Glucagon-like peptide-1 enhances cardiac L-type Ca2+ currents via activation of the cAMP-dependent protein kinase A pathway

Background: Glucagon-like peptide-1 (GLP-1) is a hormone predominately synthesized and secreted by intestinal L-cells. GLP-1 modulates multiple cellular functions and its receptor agonists are now used clinically for diabetic treatment. Interestingly, preclinical and clinical evidence suggests that GLP-1 agonists produce beneficial effects on dysfunctional hearts via acting on myocardial GLP-1 receptors. As the effects of GLP-1 on myocyte electrophysiology are largely unknown, this study was to assess if GLP-1 could affect the cardiac voltage-gated L-type Ca2+ current (I-Ca). Methods: The whole-cell patch clamp method was used to record I-Ca and action potentials in enzymatically isolated cardiomyocytes from adult canine left ventricles. Results: Extracellular perfusion of GLP-1 (7-36 amide) at 5 nM increased I-Ca by 23 +/- 8% (p < 0.05, n = 7). Simultaneous bath perfusion of 5 nM GLP-1 plus 100 nM Exendin (9-39), a GLP-1 receptor antagonist, was unable to block the GLP-1-induced increase in I-Ca; however, the increase in I-Ca was abolished if Exendin (9-39) was pre-applied 5 min prior to GLP-1 administration. Intracellular dialysis with a protein kinase A inhibitor also blocked the GLP-1-enhanced I-Ca. In addition, GLP-1 at 5 nM prolonged the durations of the action potentials by 128 +/- 36 ms (p < 0.01) and 199 +/- 76 ms (p < 0.05) at 50% and 90% repolarization (n = 6), respectively. Conclusions: Our data demonstrate that GLP-1 enhances I-Ca in canine cardiomyocytes. The enhancement of I-Ca is likely via the cAMP-dependent protein kinase A mechanism and may contribute, at least partially, to the prolongation of the action potential duration.