Selective attenuation by adenosine of arrhythmogenic action of isoproterenol on ventricular myocytes

Song, Yejia; Shryock, John C.; Knot, Harm J.; Belardinelli, Luiz

doi:10.1152/ajpheart.2001.280.6.h2789

Cited by 18 publications

(14 citation statements)

References 27 publications

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“…In addition, when the rate of Ca 2+ uptake is further enhanced, oscillatory release of Ca 2+ from the SR was also observed (Fig. 3, right lane), in agreement with Song et al [1]. From the mechanical point of view, this spontaneous release, due to Ca 2+ overload in the SR, is associated with aftercontractions.…”

Section: Discussionsupporting

confidence: 89%

“…When the I up activity was further increased (condition 2), DADs occurred in all cell types (Fig.3, left panel). The induction of DADs by isoproterenol has been reported by Song et al [1] and Burashnikov and Antzelevitch [11]. These oscillations of the membrane potential are caused by a transient outward current (I Ti ), which is active in the late phase of the cardiac cycle.…”

Section: Discussionmentioning

confidence: 80%

“…I Ca(L) 250 [1] 200 [1] I up 140 [2] 300 [2] I Kr 30 [4] I Ks 250 [3] I NaK 120 [5] I NaCa 140 [6] Pacing was obtained by a current pulse train (pulses of 1 ms in duration) of 50 A/F in amplitude with frequency of 80 bpm. Rosenbrock variable step algorithm (max step 0.1 ms) was used to numerically solve the model equations.…”

Section: Case 1 Casementioning

confidence: 99%

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Effects of β-adrenergic stimulation on the ventricular action potential: a simulation study

Grandi¹,

Vecchietti²,

Severi³

et al. 2005

Modelling in Medicine and Biology VI

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Cathecholamines increase heart rate and contraction force. This effect is mainly mediated by their interaction with the β-adrenergic receptor (β-AR) and its downstream ability to modulate Ca 2+ cycling and fluxes of a number of ions through specific channels across the cell membrane. The complex nature and broad cellular influence of the β-AR signaling cascade suggests that an integrative modelling approach is appropriate to size the relative weight of each of the single mechanisms by which β-adrenergic inputs modulate whole-cell action potential (AP) and Ca 2+ handling in cardiac myocytes. The ventricular AP was simulated by using the Luo-Rudy model. The transmural heterogeneity of the AP (epicardial, mid-myocardial and endocardial cells) was reproduced by considering three different levels of expression of the transient outward current (I To ) and three different ratios of the slow vs. the rapid component of the delayed rectifier K + current (I Ks / I Kr ). The β-AR stimulation was modelled by incorporating its effects on L-type Ca 2+ current, phospholamban, I Kr , I Ks , Na + -K + pump and Na + /Ca 2+ exchanger. Simulation of β-AR stimulation showed significant changes in the AP and in Ca 2+ handling, depending on the cell type and on the levels of ion fluxes alterations due to β-adrenergic inputs. Notably, the occurrence of early-and delayed-after-depolarizations (EADs and DADs respectively) was also reproduced. In the present analysis, EADs and DADs are suggested as mechanisms responsible for the arrhythmogenic effect of the adrenergic stimulation.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 80%

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Effects of β-adrenergic stimulation on the ventricular action potential: a simulation study

Grandi¹,

Vecchietti²,

Severi³

et al. 2005

Modelling in Medicine and Biology VI

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“…8 We hypothesized that CVT-2759 may selectively attenuate the proarrhythmic effect of a ␤-adrenoceptor agonist without significantly affecting either the contractility of ventricular myocytes or the basal electrical activity of atrial myocytes. This hypothesis is based on observations that adenosine decreases catecholamine-induced arrhythmic activity more than contractility 9 and that its potency to inhibit isoproterenol-stimulated I Ca(L) is 10-fold greater than its potency to activate I K(Ado) . 10 The hypothesis was further examined in this study.…”

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confidence: 99%

Selective Attenuation of Isoproterenol-Stimulated Arrhythmic Activity by a Partial Agonist of Adenosine A ₁ Receptor

Song

Shryock

et al. 2002

Circulation

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Background-The goal of this study was to examine the hypothesis that a partial agonist of the adenosine A 1 receptor (A 1 AdoR) may cause a greater attenuation of catecholamine-induced ventricular arrhythmic activity than of contractility. Methods and Results-The effects of CVT-2759 and adenosine, a partial and a full agonist of the A 1 AdoR, on isoproterenol-stimulated arrhythmic activity and contractility of guinea pig isolated ventricular myocytes were determined. CVT-2759 (10 mol/L) and adenosine (10 mol/L) significantly inhibited isoproterenol-induced arrhythmic activity (aftercontraction and transient inward current) but did not reduce the amplitudes of twitch shortening and L-type Ca 2ϩ current. Increasing the concentration of the full agonist adenosine from 10 to 100 mol/L, however, caused significant attenuation of twitch shortening as well as aftercontractions, whereas increasing the concentration of the partial agonist CVT-2759 from 10 to 100 mol/L did not. CVT-2759 also significantly inhibited isoproterenol-induced spontaneous ventricular beats in isolated hearts. In contrast to adenosine, CVT-2759 neither activated adenosinesensitive K ϩ current nor shortened the duration of the atrial APD. Conclusions-The

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“…33 Adenosine's effects on I Ti , on an equimolar basis, are more potent than its inhibitory effects on catecholamine-induced action potential duration prolongation, elevation of action potential duration plateau, increases in I CaL , or contractility. 34 Adenosine's suppressive effects on I Ti are reproduced by N 6 -cyclopentyladenosine, a selective A 1 receptor analogue, confirming that its action is meditated at the level of the A 1 receptor. Adenosine abolishes DADs and I Ti through its effects at several levels.…”

Section: Ventricular Tachycardia Triggered Activitymentioning

confidence: 87%

Ventricular Tachycardia

Lerman

2015

Circ: Arrhythmia and Electrophysiology

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A foundational concept in cardiac electrophysiology is that understanding the cellular mechanism of an arrhythmia provides essential insight for developing targeted therapeutic options. However, current clinical understanding of arrhythmogenic mechanisms other than re-entry is rudimentary, and the means by which to diagnose and differentiate these mechanisms are poorly defined. Grouping these mechanistic subtypes into broad and nonspecific categories, for example, non-re-entry or focal, further underscores our incomplete understanding of these arrhythmias. As the field of cardiac electrophysiology, like the rest of medicine, evolves toward the delivery of cell-based therapies, the need for a deeper understanding of clinical arrhythmia mechanisms and their arrhythmogenic cell lineages is apparent.One major difference between re-entrant and non-reentrant ventricular tachycardia (VT) is that the electrophysiological substrate for re-entry is acquired during postnatal development and is due to anatomic insult (eg, ischemic heart disease or viral myocarditis), whereas the substrate for triggered activity is likely often acquired during embryological development, occurring independent of anatomic injury or structural heart disease. 1,2 These dichotomous electrophysiological substrates, re-entry and non-re-entry, require tailored approaches to confirm diagnosis. In this review, we will elaborate on the development of a methodological approach for diagnosing non-re-entrant VT, which centers on the unique mechanism-specific properties of adenosine. This approach differs substantively from standard laboratory pacing methodologies used to validate the diagnosis of re-entrant arrhythmias and which are founded on the principles of entrainment. 3 AdenosineAdenosine is an endogenous nucleoside that exercises multiple regulatory functions that affect impulse generation and conduction, autonomic function, contractility, coronary vasodilation, and O 2 supply-demand balance. 4 Adenosine is rapidly inactivated as it is taken up by the cell through simple diffusion or a nucleoside transport system and is then deaminated to inosine or phosphorylated to adenosine monophosphate. 5 The plasma half-life of adenosine is <1.5 s. 6 Four-myocardial adenosine receptor subtypes mediate adenosine's effects. Receptors A 1 , A 2a , A 2b , and A 3 are structurally related G-protein-coupled receptors, consisting of 7 transmembrane helices. 7 A 1 and A 3 subtypes inhibit adenylyl cyclase, whereas A 2 subtypes activate it. In the heart, the A 1 R subtype has the highest level of expression and is the receptor that mediates adenosine's electrophysiolgic effects through its activation of heterotrimeric G proteins. 4 Drury and Szent-Gyorgyi 8 made the seminal observation in 1929 that adenosine had a negative chronotropic effect on the heart, causing profound slowing of the sinus rate in dogs. 8 Although research on the cardiac electrophysiological effects of adenosine followed in fits and starts over the next 50 years, the field took flight beginning in...

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Selective attenuation by adenosine of arrhythmogenic action of isoproterenol on ventricular myocytes

Cited by 18 publications

References 27 publications

Effects of β-adrenergic stimulation on the ventricular action potential: a simulation study

Effects of β-adrenergic stimulation on the ventricular action potential: a simulation study

Selective Attenuation of Isoproterenol-Stimulated Arrhythmic Activity by a Partial Agonist of Adenosine A ₁ Receptor

Ventricular Tachycardia

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Selective attenuation by adenosine of arrhythmogenic action of isoproterenol on ventricular myocytes

Cited by 18 publications

References 27 publications

Effects of β-adrenergic stimulation on the ventricular action potential: a simulation study

Effects of β-adrenergic stimulation on the ventricular action potential: a simulation study

Selective Attenuation of Isoproterenol-Stimulated Arrhythmic Activity by a Partial Agonist of Adenosine A 1 Receptor

Ventricular Tachycardia

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Product

Resources

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Selective Attenuation of Isoproterenol-Stimulated Arrhythmic Activity by a Partial Agonist of Adenosine A ₁ Receptor