic effects (p < 0.05, n = 4), which were antagonized by the GCGR antagonist adomeglivant (10 µM).
In summary, it is suggested that survodutide affects the beating rate via GCGR in mouse RA and increases the force of contraction via GLP-1R and GCGR in HAP. Further studies are needed to examine the signaling pathway in HAP. It is reasonable to hypothesize that, in the human heart, the heart rate could be elevated by both the GCGR and the GLP-1R.
