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.
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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)