After-depolarization

In order to investigate which membrane currents underlie the changes in the action potential and the arrhythmogenic oscillatory after-depolarizations, we have... 

Early after-depolarizations are purported to be the mechanism giving rise to torsades de pointes. Conditions or drugs known to prolong the action potential, especially by interventions that decrease the outward potassium currents, facilitate development of torsades de pointes tachyarrhythmias. Early after-depolarizations may develop in association with hypokalemia, hypoxia, acidosis, and a wide range of pharmacological agents that interfere with outward currents or enhance inward currents. Antiarrhythmic agents, in particular sotalol. 

Early after-depolarizations and the associated ventricular arrhythmia can be prevented or suppressed by the appropriate adjustment of plasma potassium and/or magnesium concentrations. Lidocaine or procainamide may be effective for termination of the arrhythmia. 

Exercise-induced ventricular tachycardia in persons without overt cardiac disease is an example of delayed after-depolarizations and is characterized by an increase in intracellular ionized calcium. This type of arrhythmia is known to often respond well to which of the following combinations ... 

It is an amide local anaesthetic and has rapid onset of action. It depresses diastolic depolarization and automaticity in ectopic foci in ventricular tissue. Phase 4 depolarization in partially depressed Purkinje fibres and after depolarizations are antagonised. It does not depress AV conduction and decreases action potential duration, effective refractory period. It has no effect on BP. 

Two forms of abnormal activity, early (top) and delayed after depolarizations (bottom). In both cases, abnormal depolarizations arise during or after a normally evoked action potential. They are therefore often referred to as "triggered" automaticity that is, they require a normal action potential for their initiation. 

Fig. 3 Depolarization-induced supression of Inhibition (DSI) is endocannabinoid and CB1 receptor-mediated, (a) Current traces showing evoked and spontaneous IPSCs before and after a 2 sec depolarization from —60 to OmV in the absence (top) and presence (bottom) of the CB1 antagonist SR141716A (SR). Asterisks denote the evoked IPSCs bracket indicates the period of depolarization, (b) Individual evoked IPSCs evoked before and just after depolarization shown at higher temporal resolution in the absence (left) and presence (right) of SR.

It is always best to understand a biological problem before trying to find ways to avoid it. The reason that action potential duration is important is that repolarization is a fragile process. It can fail, and when it does so, the action potential is followed by one or many oscillations. These are called early after-depolarizations (EADs). We will also encounter late after-depolarizations (DADs) later in this chapter. 

Fig. 9.1 Top action potentials computed using a model of a guinea-pig ventricular cell. Middle computed ionic currents. Bottom computed calcium transients. 90% block of the fast component of /k prevents repolariztion and generates multiple after-depolarizations [10].

Early after depolarization without mutation Re polarization failure with mutation ... 

The evaluation is based on the incidence of either an overt tachyarrhythmia or the appearance of early after depolarizations in the monophasic action potential. 

In studies by Carlsson (1990) the subsequent administration of clofilium (20.8 pmol/kg) lead to a prolongation of the QTU interval and the monophasic action potential with the appearance of early after depolarizations. This was followed by ventricular arrhythmias in all rabbits. Pretreatment with prazosin (1 mg/kg iv) was able to attenuate the arrhythmia. 

The evaluation involves determining incidence of arrhythmia or early after depolarizations after drug... 

Using an endocardial monophasic action potential recording, the incidence of early after depolarizations can be determined. The catheter (e.g. Franz combination catheter, EPT No. 1650) can be placed through the jugular vein or carotid artery under fluoroscopic guidance. 

The oviducts of the cockroaches L. maderae (31) and P. americana (32) also contain proctolin. In both instances, quantitative estimates of proctolin-like bioactivity were made following the separation of extracts on reverse-phase HPLC. After depolarization of the tissue in high potassium saline, the proctolin-like substance in . americana was released from oviducts in a calcium dependent fashion. Oviducts in L. maderae (31) showed some responsiveness to proctolin in a calcium-free medium and the peptide also appeared to facilitate the re-entry of calcium into muscle after depleted preparations were returned to normal levels of external calcium. 

An important predictor of arrhythmia is changes in the duration of the QT trace, the time for ventricular repolarization, displacement of the ST-segment, and changes in the pattern of T-waves that may sometimes be seen as a T and U wave (Roden, 2004, 2008). It can be linked to ventricular tachycardia, including TdP. Lengthened QT increases the time available for intracellular calcium accumulation, enabling early after-depolarization (BAD) in the Purkinje fibers, and activates calmodulin (CaM) and calmodulin kinase (CaMK). CaMK is believed to enhance after-... 

The main effect of adrenergic stimulation is to enhance the intracellular adenylyl cyclase activity. This in turn increases cyclic adenosine monophosphate levels. Protein kinase A is activated which modulates, i.e. phosphorylates, calcium and potassium channels. Phosphorylation of the calcium channel increases the inward current leading to early after-depolarization. 

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