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

Cardiovascular Diabetology, Jan 2011

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 (ICa). Methods The whole-cell patch clamp method was used to record ICa 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 ICa 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 ICa; however, the increase in ICa 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 ICa. 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 ICa in canine cardiomyocytes. The enhancement of ICa is likely via the cAMP-dependent protein kinase A mechanism and may contribute, at least partially, to the prolongation of the action potential duration.

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

Cardiovascular Diabetology Glucagon-like peptide-1 enhances cardiac 2+ L-type Ca currents via activation of the cAMP-dependent protein kinase A pathway Yong-Fu Xiao 0 Alena Nikolskaya 0 Deborah A Jaye 0 Daniel C Sigg 0 0 Cardiac Rhythm Disease Management, Medtronic, Inc. , 8200 Coral Sea Street NE, Mounds View, MN 55112 , USA 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 Ltype Ca2+ current (ICa). Methods: The whole-cell patch clamp method was used to record ICa 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 ICa 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 ICa; however, the increase in ICa was abolished if Exendin (9-39) was preapplied 5 min prior to GLP-1 administration. Intracellular dialysis with a protein kinase A inhibitor also blocked the GLP-1-enhanced ICa. 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 ICa in canine cardiomyocytes. The enhancement of ICa is likely via the cAMP-dependent protein kinase A mechanism and may contribute, at least partially, to the prolongation of the action potential duration. - Background Glucagon-like peptide-1 (GLP-1) is one of the transcription products from the proglucagon gene. GLP-1 is a peptide hormone predominately produced by intestinal endocrine L-cells. GLP-1 has two major isoforms (7-36 amide and 7-37) which are among the most potent stimulators of glucose-dependent insulin secretion. Both peptides are considered equipotent in terms of their biological activity[1,2]. GLP-1 stimulates glucose-dependent insulin secretion and insulin biosynthesis and inhibits glucagon secretion, gastric emptying, and food intake. The N-terminal degradation of GLP-1 by dipeptidyl peptidase-4 (DPP-4)-mediated cleavage at the position 2 alanine modifies its biological activity[3]. GLP-1 modulates multiple cellular functions believably via acting on GLP-1 receptors (GLP-1Rs)[4], which are expressed in the human pancreas, heart, lung, kidney, stomach and brain[5]. Due to the multiple beneficial effects of GLP-1R agonists in the treatment of diabetes mellitus including weight loss, pharmaceutical companies have developed and introduced GLP-1R agonists as a treatment option for patients with type 2 diabetes mellitus (e.g. Byetta (exenatide) and Victoza (liraglutide)). Various cardiovascular effects of GLP-1 have been reported. GLP-1 infusion improves glucose uptake [6] and metabolism[7], as well as cardiac function[6] and hemodynamics[8-10] in different species, including in humans[11]. In addition, GLP-1 infusion reduced infarct size in a rodent model of ischemia with no effect on ventricular function[12,13], but did not alter infarct size in an open-chest, anesthetized porcine model of ischemia[5]. Furthermore, GLP-1R knockout mice (GLP-1R-/-) have lower heart rate and blood pressure with an increase in cardiac mass[14]. In clinical studies using liraglutide (Victoza), a GLP-1R agonist, a consistent decrease in blood pressure and a reduction of cardiovascular risk markers were observed in a cohort of over 5000 patients[15]. In pancreatic b-cells, GLP-1 inhibits ATP-dependent K+ channels via the cAMP-mediated PKA pathway [16-19]. The effects of GLP-1 on myocardium observed in several studies are potentially via its G proteincoupled receptors[10,20]. Recently, a new glucagon-like peptide isolated from the intestine of the eel, Anguilla japonica[21] with a structure similar to that of oxyntomodulins has shown an inotropic effect via stimulation of Ca2+ influx and a chronotropic effect independent of extracellular Ca2+. In addition, GLP-1 and glucosedependent insulinotropic polypeptide can enhance b-cell cytoplasmic Ca2+ oscillation and increase insulin secretion via activation of cAMP-triggered cascades[22,23]. However, the effects of GLP-1 on myocyte electrophysiology have not been carefully assessed. Therefore, in the present study, we investigated the effects of GLP-1 on the voltage-gated L-type Ca2+ channel in isolated canine left ventricular myocytes. Methods The study was designed and conducted in accordance with the Guide for the Care an (...truncated)


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Yong-Fu Xiao, Alena Nikolskaya, Deborah A Jaye, Daniel C Sigg. Glucagon-like peptide-1 enhances cardiac L-type Ca2+ currents via activation of the cAMP-dependent protein kinase A pathway, Cardiovascular Diabetology, 2011, pp. 6, 10, DOI: 10.1186/1475-2840-10-6