Contribution of IKr and IK1 to ventricular repolarization in canine and human myocytes: is there any influence of action potential duration?
ABSTRACT BackgroundThe aim of the present work was to study the profile of the rapid delayed rectifier potassium current (IKr) and the inward rectifier potassium current (IK1) during ventricular repolarization as a function of action potential duration and rate of repolarization.
MethodsWhole cell configuration of the patch clamp technique was used to monitor IKr and IK1 during the action potential plateau and terminal repolarization. Action potentials recorded at various cycle lengths (0.4–5s) and repolarizing voltage ramps having various slopes (0.5–3V/s) were used as command signals. IKr and IK1 were identified as difference currents dissected by E-4031 and BaCl2, respectively.
ResultsNeither peak amplitudes nor mean values of IKr and IK1 recorded during the plateau of canine action potentials were influenced by action potential duration. The membrane potential where IKr and IK1 peaked during the terminal repolarization was also independent of action potential duration. Similar esults were obtained in undiseased human ventricular myocytes, and also in canine cells when IKr and IK1 were evoked using repolarizing voltage ramps of various slopes. Action potential voltage clamp experiments revealed that the peak values of IKr, IK1, and net outward current during the terminal repolarization were independent of the pacing cycle length within the range of 0.4 and 5s.
ConclusionsThe results indicate that action potential configuration fails to influence the amplitude of IKr and IK1 during the ventricular action potential in dogs and humans, suggesting that rate-dependent changes in action potential duration are not likely related to rate-dependent alterations in IKr or IK1 kinetics in these species.
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ABSTRACT: Dilated cardiomyopathy (DCM) is a multifactorial disease characterized by left ventricular dilation that is associated with systolic dysfunction and increased action potential duration. The Kir2.x K(+) channels (encoded by KCNJ genes) regulate the inward rectifier current (IK1) contributing to the final repolarization in cardiac muscle. Here, we describe the transitions in the gene expression profiles of 4 KCNJ genes from healthy or dilated cardiomyopathic human hearts. In the healthy adult ventricles, KCNJ2, KCNJ12, and KCNJ4 (Kir2.1-2.3, respectively) genes were expressed at high levels, while expression of the KCNJ14 (Kir2.4) gene was low. In DCM ventricles, the levels of Kir2.1 and Kir2.3 were upregulated, but those of Kir2.2 channels were downregulated. Additionally, the expression of the DLG1 gene coding for the synapse-associated protein 97 (SAP97) anchoring molecule exhibited a 2-fold decline with increasing age in normal hearts, and it was robustly downregulated in young DCM patients. These adaptations could offer a new aspect for the explanation of the generally observed physiological and molecular alterations found in DCM.Canadian Journal of Physiology and Pharmacology 08/2013; 91(8):648-56. · 1.56 Impact Factor
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ABSTRACT: The ability of human pluripotent stem cells (hPSC) to differentiate into any cell type of the three germ layers makes them a very promising cell source for multiple purposes, including regenerative medicine, drug discovery, and as a model to study disease mechanisms and progression. One of the first specialized cell types to be generated from hPSC was cardiomyocytes (CM), and differentiation protocols have evolved over the years and now allow for robust and large-scale production of hPSC-CM. Still, scientists are struggling to achieve the same, mainly ventricular, phenotype of the hPSC-CM in vitro as their adult counterpart in vivo. In vitro generated cardiomyocytes are generally described as fetal-like rather than adult. In this review, we compare the in vivo development of cardiomyocytes to the in vitro differentiation of hPSC into CM with focus on electrophysiology, structure and contractility. Furthermore, known epigenetic changes underlying the differences between adult human CM and CM differentiated from pluripotent stem cells are described. This should provide the reader with an extensive overview of the current status of human stem cell-derived cardiomyocyte phenotype and function. Additionally, the reader will gain insight into the underlying signaling pathways and mechanisms responsible for cardiomyocyte development.Journal of Molecular and Cellular Cardiology 12/2013; · 5.15 Impact Factor
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ABSTRACT: Adrenergic activation of L-type Ca(2+) and various K(+) currents is a crucial mechanism of cardiac adaptation; however, it may carry a substantial proarrhythmic risk as well. The aim of the present work was to study the timing of activation of Ca(2+) and K(+) currents in isolated canine ventricular cells in response to exposure to isoproterenol (ISO). Whole cell configuration of the patch-clamp technique in either conventional voltage clamp or action potential voltage clamp modes were used to monitor I Ca, I Ks, and I Kr, while action potentials were recorded using sharp microelectrodes. ISO (10 nM) elevated the plateau potential and shortened action potential duration (APD) in subepicardial and mid-myocardial cells, which effects were associated with multifold enhancement of I Ca and I Ks and moderate stimulation of I Kr. The ISO-induced plateau shift and I Ca increase developed faster than the shortening of APD and stimulation of I Ks and I Kr. Blockade of β1-adrenoceptors (using 300 nM CGP-20712A) converted the ISO-induced shortening of APD to lengthening, decreased its latency, and reduced the plateau shift. In contrast, blockade of β2-adrenoceptors (by 50 nM ICI 118,551) augmented the APD-shortening effect and increased the latency of plateau shift without altering its magnitude. All effects of ISO were prevented by simultaneous blockade of both receptor types. Inhibition of phosphodiesterases decreased the differences observed in the turn on of the ISO-induced plateau shift and APD shortening. ISO-induced activation of I Ca is turned on faster than the stimulation of I Ks and I Kr in canine ventricular cells due to the involvement of different adrenergic pathways and compartmentalization.Archiv für Experimentelle Pathologie und Pharmakologie 02/2014; · 2.15 Impact Factor