Abstract
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 M 2 -cholinoceptor, and this effect was reversed by 1 µM atropine, a muscarinic receptor antagonist. Likewise, the PCE of retatrutide were blocked by 1 µM (-)-N 6 -phenylisopropyladenosine (PIA), an A 1 -adenosine receptor agonist, and this effect was reversed by 1 µM DPCPX, an adenosine A 1 -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.