In mouse heart tissue, the drug retatrutide (a triple‑receptor agonist) didn't make the heart muscle contract harder, but it did speed up the heart's beating rate by activating the glucagon receptor and raising cAMP inside the cells. This heart‑rate‑raising effect works differently from classic beta‑adrenergic stimulants like isoprenaline and can be blocked by certain other drugs.

When retatrutide stimulates the glucagon receptor (GCGR), the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR), and the glucagon-like peptide-1 receptor (GLP-1R), then 3',5'cyclic adenosine monophosphate (cAMP) is increased. We tested the hypothesis that retatrutide like the β-adrenoceptor agonist isoprenaline raises force of contraction (FOC) in isolated electrically driven (1 Hz) left atrial preparations (LA) and exerts positive chronotropic effects (PCE) in isolated spontaneously beating right atrial preparations (RA) from adult CD1 mice. While 100 nM isoprenaline increased FOC, retatrutide (100 nM) failed to increase FOC in LA. In isolated mouse right atrial preparations (RA), retatrutide exerted PCE that were potentiated by 100 nM rolipram but that were antagonized by adomeglivant, a GCGR antagonist. The PCE of retatrutide but not the PCE of isoprenaline were attenuated by H89, an inhibitor of the cAMP-dependent protein kinase (PKA). The PCE of retatrutide were not weakened by the β-adrenoceptor antagonist propranolol (1 µM) but were blocked by 1 µM carbachol, an agonist at M₂-cholinoceptor, and this effect was reversed by 1 µM atropine, a muscarinic receptor antagonist. Likewise, the PCE of retatrutide were blocked by 1 µM (-)-N⁶-phenylisopropyladenosine (PIA), an A₁-adenosine receptor agonist, and this effect was reversed by 1 µM DPCPX, an adenosine A₁-receptor antagonist. We conclude that retatrutide excites the beating rate in RA via GCGR, signalling via cAMP and PKA. Isoprenaline and retatrutide might increase cAMP in different compartments of the mouse sinus node.