Class I Drug Effects on the Atrium

1992 ◽  
pp. 53-61
Author(s):  
S. Nattel ◽  
B. Fermini ◽  
Z. Wang ◽  
G. O’Hara
Keyword(s):  
Drug Effects ◽  
Class I

Class I antiarrhythmic drug effects on ouabain binding to guinea pig cardiac Na+-K+ATPase

1999 ◽  
Vol 77 (11) ◽  
pp. 866-870 ◽  
Author(s):  
Abdulrahman A Almotrefi ◽  
Chona Basco ◽  
Azadali Moorji ◽  
Nduna Dzimiri
Keyword(s):  
Guinea Pig ◽  
Drug Effects ◽  
Receptor Occupancy ◽  
Class I ◽  
Antiarrhythmic Agents ◽  
Binding Assays ◽  
Ouabain Binding ◽  
Guinea Pig Heart ◽  
Receptor Sites ◽  
Displacement Assays

The notion that the inhibition of the Mg2+-dependent ATP-hydrolytic function of the myocardial Na+-K+ATPase by class I antiarrhythmic agents occurs as a result of their binding to the same receptor sites as the digitalis glycosides was tested by performing competitive binding assays of [3H]ouabain (OUA) with eight drugs: disopyramide, encainide, lidocaine, lorcainide, phenytoin, procainamide, quinidine, and tocainide in guinea pig heart microsomal preparations. In the first set of experiments, 10-200 µM concentrations of the drugs were preincubated with the enzyme and displacement assays performed with 250 nM OUA. The drugs showed receptor occupancy of 19-32% at 50 µM, 25-44% at 100 µM, and 37-56% at 200 µM. Then, 10-500 nM concentrations of OUA were preincubated with the enzyme, and competitive assays were performed using 200 µM concentrations of the drugs. OUA occupied 39-51% of the receptor sites at 100 nM, 44-67% at 250 nM, and 62-82% at 500 nM, displacing the drugs in a concentration-dependent fashion. The results show that antiarrhythmic drugs interact with the same or similar receptor sites as ouabain on the Na+-K+ATPase, pointing to a possible contribution of these interactions to the mechanism for their inhibitory actions on the enzyme, and perhaps their arrhythmogenic effects.Key words: class I antiarrhythmic agents, proarrhythmias, Na+-K+ATPase, ouabain binding.

scholarly journals In Silico Assessment of Class I Antiarrhythmic Drug Effects on Pitx2-Induced Atrial Fibrillation: Insights from Populations of Electrophysiological Models of Human Atrial Cells and Tissues

2021 ◽  
Vol 22 (3) ◽  
pp. 1265
Author(s):  
Jieyun Bai ◽  
Yijie Zhu ◽  
Andy Lo ◽  
Meng Gao ◽  
Yaosheng Lu ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Antiarrhythmic Drugs ◽  
Drug Effects ◽  
Ionic Currents ◽  
Tissue Level ◽  
Drug Binding ◽  
Class I ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Upstroke Velocity

Electrical remodelling as a result of homeodomain transcription factor 2 (Pitx2)-dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to class I antiarrhythmic drugs (AADs). The possible reasons behind this remain elusive. The purpose of this study was to assess the efficacy of the AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling, from a single cell to the tissue level, using drug binding models with multi-channel pharmacology. Experimentally calibrated populations of human atrial action po-tential (AP) models in both sinus rhythm (SR) and Pitx2-induced AF conditions were constructed by using two distinct models to represent morphological subtypes of AP. Multi-channel pharmaco-logical effects of disopyramide, quinidine, and propafenone on ionic currents were considered. Simulated results showed that Pitx2-induced remodelling increased maximum upstroke velocity (dVdtmax), and decreased AP duration (APD), conduction velocity (CV), and wavelength (WL). At the concentrations tested in this study, these AADs decreased dVdtmax and CV and prolonged APD in the setting of Pitx2-induced AF. Our findings of alterations in WL indicated that disopyramide may be more effective against Pitx2-induced AF than propafenone and quinidine by prolonging WL.

Class I antiarrhythmic drug effects on ouabain binding to guinea pig cardiac Na+-K+ ATPase

1999 ◽  
Vol 77 (11) ◽  
pp. 866-870
Author(s):  
Abdulrahman A. Almotrefi ◽  
Chona Basco ◽  
Azadali Moorji ◽  
Nduna Dzimiri
Keyword(s):  
Guinea Pig ◽  
Antiarrhythmic Drug ◽  
Drug Effects ◽  
Class I ◽  
Ouabain Binding ◽  
Class I Antiarrhythmic Drug

scholarly journals Is Selective Late Na+ Current Inhibition Different From Class I/B Antiarrhythmic Action? Comparison of The Effects of GS967 to Mexiletine in Canine Ventricular Myocardium

2021 ◽  
Author(s):  
Tamás Hézsô ◽  
Muhammad Khan ◽  
Csaba Dienes ◽  
Dénes Kiss ◽  
János Prorok ◽  
...  
Keyword(s):  
Action Potential ◽  
Voltage Clamp ◽  
Ventricular Myocytes ◽  
Drug Effects ◽  
Ventricular Myocardium ◽  
Class I ◽  
Current View ◽  
Antiarrhythmic Action ◽  
Inward Currents ◽  
Offset Time

Abstract Enhancement of the late Na+ current (INaL) increases arrhythmia propensity in the heart, while suppression of the current is antiarrhythmic. GS967 is an agent considered as a selective blocker of INaL. In the present study, effects of GS967 on INaL, on L-type calcium current (ICa), and on action potential (AP) morphology were studied in canine ventricular myocytes by using conventional voltage clamp, action potential voltage clamp and sharp microelectrode techniques. These effects of GS967 were compared to tetrodotoxin (TTX) and to the class I/B antiarrhythmic compound mexiletine. 1 µM GS967, 40 µM mexiletine, and 10 µM TTX dissected largely similarly shaped inward currents under action potential voltage clamp conditions. In case of GS967 and mexiletine, the amplitude and integral of this current was significantly smaller when measured in the presence of 1 µM nisoldipine, while no difference was observed in case of TTX. Under conventional voltage clamp conditions, INaL was significantly decreased by 1 µM GS967 and 40 µM mexiletine (79.0±3.0% and 63.3±2.7% reduction of current integrals, respectively). The integral of ICa was moderately but significantly diminished by both drugs (reduction of 9.3±3.3% and 14.1±1.5%, respectively). These changes were associated with acceleration of inactivation of ICa. Drug effects on peak Na+ current (INaP) were also assessed by recording AP upstroke in multicellular preparations. Both GS967 and mexiletine showed fast onset and offset kinetics: 110 ms and 289 ms offset time constants, respectively, as determined from V+max measurements in right ventricular papillary muscles, while the onset kinetics was characterized by 5.3 AP and 2.6 AP, respectively, at 2.5 Hz. Effects on beat-to-beat variability of AP duration (APD) was studied in isolated myocytes. Beat-to-beat variability was significantly decreased by both GS967 and mexiletine (reduction of 42.1±6.5% and 24.6±12.8%, respectively) while their shortening effect on APD was comparable. It is concluded that the electrophysiological effects of GS967 are similar to those of mexiletine, but with somewhat faster offset kinetics of V+max block. However, since GS967 depressed V+max and INaL at the same concentration, the current view that GS967 represents a new class of drugs that selectively block INaL has to be questiond and it is suggested that GS967 should be classified as a class I/B (or I/B + IV) antiarrhythmic agent.

scholarly journals Is selective late sodium current inhibition different from class I/B antiarrhythmic action? Comparison of the effects of GS967 to mexiletine in canine ventricular myocardium

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
B Horvath ◽  
MN Khan ◽  
T Hezso ◽  
C Dienes ◽  
Z Kovacs ◽  
...  
Keyword(s):  
Action Potential ◽  
Voltage Clamp ◽  
Ventricular Myocytes ◽  
Sodium Current ◽  
Drug Effects ◽  
Ventricular Myocardium ◽  
Class I ◽  
Antiarrhythmic Action ◽  
Na Current ◽  
Inward Currents

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): National Research, Development and Innovation Office New National Excellence Programme Enhancement of the late Na+ current (INa,late) increases arrhythmia propensity in the heart, while suppression of the current is antiarrhythmic. GS-458967 (GS) is an agent considered to be a selective blocker of INa,late. In the present study, effects of GS967 on INa,late, on L-type calcium current (ICaL), and on action potential (AP) morphology were studied in canine ventricular myocytes by using conventional voltage clamp, action potential voltage clamp and sharp microelectrode techniques. These effects of GS were compared to tetrodotoxin (TTX) and to the class I/B antiarrhythmic compound mexiletine. GS (1 μM), mexiletine (40 μM) and TTX (10 μM) dissected largely similarly shaped inward currents under action potential voltage clamp conditions. In case of GS and mexiletine, the amplitude and integral of this inward current was significantly smaller when measured in the presence of 1 μM nisoldipine, while no difference was observed in case of TTX. Under conventional voltage clamp conditions, INa,late was significantly reduced by 1 μM GS and 40 μM mexiletine (about 79% and 63% reduction of current integrals, respectively). The integral of ICa,L was moderately but significantly decreased by both drugs (reduction of 9% and 14%, respectively). These changes were associated with a faster inactivation of ICa,L. Drug effects on early Na+ current (INa,early) were assessed by analyzing the maximal rate of depolarization (V + max) in multicellular preparations. Both GS and mexiletine showed fast onset and offset kinetics: 110 ms and 289 ms offset time constants, respectively, as determined from V + max measurements in right ventricular papillary muscles, while the onset kinetics was characterized by 5.3 AP and 2.6 AP lengths, respectively, at 2.5 Hz. Effects on beat-to-beat variability of AP duration (APD) was studied in isolated myocytes. Short-term variability was significantly decreased by both GS and mexiletine (average reduction of 42% and 24%, respectively) while they caused similar shortening of the APD. The electrophysiological effects of GS are similar to those of mexiletine, but with a somewhat faster offset kinetics of V + max block. However, since GS reduced V+ max and INa,late in the same concentration, the currently accepted view that GS that selectively blocks INa,late has to be questioned and it is suggested that GS should be classified as a class I/B (or I/B + IV) antiarrhythmic agent.

Electron microscopy analysis of degenerating pancreatic ß cells in transgenic mice expressing the MHC Class I antigen Dd

1990 ◽  
Vol 48 (3) ◽  
pp. 548-549
Author(s):  
T. A. Stewart ◽  
D. Liggitt ◽  
S. Pitts ◽  
L. Martin ◽  
M. Siegel ◽  
...  
Keyword(s):  
Type I Diabetes ◽  
Disease Process ◽  
Class Ii ◽  
Class I ◽  
Type I ◽  
Aberrant Expression ◽  
Mhc Molecules ◽  
Endogenous Insulin ◽  
Class Ii Mhc ◽  
Ifn Γ

Insulin-dependant (Type I) diabetes mellitus (IDDM) is a metabolic disorder resulting from the lack of endogenous insulin secretion. The disease is thought to result from the autoimmune mediated destruction of the insulin producing ß cells within the islets of Langerhans. The disease process is probably triggered by environmental agents, e.g. virus or chemical toxins on a background of genetic susceptibility associated with particular alleles within the major histocompatiblity complex (MHC). The relation between IDDM and the MHC locus has been reinforced by the demonstration of both class I and class II MHC proteins on the surface of ß cells from newly diagnosed patients as well as mounting evidence that IDDM has an autoimmune pathogenesis. In 1984, a series of observations were used to advance a hypothesis, in which it was suggested that aberrant expression of class II MHC molecules, perhaps induced by gamma-interferon (IFN γ) could present self antigens and initiate an autoimmune disease. We have tested some aspects of this model and demonstrated that expression of IFN γ by pancreatic ß cells can initiate an inflammatory destruction of both the islets and pancreas and does lead to IDDM.

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