Desipramine prevents cardiac gap junction uncoupling

Jozwiak, Joanna; Dietze, Anna; Grover, Rajiv; Savtschenko, A; Etz, Christian D.; Mohr, Friedrich W.; Dhein, Stefan

doi:10.1007/s00210-012-0795-2

Cited by 5 publications

(4 citation statements)

References 51 publications

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“…This previous study also demonstrated that hypoxia alone increases pS368-Cx43 expression. On the other hand, other studies have also reported a reduction in pS368-Cx43 induced by acidosis (5,23,34). Additionally, dynamic responses in Cx43 expression and phosphorylation during ischemia have also been previously reported.…”

Section: Gjc In Ischemiamentioning

confidence: 93%

Modulating cardiac conduction during metabolic ischemia with perfusate sodium and calcium in guinea pig hearts

George

Hoeker

Calhoun

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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We previously demonstrated that altering extracellular sodium (Nao) and calcium (Cao) can modulate a form of electrical communication between cardiomyocytes termed “ephaptic coupling” (EpC), especially during loss of gap junction coupling. We hypothesized that altering Nao and Cao modulates conduction velocity (CV) and arrhythmic burden during ischemia. Electrophysiology was quantified by optically mapping Langendorff-perfused guinea pig ventricles with modified Nao (147 or 155 mM) and Cao (1.25 or 2.0 mM) during 30 min of simulated metabolic ischemia (pH 6.5, anoxia, aglycemia). Gap junction-adjacent perinexal width ( WP), a candidate cardiac ephapse, and connexin (Cx)43 protein expression and Cx43 phosphorylation at S368 were quantified by transmission electron microscopy and Western immunoblot analysis, respectively. Metabolic ischemia slowed CV in hearts perfused with 147 mM Nao and 2.0 mM Cao; however, theoretically increasing EpC with 155 mM Nao was arrhythmogenic, and CV could not be measured. Reducing Cao to 1.25 mM expanded WP, as expected during ischemia, consistent with reduced EpC, but attenuated CV slowing while delaying arrhythmia onset. These results were further supported by osmotically reducing WP with albumin, which exacerbated CV slowing and increased early arrhythmias during ischemia, whereas mannitol expanded WP, permitted conduction, and delayed the onset of arrhythmias. Cx43 expression patterns during the various interventions insufficiently correlated with observed CV changes and arrhythmic burden. In conclusion, decreasing perfusate calcium during metabolic ischemia enhances perinexal expansion, attenuates conduction slowing, and delays arrhythmias. Thus, perinexal expansion may be cardioprotective during metabolic ischemia. NEW & NOTEWORTHY This study demonstrates, for the first time, that modulating perfusate ion composition can alter cardiac electrophysiology during simulated metabolic ischemia.

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Section: Gjc In Ischemiamentioning

confidence: 93%

Modulating cardiac conduction during metabolic ischemia with perfusate sodium and calcium in guinea pig hearts

George

Hoeker

Calhoun

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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“…Structure-activity relations together with molecular modeling, and two-dimensional NMR spectroscopy revealed that AAP10 has a semicyclic structure like a horseshoe, which is due to the two Pro residues (Dhein et al, 2010;Dhein, 1998, 2001). Moreover, it could be shown that [ 14 C]AAP10 binds to a membrane protein of rabbit cardiomyocyte membranes with a K d in the order of 0.3-0.9 nM and maximum binding B max in the order of ;42.5 pmol/mg (Jozwiak et al, 2012). The finding of the semicyclic structure and the identification of the essential chemical moieties Dhein, 1998, 2001) led to the idea of replacing some of the amino acids by D-amino acid versions.…”

Section: B Peptide Modulators Of Connexin Channelsmentioning

confidence: 99%

“…This leads to the question of the biochemical mechanisms of action of antiarrhythmic peptides. First of all, it has been shown that AAP10 and rotigaptide binds to a membrane protein with a K d in the range of 0.1-0.9 nM [[ 14 C]AAP10 Jozwiak et al, 2012); [ 125 I]di-I-AAP10 (Jørgensen et al, 2005)]. A 200-kDa membrane protein could be isolated from cardiac tissue by affinity chromatography and cross-linking techniques (Weng et al, 2002), but its identity was not determined.…”

Section: B Peptide Modulators Of Connexin Channelsmentioning

confidence: 99%

Connexins in Cardiovascular and Neurovascular Health and Disease: Pharmacological Implications

Leybaert¹,

Lampe²,

Dhein³

et al. 2017

Pharmacol Rev

Self Cite

198

192

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Connexins are ubiquitous channel forming proteins that assemble as plasma membrane hemichannels and as intercellular gap junction channels that directly connect cells. In the heart, gap junction channels electrically connect myocytes and specialized conductive tissues to coordinate the atrial and ventricular contraction/relaxation cycles and pump function. In blood vessels, these channels facilitate long-distance endothelial cell communication, synchronize smooth muscle cell contraction, and support endothelial-smooth muscle cell communication. In the central nervous system they form cellular syncytia and coordinate neural function. Gap junction channels are normally open and hemichannels are normally closed, but pathologic conditions may restrict gap junction communication and promote hemichannel opening, thereby disturbing a delicate cellular communication balance. Until recently, most connexin-targeting agents exhibited little specificity and several off-target effects. Recent work with peptide-based approaches has demonstrated improved specificity and opened avenues for a more rational approach toward independently modulating the function of gap junctions and hemichannels. We here review the role of connexins and their channels in cardiovascular and neurovascular health and disease, focusing on crucial regulatory aspects and identification of potential targets to modify their function. We conclude that peptide-based investigations have raised several new opportunities for interfering with connexins and their channels that may soon allow preservation of gap junction communication, inhibition of hemichannel opening, and mitigation of inflammatory signaling.

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“…Consistently, spermine, an endogenous polyamine with the ability to exert antidepressant effects (Limon, Mamdani, Hjelm, Vawter, & Sequeira, ), increases astroglial intercellular communication by interacting with gap junctional channels and is inhibited by gap junction blockers (Benedikt et al, ). Interestingly, the TCA desipramine prevents acidosis‐induced uncoupling and ischemia‐related loss of membrane Cx43 and Cx43 dephosphorylation in isolated hearts (Jozwiak et al, ). Thus, antidepressant drugs may exert their effects, in part, by increasing Cx43 expression or coupling.…”

Section: Gap Junctionsmentioning

confidence: 99%

An astroglial basis of major depressive disorder? An overview

Wang

Jie

Liu

et al. 2017

Glia

172

125

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Depression is a chronic, recurring, and serious mood disorder that afflicts up to 20% of the global population. The monoamine hypothesis has dominated our understanding of the pharmacotherapy of depression for more than half a century; however, our understanding of the pathophysiology and pathogenesis of major depression has lagged far behind. Astrocytes are the most abundant and versatile cells in the brain, participating in most, if not all, of brain functions as both a passive housekeeper and an active player. Mounting evidence from clinical, preclinical and post-mortem studies has revealed a decrease in the number or density of astrocytes and morphological and functional astroglial atrophy in patients with major depressive disorder (MDD) and in animal models of depression. Furthermore, currently available antidepressant treatments at least partially exert their therapeutic effects on astrocytes. More importantly, dysfunctional astrocytes lead to depressive-like phenotypes in animals. Together, current studies point to astroglial pathology as the potential root cause of MDD. Thus, a shift from a neuron-centric to an astrocyte-centric cause of MDD has gained increasing attention during the past two decades. Here we will summarize the current evidence supporting the hypothesis that MDD is a disease of astrocyte pathology and highlight previous studies on promising strategies that directly target astrocytes for the development of novel antidepressant treatments.

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Desipramine prevents cardiac gap junction uncoupling

Abstract: Desipramine seems to prevent the uncoupling of cardiac gap junctions and ischemia-related increase in dispersion.

Cited by 5 publications

References 51 publications

Modulating cardiac conduction during metabolic ischemia with perfusate sodium and calcium in guinea pig hearts

Modulating cardiac conduction during metabolic ischemia with perfusate sodium and calcium in guinea pig hearts

Connexins in Cardiovascular and Neurovascular Health and Disease: Pharmacological Implications

An astroglial basis of major depressive disorder? An overview

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