Atrial-selective drugs for treatment of atrial fibrillation

Ravens, Ursula; Christ, Torsten

doi:10.1007/s00399-010-0088-8

Cited by 4 publications

(4 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Constitutively active I K,ACh has been demonstrated in patients with persistent AF, where it may contribute to sustaining the arrhythmia (8). An increase in constitutively active I K,ACh has also been demonstrated in the canine atrial tachycardia-remodeled left atrium, and recent studies (16,24,27) have suggested that inhibition of I K,ACh may offer an atrium-specific target for the treatment of AF.…”

mentioning

confidence: 99%

Tissue-specific effects of acetylcholine in the canine heart

Calloe

Goodrow

Olesen

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Acetylcholine (ACh) release from the vagus nerve slows heart rate and atrioventricular conduction. ACh stimulates a variety of receptors and channels, including an inward rectifying current [ACh-dependent K ϩ current (IK,ACh)]. The effect of ACh in the ventricle is still debated. We compared the effect of ACh on action potentials in canine atria, Purkinje, and ventricular tissue as well as on ionic currents in isolated cells. Action potentials were recorded from ventricular slices, Purkinje fibers, and arterially perfused atrial preparations. Whole cell currents were recorded under voltageclamp conditions, and unloaded cell shortening was determined on isolated cells. The effect of ACh (1-10 M) as well as ACh plus tertiapin, an IK,ACh-specific toxin, was tested. In atrial tissue, ACh hyperpolarized the membrane potential and shortened the action potential duration (APD). In Purkinje and ventricular tissues, no significant effect of ACh was observed. Addition of ACh to atrial cells activated a large inward rectifying current (from Ϫ3.5 Ϯ 0.7 to Ϫ23.7 Ϯ 4.7 pA/pF) that was abolished by tertiapin. This current was not observed in other cell types. A small inhibition of Ca 2ϩ current (ICa) was observed in the atria, endocardium, and epicardium after ACh. ICa inhibition increased at faster pacing rates. At a basic cycle length of 400 ms, ACh (1 M) reduced ICa to 68% of control. In conclusion, IK,ACh is highly expressed in atria and is negligible/absent in Purkinje, endocardial, and epicardial cells. In all cardiac tissues, ACh caused rate-dependent inhibition of ICa.

show abstract

mentioning

confidence: 99%

Tissue-specific effects of acetylcholine in the canine heart

Calloe

Goodrow

Olesen

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…Taking these factors into consideration, we may say that atrial tissue will recover faster from inactivation (due to its less negative membrane potential), therefore I Na blockers—which binds preferably to inactivated channel state—will exhibit a larger blocking effect in atria than in ventricles [ 104 ]. For additional discussion, also compare Ravens and Christ [ 106 ].…”

Section: Therapeutic Options To Prevent and Stop Atrial Remodellingmentioning

confidence: 99%

New Strategies for the Treatment of Atrial Fibrillation

2021

View full text Add to dashboard Cite

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in the clinical practice. It significantly contributes to the morbidity and mortality of the elderly population. Over the past 25–30 years intense effort in basic research has advanced the understanding of the relationship between the pathophysiology of AF and atrial remodelling. Nowadays it is clear that the various forms of atrial remodelling (electrical, contractile and structural) play crucial role in initiating and maintaining the persistent and permanent types of AF. Unlike in ventricular fibrillation, in AF rapid ectopic firing originating from pulmonary veins and re-entry mechanism may induce and maintain (due to atrial remodelling) this complex cardiac arrhythmia. The present review presents and discusses in detail the latest knowledge on the role of remodelling in AF. Special attention is paid to novel concepts and pharmacological targets presumably relevant to the drug treatment of atrial fibrillation.

show abstract

“…As mentioned above, various potassium channels are remodeled during AF and several of them are almost only expressed in the atria (I Kur , I K,ACh , I K,2P , and I K,Ca ) ( Ravens and Christ, 2010 ; Hancox et al, 2016 ). Pharmacological inhibition of these channels prolongs the AP and therefore extends the atrial ERP.…”

Section: Computational Pharmacology In Afmentioning

confidence: 99%

Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges

et al. 2018

View full text Add to dashboard Cite

The pathophysiology of atrial fibrillation (AF) is broad, with components related to the unique and diverse cellular electrophysiology of atrial myocytes, structural complexity, and heterogeneity of atrial tissue, and pronounced disease-associated remodeling of both cells and tissue. A major challenge for rational design of AF therapy, particularly pharmacotherapy, is integrating these multiscale characteristics to identify approaches that are both efficacious and independent of ventricular contraindications. Computational modeling has long been touted as a basis for achieving such integration in a rapid, economical, and scalable manner. However, computational pipelines for AF-specific drug screening are in their infancy, and while the field is progressing quite rapidly, major challenges remain before computational approaches can fill the role of workhorse in rational design of AF pharmacotherapies. In this review, we briefly detail the unique aspects of AF pathophysiology that determine requirements for compounds targeting AF rhythm control, with emphasis on delimiting mechanisms that promote AF triggers from those providing substrate or supporting reentry. We then describe modeling approaches that have been used to assess the outcomes of drugs acting on established AF targets, as well as on novel promising targets including the ultra-rapidly activating delayed rectifier potassium current, the acetylcholine-activated potassium current and the small conductance calcium-activated potassium channel. Finally, we describe how heterogeneity and variability are being incorporated into AF-specific models, and how these approaches are yielding novel insights into the basic physiology of disease, as well as aiding identification of the important molecular players in the complex AF etiology.

show abstract

Atrial-selective drugs for treatment of atrial fibrillation

Cited by 4 publications

References 30 publications

Tissue-specific effects of acetylcholine in the canine heart

Tissue-specific effects of acetylcholine in the canine heart

New Strategies for the Treatment of Atrial Fibrillation

Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges

Contact Info

Product

Resources

About