Conduction slowing by the gap junctional uncoupler carbenoxolone

Groot, Joris R. de; Veenstra, Thijs; Verkerk, Arie O.; Wilders, Ronald; Smits, Jeroen P.P.; Wilms‐Schopman, Francien J.G.; Wiegerinck, Rob F.; Bourier, Jan; Belterman, Charly; Coronel, Ruben; Verheijck, E. E.

doi:10.1016/j.cardiores.2003.07.004

Cited by 83 publications

(66 citation statements)

References 42 publications

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“…With the use of DT-MRI and histology, our findings on subepicardial myofiber orientation patterns are consistent with Streeter et and Bassett (52), who similarly examined this in porcine. We further demonstrated that the differential effect of RSGS on CV L vs. CV T was mediated by the distribution of GJs, known to exist predominantly at endto-end intercalated disks than side-to-side in normal hearts, by inducing cellular uncoupling (14,26). This eliminated the increase in CV L during RSGS.…”

Section: Discussionmentioning

confidence: 65%

“…Given the dependence of RSGS-mediated CV increase on fiber orientation (and hence GJ distribution), we examined whether the increase in CV L was mediated via GJ modulation. Cellular uncoupling was achieved with carbenoxolone (1.4 -1.6 mg/kg), a GJ blocker (14,26), resulting in complete abrogation of the CV L response to RSGS 24.7 Ϯ 8.9, Ϫ2.6 Ϯ 3.7, and Ϫ2.8 Ϯ 3.9% (P Ͻ 0.001), respectively, for control, esmolol, and carbenoxolone, respectively (Fig. 3, E and F).…”

Section: Sympathoexcitation Increases CV In Normal Ventricularmentioning

confidence: 98%

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Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis

Ajijola

Lux

Khahera

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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The influence of cardiac sympathetic innervation on electrical activation in normal and chronically infarcted ventricular myocardium is not understood. Yorkshire pigs with normal hearts (NL, n ϭ 12) or anterior myocardial infarction (MI, n ϭ 9) underwent high-resolution mapping of the anteroapical left ventricle at baseline and during left and right stellate ganglion stimulation (LSGS and RSGS, respectively). Conduction velocity (CV), activation times (ATs), and directionality of propagation were measured. Myocardial fiber orientation was determined using diffusion tensor imaging and histology. Longitudinal CV (CV L) was increased by RSGS (0.98 Ϯ 0.11 vs. 1.2 Ϯ 0.14m/s, P Ͻ 0.001) but not transverse CV (CV T). This increase was abrogated by ␤-adrenergic receptor and gap junction (GJ) blockade. Neither CV L nor CVT was increased by LSGS. In the peri-infarct region, both RSGS and LSGS shortened ARIs in sinus rhythm (423 Ϯ 37 vs. 322 Ϯ 30 ms, P Ͻ 0.001, and 423 Ϯ 36 vs. 398 Ϯ 36 ms, P ϭ 0.035, respectively) and altered activation patterns in all animals. CV, as estimated by mean ATs, increased in a directionally dependent manner by RSGS (14.6 Ϯ 1.2 vs. 17.3 Ϯ 1.6 ms, P ϭ 0.015), associated with GJ lateralization. RSGS and LSGS inhomogeneously modulated AT and induced relative or absolute functional activation delay in parts of the mapped regions in 75 and 67%, respectively, in MI animals, and in 0 and 15%, respectively, in control animals (P Ͻ 0.001 for both). In conclusion, sympathoexcitation increases CV in normal myocardium and modulates activation propagation in peri-infarcted ventricular myocardium. These data demonstrate functional control of arrhythmogenic periinfarct substrates by sympathetic nerves and in part explain the temporal nature of arrhythmogenesis.

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Section: Discussionmentioning

confidence: 65%

Section: Sympathoexcitation Increases CV In Normal Ventricularmentioning

confidence: 98%

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis

Ajijola

Lux

Khahera

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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“…Carbenoxolone (CBX) is a glycyrrhetinic derivative and a putative GJ blocker. 28 When CBX was injected for 1 min following 30 min of ischemia, the LY/DR ratio was reduced from 2.5 to 1.2 in the risk area (0 min of reperfusion in Figure 6C). These results suggest that after 30 min of ischemia, GJIC increases in the risk area without membrane disruption, whereas it remains low in the non-risk area.…”

Section: Brief Ischemia Enhances Gjicmentioning

confidence: 93%

Ischemia Enhances Translocation of Connexin43 and Gap Junction Intercellular Communication, Thereby Propagating Contraction Band Necrosis After Reperfusion

Shintani-Ishida

Unuma

Yoshida

2009

Circ J

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“…In this regard, CBX treatment alone has little effect on expression of proinflammatory cytokines, chemokines, or MHC molecules in BM DCs, suggesting that other molecular pathways are involved. 39 It is unlikely that the mechanism involves the potential for CBX to inhibit gap junctions, 40 because these effects would be predicted to have a negative rather than positive effect on crosspresentation. 41 However, confirmation that the positive effects of CBX on DC vaccination are specific to the inhibition of 11bHSD1 in CD8a…”

Section: Discussionmentioning

confidence: 99%

Cell-intrinsic regulation of murine dendritic cell function and survival by prereceptor amplification of glucocorticoid

Soulier

Blois

Sivakumaran

et al. 2013

Blood

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Key Points• Murine dendritic cell populations are highly proficient in amplifying local glucocorticoid concentrations.• This property is critical in regulating dendritic cell survival and functions in vivo.Although the inhibitory effects of therapeutic glucocorticoids (GCs) on dendritic cells (DCs) are well established, the roles of endogenous GCs in DC homeostasis are less clear. A critical element regulating endogenous GC concentrations involves local conversion of inactive substrates to active 11-hydroxyglucocorticoids, a reduction reaction catalyzed within the endoplasmic reticulum by an enzyme complex containing 11b-hydroxysteroid dehydrogenase type 1 (11bHSD1) and hexose-6-phosphate dehydrogenase (H6PDH). In this study, we found that this GC amplification pathway operates both constitutively and maximally in steady state murine DC populations and is unaffected by additional inflammatory stimuli. Under physiologic conditions, 11bHSD1-H6PDH increases the sensitivity of plasmacytoid DCs (pDCs) to GC-induced apoptosis and restricts the survival of this population through a cell-intrinsic mechanism. Upon CpG activation, the effects of enzyme activity are overridden, with pDCs becoming resistant to GCs and fully competent to release type I interferon. CD8a1 DCs are also highly proficient in amplifying GC levels, leading to impaired maturation following toll-like receptor-mediated signaling. Indeed, pharmacologic inhibition of 11bHSD1 synergized with CpG to enhance specific T-cell responses following vaccination targeted to CD8a 1 DCs. In conclusion, amplification of endogenous GCs is a critical cell-autonomous mechanism for regulating the survival and functions of DCs in vivo. (Blood. 2013;122(19):3288-3297)

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Conduction slowing by the gap junctional uncoupler carbenoxolone

Abstract: Carbenoxolone-induced uncoupling causes atrial and ventricular conduction slowing without affecting cardiac membrane currents. Activation delay is larger in poorly coupled cells.

Cited by 83 publications

References 42 publications

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis

Ischemia Enhances Translocation of Connexin43 and Gap Junction Intercellular Communication, Thereby Propagating Contraction Band Necrosis After Reperfusion

Cell-intrinsic regulation of murine dendritic cell function and survival by prereceptor amplification of glucocorticoid

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