Role of slow delayed rectifier K<sup>+</sup>‐current in QT prolongation in the alloxan‐induced diabetic rabbit heart

Lengyel, C; Virág, László; Kovács, P.; Kristóf, Attila; Pacher, Pál; Kocsis, Erzsébet; Koltay, Zs. M.; Nánási, P. P.; Tóth, Miklós; Kecskeméti, Valéria; Papp, Julius Gy.; Varró, András; Jost, Norbert

doi:10.1111/j.1748-1716.2007.01753.x

Cited by 45 publications

(37 citation statements)

References 43 publications

(54 reference statements)

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“…This work is performed in an animal model (rat) which has only part of the cardiac K + repolarizing currents present in human heart (I to and IK 1 ). Different works carried out in different animal models showed that IK 1 is not affected by diabetes, IK s is slightly reduced, IK r is slightly or no reduced, and I to is reduced by half, being this last the main responsible for the action potential alterations found in diabetic hearts [2,14,40,41]. However, based on the results obtained with I to , we can expect that the intracellular regulation of the other channels would be impaired in diabetic hearts as well.…”

Section: Discussioncontrasting

confidence: 40%

Reduced Calmodulin Expression Accelerates Transient Outward Potassium Current Inactivation in Diabetic Rat Heart

Gallego

Ahyayauch

et al. 2008

Cell Physiol Biochem

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Background/Aims: In myocytes from diabetic hearts, the reduction in the amplitude of the transient outward potassium current (I_to) and the acceleration of its inactivation contribute to the action potential duration lengthening. Whereas the reduced amplitude is attributable to a reduced support of trophic factors, the mechanism underlying the acceleration of inactivation remains unknown. Ca²⁺/Calmodulin-dependent protein kinase II (CaMKII) modifies the inactivation kinetics of I_to. In this work we explored the role of CaMKII in the acceleration of I_to current inactivation observed in diabetic myocytes. Methods: We used patch-clamp and immunoblotting techniques in enzymatically-isolated myocytes from healthy and streptozotocin-induced diabetic rat hearts, and in blood samples from diabetic patients. Results: In control myocytes, inhibition of either calmodulin or CaMKII accelerated I_to current inactivation. However, in diabetic myocytes I_to inactivation was already accelerated, and did not respond to calmodulin or CaMKII inhibition. Calmodulin protein abundance was significantly reduced in diabetic myocytes. Incubation of diabetic myocytes with insulin recovered calmodulin expression to normal values. A similar pattern of calmodulin expression appears in the blood of diabetic patients. Insulin treatment also restored I_to current inactivation kinetics as well as the responsiveness to regulation by calmodulin. Conclusion: Diabetes-induced acceleration of I_to current inactivation is due to a reduced effect of CaMKII on I_to channels as a result of a diabetes-induced reduction in calmodulin protein expression. A correct follow up of the insulin treatment could prevent this alteration.

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Section: Discussioncontrasting

confidence: 40%

Reduced Calmodulin Expression Accelerates Transient Outward Potassium Current Inactivation in Diabetic Rat Heart

Gallego

Ahyayauch

et al. 2008

Cell Physiol Biochem

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“…In contrast, the CV at [K + ] o =4 mM was significantly slower (by ≈13%) in diabetic hearts, compared to controls (CV = 0.53±0.02 m/s in control vs. 0.46±0.02 m/s in diabetes, p<0.05). Some earlier studies suggested that I Kr was reduced in diabetic hearts [13,14], whereas others observed no change [12,15]. Since the conductance of I Kr is proportional to the square root of [K + ] o [34], we hypothesized that stressing the heart with changes in [K + ] o would exacerbate any differences in APD between control and diabetic hearts.…”

Section: Resultsmentioning

confidence: 96%

“…In contrast, Lengyel et al [12] showed a small increase in QTc, and a reduced density of I Ks in the diabetic rabbit hearts, but observed no alterations in the density/properties of I Kr . In the canine model of diabetes, only little to moderate QTc and APD prolongation were shown, with decreases in I to and I Ks , but no change in I Kr was observed [15].…”

Section: Introductionmentioning

confidence: 84%

“…Furthermore, in rabbits, I Kr and I Ks constitute the key repolarizing currents, and these currents show similar biophysical characteristics to those found in humans [10,11]. As a result, in the last 6–7 years, several studies have utilized rabbit/canine/guinea pig models to study the electrophysiological/ionic alterations in diabetes [12–16]. …”

Section: Introductionmentioning

confidence: 99%

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Reduced Na+ current density underlies impaired propagation in the diabetic rabbit ventricle

Stables

Musa

Mitra

et al. 2014

Journal of Molecular and Cellular Cardiology

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Diabetes is associated with an increased risk of sudden cardiac death, but the underlying mechanisms remain unclear. Our goal was to investigate changes occurring in the action potential duration (APD) and conduction velocity (CV) in the diabetic rabbit ventricle, and delineate the principal ionic determinants. A rabbit model of alloxan-induced diabetes was utilized. Optical imaging was used to record electrical activity in isolated Langendorff-perfused hearts in normo-, hypo- and hyper-kalemia ([K+]o=4, 2, 12 mM respectively). Patch clamp experiments were conducted to record Na+ current (INa) in isolated ventricular myocytes. The mRNA/protein expression levels for Nav1.5 (the α-subunit of INa) and connexin-43 (Cx43), as well as fibrosis levels were examined. Computer simulations were performed to interpret experimental data. We found that the APD was not different, but that the CV was significantly reduced in diabetic hearts in normo-, hypo-, and, in hyper-kalemic conditions (13%, 17% and 33% reduction in diabetic vs. control, respectively). The cell capacitance (Cm) was increased (by ~14%), and the density of INa was reduced by ~32% in diabetes compared to controls, but the other biophysical properties of INa were unaltered. The mRNA/protein expression levels for Cx43 were unaltered. For Nav1.5, the mRNA expression was not changed, and though the protein level tended to be less in diabetic hearts, this reduction was not statistically significant. Staining showed no difference in fibrosis levels between the control and diabetic ventricles. Computer simulations showed that the reduced magnitude of INa was a key determinant of impaired propagation in the diabetic ventricle, which may have important implications for arrhythmogenesis.

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“…Diabetes is a significant independent risk factor for heart failure and there are a substantial number of patients with both diabetes and heart failure [4]. The most well documented electrophysiological dysfunction of type I diabetes is a prolongation of the QT interval in the electrocardiogram [2], which is a direct effect of the prolongation of the ventricle action potential [5]. One of the less thoroughly studied effects of type I diabetes is related to the conduction of electrical activation through the heart.…”

Section: Introductionmentioning

confidence: 99%

Reduced conduction reserve of the propagating cardiac impulse in the diabetic rat heart: A model study

Ghaly

Boyle

Vigmond

et al. 2008

2008 30th Annual International Conference of the IEEE Engineering in Medicine and Biology Society

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Conduction velocity is dependent on two main factors: intercellular electrical coupling and cellular electrical excitability. There is significant redundancy, 'conduction reserve', in these parameters such that significant reduction in the conduction velocity of the action potential requires either a severe change in one of these parameters or a combined change in both parameters. Studies in diabetic rat hearts have shown a significant reduction in the conduction reserve and it was hypothesized that this is mainly due to the lateralization of the gap junction protein connexin 43 (Cx43). To gain a better understanding of the effect of reduced intercellular coupling, a rat ventricle myocyte model was used to simulate propagation along a strand of cells. Simulations were performed to assess the effect of reduction of intercellular conductance on the conduction velocity. As the conductance of the gap junction decreased a significant reduction in the conduction velocity was observed. The relationship between conduction velocity and intercellular coupling became steeper with decreasing coupling, such that conduction velocity became increasingly sensitive to further uncoupling. This is consistent with experimental results, in which application of the gap junction uncoupler heptanol caused a larger conduction slowing in diabetic hearts than in controls.

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Role of slow delayed rectifier K⁺‐current in QT prolongation in the alloxan‐induced diabetic rabbit heart

Abstract: It is concluded that type 1 diabetes mellitus, although only moderately, lengthens ventricular repolarization. Diabetes attenuates the repolarization reserve by decreasing the density of I(Ks) current, and thereby may enhance the risk of sudden cardiac death.

Cited by 45 publications

References 43 publications

Reduced Calmodulin Expression Accelerates Transient Outward Potassium Current Inactivation in Diabetic Rat Heart

Reduced Calmodulin Expression Accelerates Transient Outward Potassium Current Inactivation in Diabetic Rat Heart

Reduced Na+ current density underlies impaired propagation in the diabetic rabbit ventricle

Reduced conduction reserve of the propagating cardiac impulse in the diabetic rat heart: A model study

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Role of slow delayed rectifier K+‐current in QT prolongation in the alloxan‐induced diabetic rabbit heart

Abstract: It is concluded that type 1 diabetes mellitus, although only moderately, lengthens ventricular repolarization. Diabetes attenuates the repolarization reserve by decreasing the density of I(Ks) current, and thereby may enhance the risk of sudden cardiac death.

Cited by 45 publications

References 43 publications

Reduced Calmodulin Expression Accelerates Transient Outward Potassium Current Inactivation in Diabetic Rat Heart

Reduced Calmodulin Expression Accelerates Transient Outward Potassium Current Inactivation in Diabetic Rat Heart

Reduced Na+ current density underlies impaired propagation in the diabetic rabbit ventricle

Reduced conduction reserve of the propagating cardiac impulse in the diabetic rat heart: A model study

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Role of slow delayed rectifier K⁺‐current in QT prolongation in the alloxan‐induced diabetic rabbit heart