Modulators of Ion Channels Activated by Hypotonic Swelling in Cardiomyocytes: New Perspectives for Pharmacological Treatment of Life-Threatening Arrhythmias

Kocić, Ivan

doi:10.2174/156801605774322274

Cited by 7 publications

(9 citation statements)

References 55 publications

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“…Following the electrophysiological remodeling of the atria, changes in the structure of the atria start to follow. One of the structural changes is the dilatation of atrial myocyte plasma membrane (11,12), increasing the I Ks currents in the cells and aggravates the atrial remodeling (16,19). The present study found that losartan attenuated both the I Ks increase and the APD (26,27), providing clinical support for our experimental speculation.…”

Section: Discussionsupporting

confidence: 81%

“…Hypo-S-induced stretch of atrial myocytes fits the stretch of myocardial cell membrane, generally causing the various transport changes of related ion channels (including the increase of I Ks in atrial myocytes) in the early stage of AF (11,16,(18)(19)(20). Figure 2a-2e shows the typical I Ks current curves elicited by depolarizing voltage-clamp steps given from a −50 mV holding potential to various test potentials in the presence of Iso-S (panel A), Hypo-S (panel B), Hypo-S+1 μM losartan (panel C), Hypo-S+10 μM losartan (panel D), and Hypo-S+20 μM losartan (panel E).…”

Section: Resultsmentioning

confidence: 99%

“…Electrophysiological studies have shown that the main effect of AF on cardiac ion channels is the reduction of I Ca,L inward current and calcium overload in atrial myocytes (11), resulting in atrial systolic and diastolic dysfunction. The resultant stretch of atrial myocyte plasma membrane can increase the outward I Ks currents in the cells (16,19). Changes in I Ca,L and I Ks channel currents cause shortening of APD in atrial myocytes and physiological atrial dysrhythmia, thus contributing to the occurrence of electrophysiological and structural remodeling in the atria, which are the forming basis of persistent AF (11,20).…”

Section: Discussionmentioning

confidence: 99%

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Losartan inhibits hyposmotic-induced increase of IKs current and shortening of action potential duration in guinea pig atrial myocytes

Gao

Tian²,

Xie

et al. 2019

Anatol J Cardiol

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Losartan inhibits hyposmotic-induced increase of I Ks current and shortening of action potential duration in guinea pig atrial myocytes Objective: The present study aims to investigate the effect of losartan, an selective angiotensin II type 1 receptor (AT 1 R) blocker, on both the increase of I Ks current and shortening of action potential duration (APD) induced by stretch of atrial myocytes, and to uncover the mechanism underlying the treatment of fibrillation (AF) by AT 1 R blockers. Methods: Hyposmotic solution (Hypo-S) was applied in the guinea pig atrial myocytes to simulate cell stretch, then patch-clamp technique was applied to record the I Ks and APD in atrial myocytes. Results: Hypo-S increased the I Ks by 105.6%, while Hypo-S+1-20 μM of losartan only increased the I Ks by 70.3-75.5% (p<0.05 vs. Hypo-S). Meanwhile, Hypo-S shortened APD 90 by 20.2%, while Hypo-S+1-20 μM of losartan shortened APD 90 by 13.03-14.56% (p<0.05 vs. Hypo-S). Conclusion:The above data indicate that the effect of losartan on the electrophysiological changes induced by stretch of atrial myocytes is associated with blocking of AT 1 receptor, and is beneficial for the treatment of AF that is often accompanied by the expansion of atrial myocytes and the increase of effective refractory period.

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Section: Discussionsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Losartan inhibits hyposmotic-induced increase of IKs current and shortening of action potential duration in guinea pig atrial myocytes

Gao

Tian²,

Xie

et al. 2019

Anatol J Cardiol

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“…Meyers et al, 2006). Deregulation of cell volume homeostasis, on the other hand, has been related to different pathophysiological conditions including, but not only, cerebral edema, hypercatabolic states, diabetes mellitus, chronic renal failure, sickle cell disease and uraemia (Strange, 1992;McManus et al, 1995;Waldegger et al, 1998;Won et al, 2002;PasantesMorales et al, 2002b;Haussinger, 2004;Bringmann et al, 2005;Kimelberg, 2005;Kocic, 2005;Leis et al, 2005;Norenberg et al, 2005Norenberg et al, , 2007Sterns and Silver, 2006;Verbalis, 2006;Liang et al, 2007;Mongin, 2007;Rosenblum, 2007).…”

mentioning

confidence: 99%

Autocrine signaling involved in cell volume regulation: The role of released transmitters and plasma membrane receptors

Franco

Panayiotidis

Paz

2008

Journal Cellular Physiology

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Cell volume regulation is a basic homeostatic mechanism transcendental for the normal physiology and function of cells. It is mediated principally by the activation of osmolyte transport pathways that result in net changes in solute concentration that counteract cell volume challenges in its constancy. This process has been described to be regulated by a complex assortment of intracellular signal transduction cascades. Recently, several studies have demonstrated that alterations in cell volume induce the release of a wide variety of transmitters including hormones, ATP and neurotransmitters, which have been proposed to act as extracellular signals that regulate the activation of cell volume regulatory mechanisms. In addition, changes in cell volume have also been reported to activate plasma membrane receptors (including tyrosine kinase receptors, G-protein coupled receptors and integrins) that have been demonstrated to participate in the regulatory process of cell volume. In this review, we summarize recent studies about the role of changes in cell volume in the regulation of transmitter release as well as in the activation of plasma membrane receptors and their further implications in the regulation of the signaling machinery that regulates the activation of osmolyte flux pathways. We propose that the autocrine regulation of Ca2+-dependent and tyrosine phosphorylation-dependent signaling pathways by the activation of plasma membrane receptors and swelling-induced transmitter release is necessary for the activation/regulation of osmolyte efflux pathways and cell volume recovery. Furthermore, we emphasize the importance of studying these extrinsic signals because of their significance in the understanding of the physiology of cell volume regulation and its role in cell biology in vivo, where the constraint of the extracellular space might enhance the autocrine or even paracrine signaling induced by these released transmitters.

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“…Also, as ICl swell is involved in numerous pathophysiological processes 67 , its pharmacological inhibition is regarded as a potential strategy in the treatment of several life-threatening conditions. For example, in the heart, blockers of Cl − currents such as ICl swell may have antiarrhythmic properties 68,69 . Furthermore, pharmacological inhibition of ICl swell antagonizes apoptosis by preventing apoptotic volume decrease and downstream apoptotic events 70 .…”

Section: Discussionmentioning

confidence: 99%

Binding of the protein ICln to α-integrin contributes to the activation of IClswell current

Schedlbauer

Tamma

Rodighiero

et al. 2019

Sci Rep

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icl swell is the chloride current induced by cell swelling, and plays a fundamental role in several biological processes, including the regulatory volume decrease (RVD). ICln is a highly conserved, ubiquitously expressed and multifunctional protein involved in the activation of icl swell. In platelets, ICln binds to the intracellular domain of the integrin αIIb chain, however, whether the ICln/integrin interaction plays a role in RVD is not known. Here we show that a direct molecular interaction between ICln and the integrin α-chain is not restricted to platelets and involves highly conserved amino acid motifs. integrin α recruits ICln to the plasma membrane, thereby facilitating the activation of ICl swell during hypotonicity. Perturbation of the ICln/integrin interaction prevents the transposition of ICln towards the cell surface and, in parallel, impedes the activation of ICl swell. We suggest that the ICln/integrin interaction interface may represent a new molecular target enabling specific ICl swell suppression in pathological conditions when this current is deregulated or plays a detrimental role. Cellular volume changes occur in a variety of physiological processes, including transepithelial transport, cell migration, proliferation, and death. As limiting excessive or prolonged volume changes is essential for normal cell function and survival, most cell types are able to counteract volume perturbations by initiating the homeostatic processes of regulatory volume increase and decrease (RVI and RVD, respectively) 1-4. Activation of a chloride conductance upon cell swelling (ICl swell) is a key step in RVD and occurs via volume regulated anion channels (VRACs) 5,6. The mechanisms of osmosensing are complex and far from being completely understood. Several lines of evidence implicate integrins as upstream sensors of cell volume perturbations in mammalian cells after cell swelling or shrinkage 1,7-9. Integrins are a highly conserved family of heterodimeric adhesion molecules that consist of an αand a β-subunit and connect the extracellular matrix to intracellular signalling proteins and the cytoskeleton, and play a critical role in many vital cellular functions, such as cell adhesion, migration, invasion, differentiation, proliferation, apoptosis, growth-factor signalling and response to hypotonicity 10-13. By linking the exterior and interior space of cells, integrins permit a bidirectional transmission (outside-in and inside-out signalling) of mechanical and biochemical stimuli across the plasma membrane 14,15. Specifically, activation of integrins by hypotonicity 16 seems to trigger Cl − and organic osmolyte fluxes during RVD, possibly by recruitment of a member of the SRC family of kinases 17. Integrins also establish an intricate network of molecular interactions via their intracellular domains. The β-subunits are major players in this context, and bind signalling hubs such as talin and kindlins 18-20. The intracellular network of the α-subunits was less extensively studied. Evidence was gathered that the ...

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Modulators of Ion Channels Activated by Hypotonic Swelling in Cardiomyocytes: New Perspectives for Pharmacological Treatment of Life-Threatening Arrhythmias

Cited by 7 publications

References 55 publications

Losartan inhibits hyposmotic-induced increase of IKs current and shortening of action potential duration in guinea pig atrial myocytes

Losartan inhibits hyposmotic-induced increase of IKs current and shortening of action potential duration in guinea pig atrial myocytes

Autocrine signaling involved in cell volume regulation: The role of released transmitters and plasma membrane receptors

Binding of the protein ICln to α-integrin contributes to the activation of IClswell current

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