The study shows that retatrutide, a drug being developed for diabetes and obesity, can make human heart muscle cells contract stronger and relax faster in lab experiments. This effect comes from activating several hormone receptors that raise cAMP levels inside the cells. The findings are based on heart tissue taken from patients with severe coronary disease, not on healthy volunteers or real‑world use.

Retatrutide (LY3437943) was developed as a drug to treat type 2 diabetes and obesity. Retatrutide, a not endogenously occurring peptide, stimulated the glucagon receptor (GCGR), the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR), and the glucagon-like peptide-1 receptor (GLP-1R) in cell cultures; increased the activity of adenylyl cyclases (AC); and thus augmented the 3',5' cyclic adenosine monophosphate (cAMP) levels. We tested the hypothesis that retatrutide increased force of contraction (FOC) in human right atrial preparations (HAP) from adult patients. HAP were obtained during open heart surgery from patients who suffered from severe coronary heart disease. We noted that cumulatively applied retatrutide starting at 10 nM (up to 100 nM the highest concentration tested) elevated FOC in HAP in a concentration- and time-dependent manner. In the additional presence of the phosphodiesterase III inhibitor cilostamide (1 µM), retatrutide was more potent and more effective to increase FOC in HAP. Under these conditions, retatrutide shortened the time of muscle relaxation in HAP. These positive inotropic effects of glucagon were diminished by a GLP1-R antagonist, by a GIPR antagonist, and by a CGCR antagonist but not by propranolol, an antagonist at β-adrenoceptors. The effects of retatrutide on FOC were also reduced by 100 nM ryanodine, an inhibitor of the ryanodine receptor in the sarcoplasmic reticulum, by 1 µM carbachol, a M-cholinoceptor agonist, and by 1 µM (-)-N⁶-phenylisopropyladenosine, an A₁-adenosine receptor agonist. Summarily, we suggest that retatrutide enlarged FOC in HAP via the cAMP system through its cognate receptors.