Apico-basal inhomogeneity in distribution of ion channels in canine and human ventricular myocardium

Department of Physiology, University of Debrecen, P.O. Box 22, H-4012 Debrecen, Hungary.
Cardiovascular Research (Impact Factor: 5.81). 04/2005; 65(4):851-60. DOI: 10.1016/j.cardiores.2004.11.022
Source: PubMed

ABSTRACT The aim of the present study was to compare the apico-basal distribution of ion currents and the underlying ion channel proteins in canine and human ventricular myocardium.
Ion currents and action potentials were recorded in canine cardiomyocytes, isolated from both apical and basal regions of the heart, using whole-cell voltage clamp techniques. Density of channel proteins in canine and human ventricular myocardium was determined by Western blotting.
Action potential duration was shorter and the magnitude of phase-1 repolarization was significantly higher in apical than basal canine myocytes. No differences were observed in other parameters of the action potential or cell capacitance. Amplitude of the transient outward K(+) current (29.6+/-5.7 versus 16.5+/-4.4 pA/pF at +65 mV) and the slow component of the delayed rectifier K(+) current (5.61+/-0.43 versus 2.14+/-0.18 pA/pF at +50 mV) were significantly larger in apical than in basal myocytes. Densities of the inward rectifier K(+) current, rapid delayed rectifier K(+) current, and L-type Ca(2+) current were similar in myocytes of apical and basal origin. Apico-basal differences were found in the expression of only those channel proteins which are involved in mediation of the transient outward K(+) current and the slow delayed rectifier K(+) current: expression of Kv1.4, KChIP2, KvLQT1 and MinK was significantly higher in apical than in basal myocardium in both canine and human hearts.
The results suggest that marked apico-basal electrical inhomogeneity exists in the canine-and probably in the human-ventricular myocardium, which may result in increased dispersion, and therefore, cannot be ignored when interpreting ECG recordings, pathological alterations, or drug effects.

  • Source
    • "Apicobasal (AB): Apex-to-base dispersion of activationrecovery interval (ARI, a surrogate for APD) has been measured noninvasively in human as 42 ms [14] (mean of 7 subjects) with shorter ARI at the apex than the base. Experiments with canine and human tissue samples suggest the same [15]. We modelled this gradient by increasing g Ks by 50% of normal at the apex. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The electrocardiogram (ECG) is often used to diagnose myocardial infarction, but sensitivity and specificity are low. Here we present a computational framework for solving the bidomain equations over an image-based human geometry and simulating the 12 lead ECG. First, we demonstrate this approach by evaluating a population of eight models with varying distributions of local action potential duration, and report that only the model with apico-basal and inter-ventricular heterogeneities produces concordant T waves. Second, we simulate the effects of an old anterior infarct, which causes a reduction in T wave amplitude and width. Our methodology can contribute to the understanding of ECG alterations under challenging conditions for clinical diagnosis.
    Computing in Cardiology; 09/2014
  • Source
    • "Kir2.2, and Kir2.3) ion channels (Karle et al. 2002; Marban 2002; Rook 2007). Earlier, the asymmetrical distribution and apico-basal inhomogeneity of Kir ion channels were investigated by Szabó et al. (2005) and Szentadrassy et al. (2005). They found that there are no transmural differences, at the protein level, in Kir2.1 channels in human and dog ventricles. "
    [Show abstract] [Hide abstract]
    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. DOI:10.1139/cjpp-2012-0413 · 1.55 Impact Factor
  • Source
    • "In absence of relevant voltage clamp data on the effects of pioglitazone in mammalian cardiac preparations, we aimed to study the concentration-dependent effects of pioglitazone on action potential morphology and the underlying ion currents in isolated canine ventricular cardiomyocytes. Canine ventricular cells were chosen because their electrophysiological properties are believed to be the most similar to those of human regarding the distribution and kinetic properties of transmembrane ion currents (Szabó et al., 2005; Szentandrássy et al., 2005). The results suggest that pioglitazone, similarly to other thiazolidinedione derivatives, inhibits several ion currents in canine ventricular myocardium, including Na + , Ca 2+ , and various K + currents. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite its widespread therapeutical use there is little information on the cellular cardiac effects of the antidiabetic drug pioglitazone in larger mammals. In the present study, therefore, the concentration-dependent effects of pioglitazone on ion currents and action potential configuration were studied in isolated canine ventricular myocytes using standard microelectrode, conventional whole cell patch clamp, and action potential voltage clamp techniques. Pioglitazone decreased the maximum velocity of depolarization and the amplitude of phase-1 repolarization at concentrations≥3μM. Action potentials were shortened by pioglitazone at concentrations≥10μM, which effect was accompanied with significant reduction of beat-to-beat variability of action potential duration. Several transmembrane ion currents, including the transient outward K(+) current (Ito), the L-type Ca(2+) current (ICa), the rapid and slow components of the delayed rectifier K(+) current (IKr and IKs, respectively), and the inward rectifier K(+) current (IK1) were inhibited by pioglitazone under conventional voltage clamp conditions. Ito was blocked significantly at concentrations≥3μM, ICa, IKr, IKs at concentrations≥10μM, while IK1 at concentrations≥30μM. Suppression of Ito, ICa, IKr, and IK1 has been confirmed also under action potential voltage clamp conditions. ATP-sensitive K(+) current, when activated by lemakalim, was effectively blocked by pioglitazone. Accordingly, action potentials were prolonged by 10μM pioglitazone when the drug was applied in the presence of lemakalim. All these effects developed rapidly and were readily reversible upon washout. In conclusion, pioglitazone seems to be a harmless agent at usual therapeutic concentrations.
    European journal of pharmacology 04/2013; DOI:10.1016/j.ejphar.2013.03.047 · 2.68 Impact Factor
Show more