Yong-Fu Xiao

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

BackgroundGlucagon-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).MethodsThe whole-cell patch clamp method was used to record ICa and action potentials in enzymatically isolated cardiomyocytes from adult canine left ventricles.ResultsExtracellular 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.ConclusionsOur 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.

Basic Cardiac Electrophysiology: Excitable Membranes

Cardiomyocytes are excitable cells that have the ability to contract after excitation; therefore, each heartbeat is an event of electrical-mechanical coupling. Cardiac electrical activity at different levels can be measured through variable means and modified by different drugs or medical devices. Understanding the basic mechanisms of cardiac excitation is essential not only to a physiologist, but also to a cardiologist, because cardiac arrhythmias are a major health issue in our society and clinical practice. Diagnosis and therapy of arrhythmias requires understanding the cause or origin of each arrhythmia and making decisions to control or eliminate the arrhythmia. Advances in basic research enhance our understanding of normal cell, tissue, and organ function (physiology) and also disease processes (pathophysiol- ogy), and hopefully lead to better clinical diagnosis and improved clinical therapies, either directly or indirectly. Cardiomyocytes are the main component of a heart. Their electrical activity is fundamentally a bioprocess determined by the transmem- brane potential, a voltage difference between the intracellular and extracellular com- partments. During a normal cardiac cycle, mechanical contraction always follows electrical excitation. This chapter provides a basic overview of membrane excitabil- ity of cardiomyocytes and other excitable cells (i.e., neuronal and skeletal).