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.
Cardiac Rhythm Disease Management, Medtronic, Inc., 8200 Coral Sea Street NE, Mounds View, MN 55112, USA. yong-fu.xiao@medtronic.com
Yong-Fu
YF
Xiao
Alena
A
Nikolskaya
Deborah A
DA
Jaye
Daniel C
DC
Sigg
D000200:Action Potentials; D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004285:Dogs; D004789:Enzyme Activation; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D066298:In Vitro Techniques; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
D020746:Calcium Channels, L-Type; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D018027:Receptors, Glucagon; C055453:glucagon-like peptide 1 (7-36)amide; C083773:exendin (9-39); D052216:Glucagon-Like Peptide 1; D017868:Cyclic AMP-Dependent Protein Kinases
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