Glucagon-like peptide-1 increases cAMP but fails to augment contraction inadult rat cardiac myocytes

The gut hormone, glucagon-like peptide-1 (GLP-1), which is secreted in nano molar amounts in response to nutrients in the intestinal lumen, exerts cAMP /protein kinase A-mediated insulinotropic actions in target endocrine tissu es, but its actions in heart cells are unknown. GLP-1 (10 nmol/L) increased intracellular cAMP (from 5.7+/-0.5 to 13.1 +/- 0.12 pmol/mg protein) in ra t cardiac myocytes. The effects of cAMP-doubling concentrations of both GLP -1 and isoproterenol (ISO. 10 nmol/L) on contraction amplitude, intracellul ar Ca2+ transient (CaT), and pH(i) in indo-1 and seminaphthorhodafluor (SNA RF)-1 loaded myocytes were compared. Whereas ISO caused a characteristic in crease (above baseline) in contraction amplitude (160+/-34%) and CaT (70+/- 5%), GLP-1 induced a significant decrease in contraction amplitude (-27+/-5 %) with no change in the CaT after 20 minutes. Neither pertussis toxin trea tment nor exposure to the cGMP-stimulated phosphodiesterase (PDE2) inhibito r erythro-9-(2-hydroxy-3-nonyl)adenine or the nonselective PDE inhibitor 3- isobutyl-1-methylxanthine nor the phosphatase inhibitors okadaic acid or ca lyculin A unmasked an ISO-mimicking response of GLP-1. In SNARF-1-loaded my ocytes, however, both ISO and GLP-1 caused an intracellular acidosis (Delta pH(i) -0.09+/-0.02 and -0.08+/-0.03, respectively). The specific GLP-1 ant agonist exendin 9-39 and the cAMP inhibitory analog Rp-8CPT-cAMPS inhibited both the GLP-1-induced intracellular acidosis and the negative contractile effect. We conclude that in contrast to beta -adrenergic signaling, GLP-1 increases cAMP but fails to augment contraction, suggesting the existence o f functionally distinct adenylyl cyclase/cAMP/protein kinase A compartments , possibly determined by unique receptor signaling microdomains that are no t controlled by pertussis toxin-sensitive G proteins or by enhanced local P DE or phosphatase activation. Furthermore, GLP-1 elicits a cAMP-dependent m odest negative inotropic effect produced by a decrease in myofilament-Ca2responsiveness probably resulting from intracellular acidification.