piperidines and propisomide

Voltage-dependent modification of Vmax (the maximum upstroke velocity of the action potential) recovery from use-dependent block (UDB) by pirmenol was examined and compared with those observed with other Class I drugs using standard microelectrode techniques. A partial depolarization of the resting membrane by increasing extracellular potassium concentration ([K+]o) from 4 to 8 mM potentiated UDB at 2 Hz stimulation by any of the following drugs: pirmenol (10 microM), disopyramide (20 microM), pentisomide (50 microM), quinidine (20 microM), mexiletine (30 microM), and flecainide (5 microM). The recovery time constants from UDB of quinidine and mexiletine were prolonged and that of flecainide was unchanged in 8 mM [K+]o. However, the recovery time constant from UDB of pirmenol was shortened in high K+ solution, as observed with disopyramide and pentisomide. Thus, disopyramide and its analogues, including pirmenol, show a voltage dependency of recovery process, which is different from those of other class Ia, Ib, and Ic drugs. The main unblocking pathway of disopyramide and its analogues from sodium channels during diastolic interval may be different from that of other Class I drugs.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Disopyramide; Flecainide; Guinea Pigs; Heart; In Vitro Techniques; Membrane Potentials; Mexiletine; Microelectrodes; Neuromuscular Depolarizing Agents; Papillary Muscles; Piperidines; Propylamines; Pyridines; Quinidine; Sodium Channels

The interactions of the class I antiarrhythmic agents, disopyramide, pirmenol, and pentisomide with peripheral muscarinic receptors were investigated by binding assay with [3H]N-methylscopolamine ([3H]NMS) as a ligand. All the agents inhibited the specific [3H]NMS binding to membrane preparations obtained from guinea pig submandibular gland (SG) and urinary bladder (UB) smooth muscle. The competition curves of these agents for [3H]NMS binding to SG membranes were monophasic, indicating competition with [3H]NMS at a single site. Comparison of results with those of our previous binding experiments using guinea pig left atrial (LA) membranes, showed that pirmenol had sevenfold lower affinity for glandular-type muscarinic receptors (M3) than for cardiac-type muscarinic receptors (M2). On the other hand, the dissociation constants (Ki) for disopyramide and pentisomide in SG were comparable to the high-affinity Ki values for these agents at M2 receptors. The competition curves of the three agents for [3H]NMS binding to UB membranes were biphasic and showed high- and low-affinity states of binding. The high- and low-affinity Ki values for pirmenol in UB were similar to its Ki values at M2 and M3 receptors obtained in LA and SG, respectively. The high-affinity Ki values for disopyramide and pentisomide were consistent with the respective Ki values determined in SG, whereas the low-affinity binding sites for these agents were presumably the result of their allosteric interactions with the receptors. All agents at higher concentrations slowed the dissociation of [3H]NMS elicited by an excess of atropine in both UB and SG, thus indicating allosteric interactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Arrhythmia Agents; Binding, Competitive; Disopyramide; Female; Guinea Pigs; Kinetics; Male; Muscle, Smooth; N-Methylscopolamine; Piperidines; Propylamines; Pyridines; Receptors, Muscarinic; Scopolamine Derivatives; Submandibular Gland; Urinary Bladder

Topics: Adrenergic beta-Antagonists; Amiodarone; Anti-Arrhythmia Agents; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Calcium Channel Blockers; Chlorobenzenes; Flecainide; Humans; Membrane Potentials; Moricizine; Piperidines; Propylamines; Pyridines; Sodium Channels

Effects of new antiarrhythmic drugs, pentisomide [3.5 +/- 0.5 mg/kg intravenously (i.v.) n = 8], and E-4031 (5.6 +/- 1.0 micrograms/kg, n = 8), a class III drug, on atrial flutter (AF) caused by reentry were compared with those of disopyramide (1.6 +/- 0.2 mg/kg, n = 8) and propafenone (2.2 +/- 0.2 mg/kg, n = 8). AF was induced with burst atrial pacing after we made an intercaval crush in anesthetized, open-chest dogs. Termination of AF did not differ among test drugs (8 of 8 with disopyramide, 7 of 8 with propafenone, 6 of 8 with pentisomide, and 8 of 8 with E-4031). Cycle length (CL) of AF was prolonged more with propafenone (57 +/- 10%) and pentisomide (41 +/- 5%) than with E-4031 (12 +/- 3%, p less than 0.05). This was also true for increase in interatrial conduction time determined at a pacing CL of 150 ms. Increase in atrial effective refractory period (ERP) determined at a basic pacing CL of 300 ms did not differ among test drugs. Changes in CL of AF correlated significantly with those in interatrial conduction time (r = 0.84, p less than 0.001), but not with those of ERP (r = 0.10, NS). Reinitiation of AF was significantly greater in propafenone (7 of 7) and pentisomide (5 of 6) groups than in disopyramide (1 of 8) and E-4031 (0 of 8) groups (p less than 0.001). Pentisomide and E-4031 were effective in terminating canine AF due to reentry, as were disopyramide and propafenone. Reinitiation of AF was greater in dogs treated with antiarrhythmic drugs that had more prominent effects on conduction time than on ERP.

Topics: Animals; Anti-Arrhythmia Agents; Atrial Flutter; Disopyramide; Dogs; Electrocardiography; Electrophysiology; Heart Conduction System; Piperidines; Propafenone; Propylamines; Pyridines; Refractory Period, Electrophysiological

The binding profiles of the class I antiarrhythmic agents disopyramide, pirmenol and pentisomide (CM7857) to cardiac muscarinic receptors were characterized by the binding assay using [3H]-N-methyl scopolamine ([3H]NMS) as a ligand and their anti-muscarinic actions were investigated functionally in left atrial preparations. All the agents displaced the specific binding of 200 pM [3H]NMS from guinea pig left atrial membranes. Computer-assisted analysis indicated that pirmenol interacted with a single class of binding sites, but the displacement curves of disopyramide and pentisomide were shallow and best fitted to a two-site model. When the concentration of [3H]NMS was increased to 1 nM, the displacement curve of pirmenol was best fitted to a two-site model. In higher concentrations, these agents inhibited the dissociation of [3H]NMS initiated by 1 microM atropine in a concentration-dependent manner, thus revealing allosteric interactions. Two enantiomers of pirmenol possessed qualitatively the same binding properties as the racemate. In guinea pig left atria, disopyramide, pirmenol and pentisomide shifted the concentration-response curves for the negative inotropic effect of carbachol in a parallel manner. The slopes of Schild plot were not significantly different from unity, indicating that they act as a competitive antagonist of cardiac muscarinic receptors. Excellent correlation between the high affinity pKi values and the pA2 values was established for the antiarrhythmic agents. These findings suggest that disopyramide, pirmenol and pentisomide all interact with cardiac muscarinic receptors in both a competitive fashion and an allosteric one. The dual mode of the interaction with cardiac muscarinic receptors seems to be independent of their chiralities.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Arrhythmia Agents; Binding, Competitive; Depression, Chemical; Disopyramide; Female; Guinea Pigs; Heart; Heart Atria; Kinetics; Male; Membranes; Myocardial Contraction; Myocardium; Piperidines; Propylamines; Pyridines; Receptors, Muscarinic

The interactions of the antiarrhythmic agents, disopyramide (D) and its congeners, pirmenol (Pr) and pentisomide (Pt), with peripheral muscarinic receptors (m-AchR) were investigated using binding and functional assays. D, Pr and Pt inhibited the specific binding of [3H]-N-methyl scopolamine ([3H]-NMS) to membrane fractions prepared from guinea pig left atria (LA), submandibular glands (SG) and urinary bladders (UB) in a concentration-dependent manner. Computer-assisted analysis showed that the displacement curves with D obtained from LA and UB were shallow and best fitted by a two-site model, whereas D interacted with a single class of binding sites in SG. Kinetic experiments measuring [3H]-NMS dissociation revealed the existence of allosteric interaction of D with m-AChR, and it might be responsible for the low affinity components of the displacement curves in LA and UB. The pKi values for D in high-affinity receptor sites in LA and UB (pKH) were very close to the pKi for D obtained in SG, and corresponded well to the pA2 values of around 6.0 for antagonism against the carbachol-induced mechanical responses of LA and UB. Pt interacted with m-AChR with qualitatively very similar fashion to that of D, but its potency was very weak (1/10 of D). Pr interacted with a single class of binding sites in LA and SG with pKi of 6.02 and 5.18, respectively, indicating that the affinity of Pr to glandular m-AChR (M3) was 7 fold lower than that to cardiac one (M2). The displacement curve with Pr in UB was best fitted by a two-site model with pKH of 5.93 and pKL of 5.20. The pA2 for Pr in LA and UB were 6.47 and 5.55, respectively, suggesting the existence of a mixed population of M2 and M3 in UB and the contribution of M3 to its contractile response. It is concluded that Pr is able to distinguish M2 from M3, and that D and Pt have almost similar affinity to both subtypes of m-AChR. Pr was less potent than D in interaction with M3.

Topics: Animals; Binding, Competitive; Carbachol; Disopyramide; Drug Interactions; Female; Guinea Pigs; In Vitro Techniques; Male; Muscle Contraction; Myocardial Contraction; N-Methylscopolamine; Piperidines; Propylamines; Pyridines; Receptors, Muscarinic; Scopolamine Derivatives