Bronchodilator aminophylline may induce atrial or less often ventricular arrhythmias. The mechanism of this proarrhythmic side effect has not been fully explained. Modifications of inward rectifier potassium (Kir) currents including IK1 are known to play an important role in arrhythmogenesis; however, no data on the aminophylline effect on these currents have been published. Hence, we tested the effect of aminophylline (3-100 µM) on IK1 in enzymatically isolated rat ventricular myocytes using the whole-cell patch-clamp technique. A dual steady-state effect of aminophylline was observed; either inhibition or activation was apparent in individual cells during the application of aminophylline at a given concentration. The smaller the magnitude of the control IK1, the more likely the activation of the current by aminophylline and vice versa. The effect was reversible; the relative changes at -50 and -110 mV did not differ. Using IK1 channel population model, the dual effect was explained by the interaction of aminophylline with two different channel populations, the first one being inhibited and the second one being activated. Considering various fractions of these two channel populations in individual cells, varying effects observed in the measured cells could be simulated. We propose that the dual aminophylline effect may be related to the direct and indirect effect of the drug on various Kir2.x subunits forming the homo- and heterotetrameric IK1 channels in a single cell. The observed IK1 changes induced by clinically relevant concentrations of aminophylline might contribute to arrhythmogenesis related to the use of this bronchodilator in clinical medicine.

• Keywords
• Aminophylline, Arrhythmia, Dual effect, Fibrillation, Inward rectifier, Population channel model,
• MeSH
• Aminophylline adverse effects   MeSH
• Bronchodilator Agents adverse effects   MeSH
• Potassium pharmacology   MeSH
• Potassium Channels, Inwardly Rectifying * MeSH
• Myocytes, Cardiac physiology   MeSH
• Rats MeSH
• Arrhythmias, Cardiac MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Aminophylline MeSH
• Bronchodilator Agents MeSH
• Potassium MeSH
• Potassium Channels, Inwardly Rectifying * MeSH

Recent experimental work has revealed unusual features of the effect of certain drugs on cardiac inwardly rectifying potassium currents, including the constitutively active and acetylcholine-induced components of acetylcholine-sensitive current (IKAch). These unusual features have included alternating susceptibility of the current components to activation and inhibition induced by ethanol or nicotine applied at various concentrations, and significant correlation between the drug effect and the current magnitude measured under drug-free conditions. To explain these complex drug effects, we have developed a new type of quantitative model to offer a possible interpretation of the effect of ethanol and nicotine on the IKAch channels. The model is based on a description of IKAch as a sum of particular currents related to the populations of channels formed by identical assemblies of different α-subunits. Assuming two different channel populations in agreement with the two reported functional IKAch-channels (GIRK1/4 and GIRK4), the model was able to simulate all the above-mentioned characteristic features of drug-channel interactions and also the dispersion of the current measured in different cells. The formulation of our model equations allows the model to be incorporated easily into the existing integrative models of electrical activity of cardiac cells involving quantitative description of IKAch. We suppose that the model could also help make sense of certain observations related to the channels that do not show inward rectification. This new ionic channel model, based on a concept we call population type, may allow for the interpretation of complex interactions of drugs with ionic channels of various types, which cannot be done using the ionic channel models available so far.

• MeSH
• Acetylcholine pharmacology   MeSH
• Models, Biological MeSH
• Time Factors MeSH
• G Protein-Coupled Inwardly-Rectifying Potassium Channels metabolism   MeSH
• Ethanol pharmacology   MeSH
• Ion Channel Gating drug effects   MeSH
• Nicotine pharmacology   MeSH
• Computer Simulation MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Acetylcholine MeSH
• G Protein-Coupled Inwardly-Rectifying Potassium Channels MeSH
• Ethanol MeSH
• Nicotine MeSH

Inward rectifier potassium currents (I Kir,x) belong to prominent ionic currents affecting both resting membrane voltage and action potential repolarization in cardiomyocytes. In existing integrative models of electrical activity of cardiac cells, they have been described as single current components. The proposed quantitative model complies with findings indicating that these channels are formed by various homomeric or heteromeric assemblies of channel subunits with specific functional properties. Each I Kir,x may be expressed as a total of independent currents via individual populations of identical channels, i.e., channels formed by the same combination of their subunits. Solution of the model equations simulated well recently observed unique manifestations of dual ethanol effect in rat ventricular and atrial cells. The model reflects reported occurrence of at least two binding sites for ethanol within I Kir,x channels related to slow allosteric conformation changes governing channel conductance and inducing current activation or inhibition. Our new model may considerably improve the existing models of cardiac cells by including the model equations proposed here in the particular case of the voltage-independent drug-channel interaction. Such improved integrative models may provide more precise and, thus, more physiologically relevant results.

• Keywords
• Cardiomyocytes, Dual effect, Ethanol, I K1, Inward rectifier potassium currents, Quantitative model,
• MeSH
• Action Potentials * MeSH
• Allosteric Regulation MeSH
• Potassium Channels, Inwardly Rectifying chemistry   metabolism   MeSH
• Ethanol pharmacology   MeSH
• Myocytes, Cardiac drug effects   metabolism   physiology   MeSH
• Rats MeSH
• Models, Cardiovascular MeSH
• Protein Multimerization MeSH
• Ventricular Function MeSH
• Heart Ventricles cytology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Potassium Channels, Inwardly Rectifying MeSH
• Ethanol MeSH

Nicotine abuse is associated with variety of diseases including arrhythmias, most often atrial fibrillation (AF). Altered inward rectifier potassium currents including acetylcholine-sensitive current I K(Ach) are known to be related to AF pathogenesis. Since relevant data are missing, we aimed to investigate I K(Ach) changes at clinically relevant concentrations of nicotine. Experiments were performed by the whole cell patch clamp technique at 23 ± 1 °C on isolated rat atrial myocytes. Nicotine was applied at following concentrations: 4, 40 and 400 nM; ethanol at 20 mM (∼0.09%). Nicotine at 40 and 400 nM significantly activated constitutively active component of I K(Ach) with the maximum effect at 40 nM (an increase by ∼100%); similar effect was observed at -110 and -50 mV. Changes at 4 nM nicotine were negligible on average. Coapplication of 40 nM nicotine and 20 mM ethanol (which is also known to activate this current) did not show cumulative effect. In the case of acetylcholine-induced component of I K(Ach), a dual effect of nicotine and its correlation with the current magnitude in control were apparent: the current was increased by nicotine in the cells showing small current in control and vice versa. The effect of 40 and 400 nM nicotine on acetylcholine-induced component of I K(Ach) was significantly different at -110 and -50 mV. We conclude that nicotine at clinically relevant concentrations significantly increased constitutively active component of I K(Ach) and showed a dual effect on its acetylcholine-induced component, similarly as ethanol. Synchronous application of nicotine and ethanol did not cause additive effect.

• Keywords
• Acetylcholine-sensitive, Dual effect, Inward rectifier, Nicotine,
• MeSH
• Acetylcholine pharmacology   MeSH
• Time Factors MeSH
• G Protein-Coupled Inwardly-Rectifying Potassium Channels agonists   drug effects   MeSH
• Ethanol toxicity   MeSH
• Risk Assessment MeSH
• Myocytes, Cardiac drug effects   metabolism   MeSH
• Membrane Potentials MeSH
• Nicotine toxicity   MeSH
• Rats, Wistar MeSH
• Arrhythmias, Cardiac chemically induced   metabolism   MeSH
• Heart Atria drug effects   metabolism   MeSH
• In Vitro Techniques MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholine MeSH
• G Protein-Coupled Inwardly-Rectifying Potassium Channels MeSH
• Ethanol MeSH
• Nicotine MeSH