Characterization of a novel multifunctional resveratrol derivative for the treatment of atrial fibrillation

被引：33

作者：

Baczko, Istvan ^{[1
]}

Liknes, David ^{[2
,3
]}

Yang, Wei ^{[2
,3
]}

Hamming, Kevin C. ^{[2
,3
]}

Searle, Gavin ^{[2
,3
]}

Jaeger, Kristian ^{[2
,3
]}

Husti, Zoltan ^{[1
]}

Juhasz, Viktor ^{[1
]}

Klausz, Gergely ^{[4
,5
]}

Pap, Robert ^{[4
,5
]}

Saghy, Laszlo ^{[4
,5
]}

Varro, Andras ^{[1
,6
]}

Dolinsky, Vernon ^{[7
]}

Wang, Shaohua ^{[8
]}

Rauniyar, Vivek ^{[9
]}

Hall, Dennis ^{[9
]}

Dyck, Jason R. B. ^{[10
,11
]}

Light, Peter E. ^{[2
,3
]}

机构：

[1] Univ Szeged, Dept Pharmacol & Pharmacotherapy, Szeged, Hungary

[2] Univ Alberta, Dept Pharmacol, Cardiovasc Res Ctr, Edmonton, AB T6G 2E1, Canada

[3] Univ Alberta, Alberta Diabet Inst, Li Ka Shing Res Ctr, Edmonton, AB T6G 2E1, Canada

[4] Univ Szeged, Dept Med 2, Szeged, Hungary

[5] Univ Szeged, Ctr Cardiol, Szeged, Hungary

[6] Hungarian Acad Sci, Div Cardiovasc Pharmacol, Szeged, Hungary

[7] Univ Manitoba, Dept Pharmacol & Therapeut, Manitoba Inst Child Hlth, Winnipeg, MB, Canada

[8] Univ Alberta, Fac Med & Dent, Div Cardiac Surg, Edmonton, AB T6G 2E1, Canada

[9] Univ Alberta, Dept Chem, Edmonton, AB T6G 2E1, Canada

[10] Univ Alberta, Cardiovasc Res Ctr, Dept Pediat, Edmonton, AB T6G 2E1, Canada

[11] Univ Alberta, Alberta Diabet Inst, Edmonton, AB T6G 2E1, Canada

来源：

BRITISH JOURNAL OF PHARMACOLOGY | 2014年 / 171卷 / 01期

基金：

匈牙利科学研究基金会; 加拿大健康研究院;

关键词：

atrial fibrillation; pharmacology; K(v)1; 5; resveratrol; electrophysiology; ion channels; ACTIVATED PROTEIN-KINASE; HEART-FAILURE; K+ CURRENT; CALORIE RESTRICTION; POTASSIUM CHANNELS; OUTWARD CURRENT; DYSFUNCTION; DECREASES; PHARMACOLOGY; MECHANISMS;

D O I：

10.1111/bph.12409

中图分类号：

R9 [药学];

学科分类号：

100702 [药剂学];

摘要：

Background and Purpose Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with an increased risk for stroke, heart failure and cardiovascular-related mortality. Candidate targets for anti-AF drugs include a potassium channel K(v)1.5, and the ionic currents I-KACh and late I-Na, along with increased oxidative stress and activation of NFAT-mediated gene transcription. As pharmacological management of AF is currently suboptimal, we have designed and characterized a multifunctional small molecule, compound 1 (C1), to target these ion channels and pathways. Experimental Approach We made whole-cell patch-clamp recordings of recombinant ion channels, human atrial I-Kur, rat atrial I-KACh, cellular recordings of contractility and calcium transient measurements in tsA201 cells, human atrial samples and rat myocytes. We also used a model of inducible AF in dogs. Key Results C1 inhibited human peak and late K(v)1.5 currents, frequency-dependently, with IC50 of 0.36 and 0.11molL(-1) respectively. C1 inhibited I-KACh (IC50 of 1.9molL(-1)) and the Na(v)1.5 sodium channel current (IC(50)s of 3 and 1molL(-1) for peak and late components respectively). C1 (1molL(-1)) significantly delayed contractile and calcium dysfunction in rat ventricular myocytes treated with 3nmolL(-1) sea anemone toxin (ATX-II). C1 weakly inhibited the hERG channel and maintained antioxidant and NFAT-inhibitory properties comparable to the parent molecule, resveratrol. In a model of inducible AF in conscious dogs, C1 (1mgkg(-1)) reduced the average and total AF duration. Conclusion and Implications C1 behaved as a promising multifunctional small molecule targeting a number of key pathways involved in AF.

引用

页码：92 / 106

页数：15

共 57 条

[1]

THE CONCISE GUIDE TO PHARMACOLOGY 2013/14: OVERVIEW [J].