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.
"Apicobasal (AB): Apex-to-base dispersion of activationrecovery interval (ARI, a surrogate for APD) has been measured noninvasively in human as 42 ms  (mean of 7 subjects) with shorter ARI at the apex than the base. Experiments with canine and human tissue samples suggest the same . 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.
"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 · 1.77 Impact Factor
"TTX-sensitive Ca2+ current components have been identified in cardiac tissues under pathological conditions, such as in hypertrophied guinea pig or infarcted rat hearts [4,5]. TTX was shown to block L-type Ca2+ current in ventricular cardiomyocytes isolated from healthy dogs , i.e., in a preparation having electrophysiological properties most similar to those of human ventricular myocardium regarding the distribution and kinetic properties of transmembrane ion currents [7,8]. "
[Show abstract][Hide abstract] ABSTRACT: Tetrodotoxin (TTX) is believed to be one of the most selective inhibitors of voltage-gated fast Na+ channels in excitable tissues. Recently, however, TTX has been shown to block L-type Ca2+ current (ICa) in canine cardiac cells. In the present study, the TTX-sensitivity of ICa was studied in isolated canine ventricular myocytes as a function of (1) channel phosphorylation, (2) extracellular pH and (3) the redox potential of the bathing medium using the whole cell voltage clamp technique. Fifty-five micromoles of TTX (IC50 value obtained under physiological conditions) caused 60% ± 2% inhibition of ICa in acidic (pH = 6.4), while only a 26% ± 2% block in alkaline (pH = 8.4) milieu. Similarly, the same concentration of TTX induced 62% ± 6% suppression of ICa in a reductant milieu (containing glutathione + ascorbic acid + dithiothreitol, 1 mM each), in contrast to the 31% ± 3% blockade obtained in the presence of a strong oxidant (100 μM H2O2). Phosphorylation of the channel protein (induced by 3 μM forskolin) failed to modify the inhibiting potency of TTX; an IC50 value of 50 ± 4 μM was found in forskolin. The results are in a good accordance with the predictions of our model, indicating that TTX binds, in fact, to the selectivity filter of cardiac L-type Ca channels.
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