Participation of α1 adrenoceptors in the proarrhythmic effect of class III antiarrhythmic agents in halothane anesthetized dogs

An envelope of tails test was used to show that the delayed rectifier K+ current (IK) of guinea pig ventricular myocytes results from the activation of two outward K+ currents. One current was specifically blocked by the benzenesulfonamide antiarrhythmic agent, E-4031 (IC50 = 397 nM). The drug-sensitive current, "IKr" exhibits prominent rectification and activates very rapidly relative to the slowly activating drug-insensitive current, "IKs." IKs was characterized by a delayed onset of activation that occurs over a voltage range typical of the classically described cardiac IK. Fully activated IKs, measured as tail current after 7.5-s test pulses, was 11.4 times larger than the fully activated IKr. IKr was also blocked by d-sotalol (100 microM), a less potent benzenesulfonamide Class III antiarrhythmic agent. The activation curve of IKr had a steep slope (+7.5 mV) and a negative half-point (-21.5 mV) relative to the activation curve of IKs (slope = +12.7 mV, half-point = +15.7 mV). The reversal potential (Erev) of IKr (-93 mV) was similar to EK (-94 mV for [K+]o = 4 mM), whereas Erev of IKs was -77 mV. The time constants for activation and deactivation of IKr made up a bell-shaped function of membrane potential, peaking between -30 and -40 mV (170 ms). The slope conductance of the linear portion of the fully activated IKr-V relation was 22.5 S/F. Inward rectification of this relation occurred at potentials greater than -50 mV, resulting in a voltage-dependent decrease in peak IKr at test potentials greater than 0 mV. Peak IKr at 0 mV averaged 0.8 pA/pF (n = 21). Although the magnitude of IKr was small relative to fully activated IKs, the two currents were of similar magnitude when measured during a relatively short pulse protocol (225 ms) at membrane potentials (-20 to +20 mV) typical of the plateau phase of cardiac action potentials.

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QTU-Prolongation and Torsades de Pointes Induced by Putative Class III Antiarrhythmic Agents in the Rabbit

Journal of Cardiovascular Pharmacology ◽

10.1097/00005344-199008000-00014 ◽

1990 ◽

Vol 16 (2) ◽

pp. 276-285 ◽

Cited By ~ 183

Author(s):

Leif Carlsson ◽

Olle Almgren ◽

Goran Duker

Keyword(s):

Torsades De Pointes ◽

Antiarrhythmic Agents ◽

Class Iii

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The pharmacophore hypotheses of IKr potassium channel blockers: novel class III antiarrhythmic agents

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2004.06.070 ◽

2004 ◽

Vol 14 (18) ◽

pp. 4771-4777 ◽

Cited By ~ 30

Author(s):

Lü-Pei Du ◽

Keng-Chang Tsai ◽

Min-Yong Li ◽

Qi-Dong You ◽

Lin Xia

Keyword(s):

Potassium Channel ◽

Channel Blockers ◽

Antiarrhythmic Agents ◽

Class Iii ◽

Potassium Channel Blockers ◽

Pharmacophore Hypotheses

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Abstract MP44: Biomarker Measures of Fish-Derived Omega-3 Fatty Acids and J-Point Elevation in the Atherosclerosis Risk in Communities (ARIC) Study

Circulation ◽

10.1161/circ.127.suppl_12.amp44 ◽

2013 ◽

Vol 127 (suppl_12) ◽

Author(s):

Noelle N Gronroos ◽

Pamela J Schreiner ◽

Elsayed Z Soliman ◽

Lisa Harnack ◽

Richard F MacLehose ◽

...

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Linear Trend ◽

Antiarrhythmic Agents ◽

Omega 3 ◽

Class Iii ◽

Atherosclerosis Risk In Communities ◽

Surface Ecg ◽

Atherosclerosis Risk ◽

Aric Study

Background: Higher intake of fish-derived omega-3 polyunsaturated fatty acids (PUFAs) has been associated with lower incidence of Sudden Cardiac Death (SCD), but the exact mechanisms underlying this association are unconfirmed. Early ventricular repolarization characterized by an elevation of the QRS-ST junction (J-Point) in the surface ECG has been associated with idiopathic ventricular fibrillation, the most common cause of SCD. We aimed to study the association of fish-derived PUFAs in plasma with the prevalence of J-Point elevation. Methods: We conducted a cross-sectional analysis of participants aged 45-64 (45.7% male, 100% whites) from the Minnesota Field Center of the Atherosclerosis Risk in Communities (ARIC) Study. Participants were excluded if they did not have an ECG, had a QRS duration ≥ 120 ms, were taking Class I or Class III antiarrhythmic agents, or had prevalent cardiovascular disease. Fish-derived PUFAs were measured in plasma phospholipids as a percentage of total fatty acids, categorized into quartiles, and logistic regression was used to estimate the odds of J-Point Elevation, defined as elevation of greater than 100 microvolts in at least two contiguous leads. Models were adjusted for potential confounders and tests of linear trend were conducted by assigning the median values for each exposure category and modeling as a continuous variable. Results: Among 3,330 eligible individuals, 126 presented J-Point elevation. Median fish-derived fatty acid percentage was 3.2% (range: 0.7-12.2). Using multivariable analyses, plasma measures of fish-derived omega-3 PUFAs were linearly associated with the log odds of J-Point elevation with increasing fatty acid percentages associated with lower odds of J-Point elevation (see Table). Conclusions: In this population, higher plasma levels of fish-derived PUFAs were inversely associated with J-Point elevation. Fish-derived PUFAs could reduce risk of SCD through decreased prevalence of early repolarization.

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