Patch-Clamp Analysis of Anesthetic Interactions with Recombinant SK2 Subtype Neuronal Calcium-Activated Potassium Channels

Dreixler, John C.; Jenkins, Andrew; Cao, Ying-Jun; Roizen, Jeffrey D.; Houamed, Khaled M.

doi:10.1097/00000539-200003000-00040

Cited by 30 publications

(19 citation statements)

References 29 publications

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“…These findings indicate that I KAS is important in ventricular arrhythmogenesis during hypokalemia. This may be relevant to drug safety, since a number of commonly used clinical drugs are known inhibitors of I KAS , such as anesthetic agents, 43 quinine, d -tubocurarine 44 and amiodarone. 45 It is possible that further investigations will discover the I KAS blocking action of other drugs used commonly in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Small-Conductance Calcium-Activated Potassium Current Is Activated During Hypokalemia and Masks Short-Term Cardiac Memory Induced by Ventricular Pacing

Chan

Tsai

et al. 2015

Circulation

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Background Hypokalemia increases the vulnerability to ventricular fibrillation (VF). We hypothesize that the apamin-sensitive small conductance calcium-activated potassium current (IKAS) is activated during hypokalemia and that IKAS blockade is proarrhythmic. Methods and Results Optical mapping was performed in 23 Langendorff perfused rabbit ventricles with atrioventricular block and either right ventricular (RV) or left ventricular (LV) pacing during normokalemia or hypokalemia. Apamin prolonged the action potential duration (APD) measured to 80% repolarization (APD80) by 26 ms [95% confidence interval, CI, 14–37] during normokalemia and by 54 ms [CI, 40 to 68] during hypokalemia (P=0.01) at 1000 ms pacing cycle length (PCL). In hypokalemic ventricles, apamin increased the maximal slope of APD restitution, the PCL threshold of APD alternans, the PCL for wavebreak induction and the area of spatially discordant APD alternans. Apamin significantly facilitated the induction of sustained VF (from 3/9 hearts to 9/9 hearts, P=0.009). Short term cardiac memory was assessed by the slope of APD80 versus activation time. The slope increased from 0.01 [CI, −0.09 to 0.12] at baseline to 0.34 [CI, 0.23 to 0.44] after apamin (P<0.001) during RV pacing, and from 0.07 [CI, −0.05 to 0.20] to 0.54 [CI, 0.06 to 1.03] after apamin infusion (P=0.045) during LV pacing. Patch-clamp studies confirmed increased IKASin isolated rabbit ventricular myocytes during hypokalemia (P=0.038). Conclusions Hypokalemia activates IKAS to shorten APD and maintain repolarization reserve at late activation sites during ventricular pacing. IKAS blockade prominently lengthens the APD at late activation sites and facilitates VF induction.

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Section: Discussionmentioning

confidence: 99%

Small-Conductance Calcium-Activated Potassium Current Is Activated During Hypokalemia and Masks Short-Term Cardiac Memory Induced by Ventricular Pacing

Chan

Tsai

et al. 2015

Circulation

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“…In addition to apamin, previous studies have shown that anesthetic agents, such as butanol, ethanol, ketamine, lidocaine, and methohexital block recombinant SK2 channel currents. 21 In addition, quinine, quinidine, d-tubocurarine, tetraethylammonium chloride and 4-aminopyridine are also I KAS blockers. 22 Preliminary investigation from our laboratory indicates that amiodarone is an effective I KAS blocker.…”

Section: Discussionmentioning

confidence: 99%

Apamin induces early afterdepolarizations and torsades de pointes ventricular arrhythmia from failing rabbit ventricles exhibiting secondary rises in intracellular calcium

Chang¹,

Hsieh²,

Hsueh³

et al. 2013

Heart Rhythm

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Background A secondary rise of intracellular Ca2+ (Cai) and an upregulation of IKAS are characteristic findings of failing ventricular myocytes. We hypothesize that apamin, a specific IKAS blocker, may induce torsades de pointes (TdP) ventricular arrhythmia from failing ventricles exhibiting secondary rises of Cai. Objectives To test the hypothesis that small conductance Ca2+ activated apamin sensitive K+ current (IKAS) maintains repolarization reserve and prevents ventricular arrhythmia in a rabbit model of heart failure (HF). Methods We performed Langendorff perfusion and optical mapping studies in 7 hearts with pacing-induced HF and in 5 normal control rabbit hearts. Atrioventricular (AV) block was created by cryoablation to allow pacing at slow rates. Results The left ventricular ejection fraction reduced from 69.1 [95% confidence interval 62.3–76.0]% pre-pacing to 30.4 [26.8–34.0]% (N=7, p<0.001) post-pacing. The QTc in failing ventricles was 337 [313–360] ms at baseline and 410 [381–439] ms after applying 100 nmol/L of apamin (p=0.01). Apamin induced early afterdepolarizations (EADs) in 6 ventricles, premature ventricular beats (PVBs) in 7 ventricles and polymorphic ventricular tachycardia consistent with TdP in 4 ventricles. The earliest activation site of the EADs and PVBs always occurred at the site with long APD and large amplitude of the secondary rises of Cai. Apamin induced secondary rises of Cai in 1 non-failing ventricles, but no EAD or TdP were observed. Conclusion In HF ventricles, apamin induces EADs, PVBs and TdP from areas with secondary rises of Cai. IKAS is important in maintaining repolarization reserve and preventing TdP in HF ventricles.

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“…Ethanol (≥10 mM) has been shown to inhibit SK channel (SK2 subtype)–mediated currents in a heterologous expression system (Dreixler et al ., 2000). Reduction in SK conductance may well lead to an enhancement of DA neuron pacemaker firing by suppressing AHPs.…”

Section: Acute Ethanol Action On Da Neuron Activitymentioning

confidence: 99%

Ethanol Action on Dopaminergic Neurons in the Ventral Tegmental Area

Morikawa

Morrisett

2010

International Review of Neurobiology

121

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The dopaminergic system originating in the midbrain ventral tegmental area (VTA) has been extensively studied over the past decades as a critical neural substrate involved in the development of alcoholism and addiction to other drugs of abuse. Accumulating evidence indicates that ethanol modulates the functional output of this system by directly affecting the firing activity of VTA dopamine neurons, whereas withdrawal from chronic ethanol exposure leads to a reduction in the functional output of these neurons. This chapter will provide an update on the mechanistic investigations of the acute ethanol action on dopamine neuron activity and the neuroadaptations/ plasticities in the VTA produced by previous ethanol experience.

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Patch-Clamp Analysis of Anesthetic Interactions with Recombinant SK2 Subtype Neuronal Calcium-Activated Potassium Channels

Abstract: We describe differential effects of anesthetics on cloned small conductance calcium-activated potassium channels from brain that may play a role in generating the effects or side effects of anesthetics.

Cited by 30 publications

References 29 publications

Small-Conductance Calcium-Activated Potassium Current Is Activated During Hypokalemia and Masks Short-Term Cardiac Memory Induced by Ventricular Pacing

Small-Conductance Calcium-Activated Potassium Current Is Activated During Hypokalemia and Masks Short-Term Cardiac Memory Induced by Ventricular Pacing

Apamin induces early afterdepolarizations and torsades de pointes ventricular arrhythmia from failing rabbit ventricles exhibiting secondary rises in intracellular calcium

Ethanol Action on Dopaminergic Neurons in the Ventral Tegmental Area

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