Rapid onset and calcium independence of the gap junction uncoupling induced by heptanol in cultured heart cells

Bastide, Bruno; Hervé, Jean Claude; Cronier, Laurent; Délèze, J.

doi:10.1007/bf00374154

Cited by 32 publications

(29 citation statements)

References 33 publications

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“…1B), it seems unlikely that n-alkanols and arachidonic acid act via intracellular H + and/or Ca 2+ . This conclusion agrees with previous observations that n-heptanol and arachidonic acid do not elevate [Ca 2+ ] i in rat heart cells and lacrimal gland cells ( [4,11,15]; but see also [14]. It is also consistent with the time course of uncoupling and recoupling during rapid application and removal of n-heptanol (0.5 s [4]).…”

Section: Site Of Action Of Lipophilic Agentssupporting

confidence: 93%

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Long-chain n-alkanols and arachidonic acid interfere with the V m -sensitive gating mechanism of gap junction channels

Weingart

Bukauskas

1997

Pfl�gers Archiv European Journal of Physiology

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Experiments were carried out on preformed cell pairs and induced cell pairs of an insect cell line (mosquito Aedes albopictus, clone C6/36). The coupling conductance, gj, was determined with the dual voltage-clamp method. Exposure of preformed cell pairs to lipophilic agents, such as long-chain n-alkanols (n-hexanol, n-heptanol, n-octanol, n-nonanol, n-decanol) or arachidonic acid, provoked a decrease in gj. Hyperpolarization of both cells led to a recovery of gj. Systematic studies revealed that this phenomenon is caused by a shift of the sigmoidal relationship gj(ss) = f(Vm) towards more negative values of Vm (where gj(ss) = conductance at steady-state; Vm = membrane potential). The shift was dose dependent, it developed with time and was reversible. The longer the hydrocarbon chain of n-alkanols, the lower was the concentration required to produce a given shift. Besides shifting the function gj(ss) = f(Vm), arachidonic acid decreased the maximal conductance, gj(max). Single-channel records gained from induced cell pairs revealed that the lipophilic agents interfere with the Vm-sensitive slow channel gating mechanism. Application provoked slow current transitions (transition time: 5-40 ms) between an open state of the channel (i.e. main state or residual state) and the closed state; subsequently, fast channel transitions (transition time: < 2 ms) involving the main state and the residual state ceased completely. Hyperpolarization of Vm or washout of the lipophilic agents gave rise to the inverse sequence of events. The single-channel conductances gammaj(main state) and gammaj(residual state) were not affected by n-heptanol. We conclude that long-chain n-alkanols and arachidonic acid interact with the Vm-sensitive gating mechanism.

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Section: Site Of Action Of Lipophilic Agentssupporting

confidence: 93%

“…Burt et al [10] proposed that lipophilic agents produce local disorder at the lipid-protein interface of cell membranes which leads to conformational changes of connexins and hence connexon dysfunction. Bastide et al [4] recently reported that [Ca 2+ ] i is not involved in n-heptanol-dependent uncoupling.…”

Section: Introductionmentioning

confidence: 99%

Long-chain n-alkanols and arachidonic acid interfere with the V m -sensitive gating mechanism of gap junction channels

Weingart

Bukauskas

1997

Pfl�gers Archiv European Journal of Physiology

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“…The two substance classes alcohols and saponins probably act on gap junctional conductance by two different mechanisms. Alcohols are thought to interrupt cell-cell communication by direct interaction with channel proteins or with their lipid environment (Bastide et al, 1995), while AGA most likely disrupts connexon particle arrangement within gap junction plaques (Goldberg et al, 1996; see also Kumar and Gilula, 1996).…”

Section: Do Uncoupling Agents Affect Astrocyte [Na 1 ] I By Blocking mentioning

confidence: 99%

Gap junctions equalize intracellular Na+ concentration in astrocytes

Rose

Ransom

1997

Glia

126

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“…Heptanol is one of several lipophilic agents known to inhibit gap junctions reversibly [4,15,17,22]. In both normal dog hearts [6] and the canine model of healed myocardial infarction [7] selective intracoronary infusion of heptanol increases the susceptibility to arrhythmias, consistent with altered cellular coupling being an important risk factor for arrhythmogenesis [37].…”

Section: Introductionmentioning

confidence: 99%

The effect of heptanol on the electrical and contractile function of the isolated, perfused rabbit heart

Keevil

Huang

Chau

et al. 2000

Pflugers Arch - Eur J Physiol

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Changes in cardiac gap junction expression, such as those following myocardial infarction and produced in connexin knockout mice, are associated with a predisposition to arrhythmias. The present experiments investigated the effects of heptanol, a reversible gap junction inhibitor, on isolated Langendorff-perfused rabbit hearts. The introduction and withdrawal of heptanol inhibited both pressure generation and electrical conduction. These effects were completely reversible. Possible mechanisms for these findings were investigated through measurement of the concentration dependence of heptanol's effects upon conduction velocity and repolarization duration. Low concentrations of heptanol (less than 0.3 mM) caused small but significant increases in the delay between the stimulus (delivered to the basal septum) artefact and local activation of the left ventricle, as measured from bipolar electrogram (BEG) recordings. There was a steep increase in the latency between stimulus and left-ventricular activation at concentrations of heptanol above 0.3 mM. These findings are explicable by earlier reports of heptanol actions on gap junctions in vitro and modelling studies of the effects of reduced gap junction conductance on conduction velocity. Heptanol decreased repolarization duration, measured from the activation recovery interval (ARI) of BEGs, and monophasic action potential duration at 70% repolarization (MAPD70). Heptanol also reduced left-ventricular developed pressure (LVDP), and the maximum rates of contraction and relaxation of the left ventricle; these effects were concentration dependent and reversible. However, changes in ARIs, LVDP and the maximum rates of change of pressure lacked the steep response to 0.3-1.0 mM heptanol shown by the latency. These other effects are therefore likely to be mediated by cellular targets other than gap junctions. Perfusion of hearts with heptanol was also associated with a high incidence of arrhythmias. During premature stimulation protocols arrhythmias could be induced in hearts perfused with 0.1-0.3 mM heptanol but not at higher concentrations. This suggests that there is a critical range of slowed conduction that permits the development of re-entrant arrhythmias in the normal heart, although the effects of heptanol on repolarization duration may also contribute to its pro-arrhythmic activity.

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Rapid onset and calcium independence of the gap junction uncoupling induced by heptanol in cultured heart cells

Cited by 32 publications

References 33 publications

Long-chain n-alkanols and arachidonic acid interfere with the V m -sensitive gating mechanism of gap junction channels

Long-chain n-alkanols and arachidonic acid interfere with the V m -sensitive gating mechanism of gap junction channels

Gap junctions equalize intracellular Na+ concentration in astrocytes

The effect of heptanol on the electrical and contractile function of the isolated, perfused rabbit heart

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