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

Xiao YF, Nikolskaya A, Jaye DA, Sigg DC - Cardiovasc Diabetol (2011)

Bottom Line: Interestingly, preclinical and clinical evidence suggests that GLP-1 agonists produce beneficial effects on dysfunctional hearts via acting on myocardial GLP-1 receptors.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cardiac Rhythm Disease Management, Medtronic, Inc., 8200 Coral Sea Street NE, Mounds View, MN 55112, USA. yong-fu.xiao@medtronic.com

ABSTRACT

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.

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Effects of GLP-1 on action potentials in isolated canine left ventricular cardiomyocytes. A, Extracellular perfusion of 5 nM GLP-1 (GLP-1) prolonged the action potential duration and the effect was removable after washing out of GLP-1 (Washout). B, GLP-1 at 5 nM prolonged the action potential durations measured at 50% (APD50) and 90% (APD90) repolarization. ΔAPD, the differences between control and 5 nM GLP-1. *, p < 0.05; **, p < 0.01; versus control.
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Figure 4: Effects of GLP-1 on action potentials in isolated canine left ventricular cardiomyocytes. A, Extracellular perfusion of 5 nM GLP-1 (GLP-1) prolonged the action potential duration and the effect was removable after washing out of GLP-1 (Washout). B, GLP-1 at 5 nM prolonged the action potential durations measured at 50% (APD50) and 90% (APD90) repolarization. ΔAPD, the differences between control and 5 nM GLP-1. *, p < 0.05; **, p < 0.01; versus control.

Mentions: As L-type Ca2+ currents can affect the plateau of a cardiac action potential (AP) and as GLP-1 could enhance ICa, we next investigated the effects of GLP-1 on the AP duration (APD). Figure 4A shows that extracellular perfusion of 5 nM GLP-1 gradually prolonged the APDs of the patched cardiomyocyte. The prolongation effect was initiated within 2 min after GLP-1 perfusion and reached the maximal level around 10 min. The GLP-1-induced APD prolongation was recoverable after washing out of the compound (Fig. 4A and Table 1). The durations of the APs measured at 50% and 90% repolarization were significantly prolonged in the presence of 5 nM GLP-1 (Fig. 4B and Table 1). Other AP parameters, such as amplitude, threshold, and maximum upstroke velocity of AP, were not significantly altered in the presence of 5 nM GLP-1. The APD prolongations showed a concentration-dependent trend. The delta prolongations were 24.8 ± 11.5 ms and 25.7 ± 15.7 ms for 0.05 nM GLP-1, and 42.2 ± 25.1 ms and 48.5 ± 25.2 ms for 0.5 nM GLP-1 measured at 50% and 90% repolarization, respectively, but these changes did not reach statistical significance at both concentrations (p > 0.05, n = 6).


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

Xiao YF, Nikolskaya A, Jaye DA, Sigg DC - Cardiovasc Diabetol (2011)

Effects of GLP-1 on action potentials in isolated canine left ventricular cardiomyocytes. A, Extracellular perfusion of 5 nM GLP-1 (GLP-1) prolonged the action potential duration and the effect was removable after washing out of GLP-1 (Washout). B, GLP-1 at 5 nM prolonged the action potential durations measured at 50% (APD50) and 90% (APD90) repolarization. ΔAPD, the differences between control and 5 nM GLP-1. *, p < 0.05; **, p < 0.01; versus control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3037307&req=5

Figure 4: Effects of GLP-1 on action potentials in isolated canine left ventricular cardiomyocytes. A, Extracellular perfusion of 5 nM GLP-1 (GLP-1) prolonged the action potential duration and the effect was removable after washing out of GLP-1 (Washout). B, GLP-1 at 5 nM prolonged the action potential durations measured at 50% (APD50) and 90% (APD90) repolarization. ΔAPD, the differences between control and 5 nM GLP-1. *, p < 0.05; **, p < 0.01; versus control.
Mentions: As L-type Ca2+ currents can affect the plateau of a cardiac action potential (AP) and as GLP-1 could enhance ICa, we next investigated the effects of GLP-1 on the AP duration (APD). Figure 4A shows that extracellular perfusion of 5 nM GLP-1 gradually prolonged the APDs of the patched cardiomyocyte. The prolongation effect was initiated within 2 min after GLP-1 perfusion and reached the maximal level around 10 min. The GLP-1-induced APD prolongation was recoverable after washing out of the compound (Fig. 4A and Table 1). The durations of the APs measured at 50% and 90% repolarization were significantly prolonged in the presence of 5 nM GLP-1 (Fig. 4B and Table 1). Other AP parameters, such as amplitude, threshold, and maximum upstroke velocity of AP, were not significantly altered in the presence of 5 nM GLP-1. The APD prolongations showed a concentration-dependent trend. The delta prolongations were 24.8 ± 11.5 ms and 25.7 ± 15.7 ms for 0.05 nM GLP-1, and 42.2 ± 25.1 ms and 48.5 ± 25.2 ms for 0.5 nM GLP-1 measured at 50% and 90% repolarization, respectively, but these changes did not reach statistical significance at both concentrations (p > 0.05, n = 6).

Bottom Line: Interestingly, preclinical and clinical evidence suggests that GLP-1 agonists produce beneficial effects on dysfunctional hearts via acting on myocardial GLP-1 receptors.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cardiac Rhythm Disease Management, Medtronic, Inc., 8200 Coral Sea Street NE, Mounds View, MN 55112, USA. yong-fu.xiao@medtronic.com

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus