guanosine-5--o-(3-thiotriphosphate) and Atrial-Fibrillation

This review provides a molecular perspective of partial agonism at the A(1) adenosine receptor. The structure-activity relationships (SAR) for affinity and intrinsic efficacy of analogues of the full agonist N6-cyclopentyladenosine (CPA) are emphasized. Both general models of activation of G protein-coupled receptors and specific molecular models of the A(1)-adenosine receptor are used to interpret the results of efforts to synthesize and assay effects of partial agonists. The SAR of affinity and intrinsic efficacy of the 2', 3', and especially the 5'-deoxy derivatives of CPA is presented. From this analysis, the nature of the interactions of specific atoms and substituents of the CPA molecule with the A(1)-adenosine receptor are deduced and presented pictorially. As an example of the therapeutic potential of partial agonists, the design and testing of analogues of CPA to provide chronic ventricular rate control during atrial fibrillation is described. The challenges associated with designing a partial A(1)-adenosine receptor agonist for providing chronic ventricular rate control during atrial fibrillation are many. To meet these challenges, further medicinal chemistry efforts in the area of partial A(1)-adenosine receptor agonism are still needed.

Topics: Adenosine; Adenosine A1 Receptor Agonists; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Entropy; Guanosine 5'-O-(3-Thiotriphosphate); Heart Rate; Humans; Ligands; Protein Conformation; Receptor, Adenosine A1; Receptors, G-Protein-Coupled; Structure-Activity Relationship

Effects of azimilide, a class III antiarrhythmic drug, on the acetylcholine (ACh) receptor-operated K+ current (I K.ACh) and the delayed rectifier K+ current (IK) were examined in guinea-pig atrial cells using patch-clamp techniques. Effects of azimilide on experimental atrial fibrillation (AF) were also examined in isolated guinea-pig hearts. In single atrial myocytes, azimilide inhibited both the rapid (IKr) and slow component of IK (IKs). Azimilide inhibited the I K.ACh induced by carbachol (CCh, 1 microM), adenosine (10 microM), and intracellular loading of GTPgammaS (100 microM) in a concentration-dependent manner. The IC50 values of azimilide for inhibiting the CCh-, adenosine-, and GTPgammaS-induced I K.ACh were 1.25, 29.1, and 20.9 microM, respectively, suggesting that azimilide inhibits I K.ACh mainly by blocking the muscarinic receptors. Azimilide concentration-dependently (0.3 - 10 microM) prolonged the action potential duration (APD) in the absence and presence of muscarinic stimulation. In isolated hearts, perfusion of CCh shortened the duration of the monophasic action potential (MAP) and effective refractory period (ERP) of the left atrium and lowered the atrial fibrillation threshold (AFT). Addition of azimilide inhibited the induction of AF by prolonging the duration of MAP and ERP. The I K.ACh inhibition by azimilide may at least in part contribute to the effectiveness to prevent parasympathetic-type AF.

Topics: Action Potentials; Animals; Atrial Fibrillation; Carbachol; Delayed Rectifier Potassium Channels; Dose-Response Relationship, Drug; Female; Guanosine 5'-O-(3-Thiotriphosphate); Guinea Pigs; Heart Atria; Hydantoins; Imidazolidines; In Vitro Techniques; Muscarinic Antagonists; Patch-Clamp Techniques; Piperazines; Potassium Channel Blockers; Refractory Period, Electrophysiological

1. We investigated the effects of JTV-519 (4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4, 5-tetrahydro-1,4-benzothiazepine monohydrochloride), a novel cardioprotective drug, on the repolarizing K(+) currents in guinea-pig atrial cells by use of patch-clamp techniques. We also evaluated the effects of JTV-519 on experimental atrial fibrillation (AF) in isolated guinea-pig hearts. 2. In atrial cells stimulated at 0.2 Hz, JTV-519 in concentrations of 0.3 and 1 microM slightly prolonged the action potential duration (APD). The drug also reversed the action potential shortening induced by the muscarinic agonist carbachol in a concentration-dependent manner. 3. The muscarinic acetylcholine receptor-operated K(+) current (I(K.ACh)) was activated by the extracellular application of carbachol (1 microM), adenosine (10 microM) or by the intracellular loading of GTP gamma S (100 microM). JTV-519 inhibited the carbachol-, adenosine- and GTP gamma S-induced I(K.ACh) with the IC(50) values of 0.12, 2.29 and 2.42 microM, respectively, suggesting that the drug may inhibit I(K.ACh) mainly by blocking the muscarinic receptors. 4. JTV-519 (1 microM) inhibited the delayed rectifier K(+) current (I(K)). Electrophysiological analyses indicated that the drug preferentially inhibits I(Kr) (rapidly activating component) but not I(Ks) (slowly activating component). 5. In isolated hearts, perfusion of carbachol (1 microM) shortened monophasic action potential (MAP) and effective refractory period (ERP), and lowered atrial fibrillation threshold (AFT). Addition of JTV-519 (1 microM) inhibited the induction of AF by prolonging MAP and ERP. 6. We conclude that JTV-519 can exert antiarrhythmic effects against AF by inhibiting repolarizing K(+) currents. The drug may be useful for the treatment of AF in patients with ischaemic heart disease.

Topics: Action Potentials; Adenosine; Animals; Atrial Fibrillation; Atrial Function; Calcium Channel Blockers; Carbachol; Cardiovascular Agents; Dose-Response Relationship, Drug; Guanosine 5'-O-(3-Thiotriphosphate); Guinea Pigs; Heart; Heart Atria; In Vitro Techniques; Membrane Potentials; Potassium Channels; Receptors, Muscarinic; Thiazepines

Dronedarone (SR33589), an amiodarone-like noniodinated antiarrhythmic agent, is undergoing clinical trials in atrial fibrillation. Because vagal activation plays a role in the pathophysiology of supraventricular arrhythmias, we have assessed the ability of dronedarone (0.01, 0.1, and 1 microM), compared with amiodarone (0.1, 1, and 10 microM) to inhibit the muscarinic acetylcholine receptor-operated K+ current (I(K(ACh))) in single cells isolated from guinea pig atria (patch-clamp technique). I(K(ACh)) was activated by extracellular application of carbachol (10 microM) or by intracellular loading with GTP-gamma-S (100 microM). Dronedarone and amiodarone reduced the carbachol-induced I(K(ACh)) with an IC50 (concentration required for 50% inhibition) slightly above 10 nM and 1 microM, respectively. Dronedarone also inhibited the GTP-gamma-S induced K+ current by 28% and 58% at 0.01 and 0.1 microM, respectively. These data suggest that dronedarone inhibits I(K(ACh)) by depressing the function of K(ACh) channel itself or associated GTP-binding proteins. Compared with amiodarone, dronedarone is approximately 100 times more potent on I(K(ACh)) and seems more selective in inhibiting I(K(ACh)) with respect to its antagonism of other inward and outward currents reported in the literature. This relative high potency of dronedarone to reduce I(K(ACh)) may be involved, at least in part, in the antiarrhythmic action of dronedarone against atrial fibrillation.

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Cell Separation; Dronedarone; Guanosine 5'-O-(3-Thiotriphosphate); Guinea Pigs; Heart Atria; In Vitro Techniques; Myocardium; Patch-Clamp Techniques; Potassium Channels; Receptors, Muscarinic; Stimulation, Chemical