Vasoinhibitory effects of NC 1005 and NC 1006, new synthesized antiarrhythmic agents,in isolated rat aorta

1. NC 1005 and NC 1006 (3 × 10⁻⁶M−10⁻⁴M) inhibited the contractions induced by phenylephrine (PE) and KCl in isolated rat aortas with or without endothelium.2. In a Ca²⁺-free medium containing EGTA and nifedipine, NC 1005 and NC 1006 inhibited PE-response and a subsequent response to Ca²⁺ in the presence of PE.3. NC 1005 and NC 1006 also caused relaxations of endothelium-removed aortas precontracted with PE.4. The relaxations induced by NC 1005 and NC 1006 were potentiated by amiloride, zaprinast and theophylline but not by increasing the external Na⁺ concentration.5. Methylene blue and ouabain slightly potentiated NC 1005-relaxation, but not NC 1006-relaxation.6. Glyburide, apamine and nifedipine had no effect on the relaxations.7. NC 1005 and NC 1006 potentiated the relaxation induced by nitroglycerin (NG) without affecting isoproterenol-relaxation.8. In the presence of forskolin, NC 1005 and NC 1006 failed to potentiate NG-relaxation.9. These results suggest that the vasoinhibitory effects of NC 1005 and NC 1006 may be due to an increase in the level of cAMP.     

抗心律失常药物作用的新靶点--M3-R/IKM3

目的　研究心脏M3受体 /M3受体介导的钾通道与心律失常的关系,寻找抗心律失常药物的新靶点。方法分别以结扎大鼠左冠状动脉前降支所致急性心律失常模型和膜片钳技术为基础,观察M3受体的干预作用及作用机制。结果　M3受体阻断剂 4DAMP(4 diphenylacetoxy N methylpiperidine methiodide)加重结扎大鼠冠状动脉前降支所致心律失常,而M3受体激动剂胆碱能明显对抗其作用。其他亚型受体阻断剂,M1受体阻断剂 (prienzepine)、M2受体阻断剂(methotramine)和M4受体阻断剂 (tropicamide)对结扎大鼠左冠状动脉前降支所致急性心律失常无影响。在膜片钳实验中发现,胆碱可激活一种延迟整流钾电流(IKM3 ),此电流可被M3受体阻断剂 4DAMP明显抑制。而M1,M2和M4受体阻断剂对胆碱介导的电流无作用。结论　胆碱通过激动心肌M3受体诱发一外向钾电流 (IKM3 ),并在维持心脏离子通道平衡中起重要作用。M3受体 /IKM 可能是抗心律失常新靶点。     

Heterocyclic analogues of benzamide antiarrhythmic agents

A series of heterocyclic N-[(diethylamino)alkyl]arenamides related to acecainide was prepared and examined for antiarrhythmic activity. The compounds were synthesized from the corresponding known heterocyclic carboxylic acids or esters by using standard amide formation methods. The effects of the compounds on the electrophysiological properties of canine Purkinje fibers and ventricular muscle strips were determined. Most of the compounds showed effects consistent with weak class I activity. Two compounds, N-[2-(diethylamino)ethyl]-3,4,5-trimethyl-1H-pyrrole-2-carboxamide and N-[2-(diethylamino)ethyl]-1H-indole-2-carboxamide, displayed prolongation of the action potential duration and functional refractory period indicative of modest class III electrophysiological activity. Representative compounds were examined by using molecular modeling techniques. Compounds of differing activity classes displayed qualitatively different electrostatic potential maps.     

Clinical potential of emerging antiarrhythmic agents

Analyses of randomised clinical trials have suggested that only in selective populations may antiarrhythmic drugs be effective in improving prognosis: therapy of cardiac arrhythmias, in contrast to other cardiovascular pathological conditions, has not been fully successful. The ideal treatment of arrhythmias should be guided by a sound understanding of the relative arrhythmogenic mechanisms and vulnerable parameters of the different arrhythmias. New model agents are pure class III agents, developed to fulfil these ideal characteristics and are now under active investigation (dofetilide, ibutilide, azimilide, ambasilide, E 4031, almokalant, sematilide, RP 58866 and tedisamil).     

Basic cardiac electrophysiology and mechanisms of antiarrhythmic agents

Basic cardiac electrophysiology and how it applies to antiarrhythmic drug therapy are reviewed. Normal impulse propagation through the heart proceeds in sequence from the sinoatrial (SA) node, through the atrial specialized conducting system, the atrioventricular (AV) node, the His-Pur-kinje system, and into the ventricles. The cardiac cell maintains a resting membrane potential until an electrical stimulus depolarizes the cell and generates an action potential. The action potential is composed of five phases that represent the changing ionic fluxes and membrane potentials of the cardiac cell. The heart contains two types of cardiac conducting fibers. The fast- and slow-current action potentials generated by these fiber types exhibit distinctly different electrophysiologic properties. Cardiac arrhythmias generally result from an abnormality in the rate, rhythm, or conduction of an electrical impulse in the heart. They may be described as disturbances in normal impulse initiation (automaticity), impulse conduction, or both. Various portions of the conduction system are under the control of the autonomic nervous system, which depends on the balance between the activity of the parasympathetic and sympathetic nervous systems. Intracellular and extracellular concentrations of potassium, calcium, and magnesium have important effects on the electrophysiology of the heart. These changes can be critical in the production of various arrhythmias or may affect the efficacy or toxicity of various antiarrhythmic agents. The electrophysiology of quinidine, procainamide, disopyramide, lidocaine, tocainide, phenytoin, flecainide, amiodarone, and bretylium tosylate is discussed to detail the relationship between drug action and antiarrhythmic efficacy. The electrophysiologic effects of beta-blocking agents and calcium-channel antagonists are also presented. This basic primer on cardiac electrophysiology should provide the practitioner with an improved understanding of the effects, indications, and limitations of antiarrhythmic drugs.     

Isolation, synthesis, and evaluation of a series of indencarbazates as hypotensive agents

Two indencarbazates, 1 and 2, were isolated from the sponge Cliona caribboea. These compounds were found to possess mild hypotensive activity. A series of analogues of 1 was synthesized in order to study the structure-activity relationship of this unique class of compounds. A variety of structural changes did not result in a consistent pattern of biological activity.     

Vascular effects of class III antiarrhythmic agents

Methanesulfonanilide Class III antiarrhythmic agents have been shown to block a specific outward delayed rectifier K⁺ current, I_kr in cardiac cells. K⁺ conductance also is recognized to be an important regular of contractile tone in vascular smooth muscle. The purpose of the present investigation was to assess the effects of the new and potent methanesulfoanilide Class III agents E-4031, UK-68,798, UK-66,914 and the Class III standard d-sotalol in vitro in phasically active and electrically quiescent vascular smooth muscle preparations. All four Class III agents augmented phasic contractile tension in spontaneously active rat portal veins at concentrations similar to those effecting significant Class III electrophysiologic activity in cardiac muscle, but failed to contract electrically quiescent rabbit aortic rings. At concentrations exceeding effective cardiac Class III electrophysiologic concentrations, E-4031 relaxed methoxamine- and histamine-contracted rabbit aortic rings, and d-sotalol relaxed methoxamine-contracted aortic rings. UK-68,798 and UK-66,914 failed to relax spasmogen-contracted aortic rings. The similarity in effective concentrations required for the four Class III agents to augment phasic contractile tension in the rat portal vein and increase myocardial refractoriness in cardiac muscle is consistent with the presence of similar K⁺ channel subtypes in the two tissues. Alternatively, the observed activities in the two tissues may be due to actions of these four Class III agents on another, non-I_kr ion channel present in rat portal vein, with an order of potency for blockade similar to block of I_kr in cardiac tissue. © 1992 wiley-Liss, Inc.     

Novel quinolizidinyl derivatives as antiarrhythmic agents

Eighteen analogues of lidocaine, mexiletine, and procainamide were synthesized, replacing their aminoalkyl chains with the rigid and cumbersome quinolizidine nucleus. The target compounds were tested for antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig (gp) heart tissues and to assess calcium antagonist activity. Most compounds exhibited from moderate to high antiarrhythmic activity, and compounds 7, 9, and 19 were more active and potent than quinidine and lidocaine, while producing only modest inotropic, chronotropic, and vasorelaxant effects. These compounds were studied on spontaneously beating Langendorff-perfused gp heart. While quinidine and amiodarone produced a dose-dependent prolongation of all the ECG intervals, compounds 7, 9, and 19, even at concentrations 10-20 times higher than EC50 for the antiarrhythmic activity, only moderately prolonged the PR and QT intervals, leaving unchanged the QRS complex. Ether 7 deserves further investigations due to its interesting cardiovascular profile.     

Synthesis and structure-activity relationships of a new series of antiarrhythmic agents: monobasic derivatives of disobutamide

Analogues of the dibasic antiarrhythmic agent disobutamide (2) were prepared and evaluated for antiarrhythmic efficacy, myocardial depression, and anticholinergic activity. The replacement of an isopropyl group in disobutamide by an acetyl group led to the monobasic analogue SC-40230, 7a, which demonstrated good antiarrhythmic activity accompanied by less myocardial depressant and anticholinergic activities. In addition, it did not induce clear cytoplasmic vacuoles as did the parent compound. SC-40230 was chosen from among other analogues as a candidate for clinical evaluation. Other compounds prepared and evaluated included indolizidinones and a secondary amine isomer of disobutamide.     

Investigation of the arcane inhibition of human organic anion transporter 3 by benzofuran antiarrhythmic agents

The combination of antiarrhythmic agents, amiodarone or dronedarone, with the anticoagulant rivaroxaban is used clinically in the management of atrial fibrillation for rhythm control and secondary stroke prevention respectively. Renal drug-drug interactions (DDIs) between amiodarone or dronedarone and rivaroxaban were previously ascribed to inhibition of rivaroxaban secretion by P-glycoprotein at the apical membrane of renal proximal tubular epithelial cells. Benzbromarone, a known inhibitor of organic anion transporter 3 (OAT3), shares a benzofuran scaffold with amiodarone and dronedarone. However, inhibitory activity of amiodarone and dronedarone against OAT3 remains arcane. Here, we conducted in vitro transporter inhibition assays in OAT3-transfected HEK293 cells which revealed amiodarone, dronedarone and their respective major pharmacologically-active metabolites N-desethylamiodarone and N-desbutyldronedarone possess inhibitory activity against OAT3, with corrected K_i values of 0.042, 0.019, 0.028 and 0.0046 μM respectively. Protein binding effects and probe substrate dependency were accounted for in our assays. Static modelling predicted 1.29-, 1.01-, 1.29- and 1.16-fold increase in rivaroxaban exposure, culminating in a predicted 1.29-, 1.01-, 1.28- and 1.15-fold increase in major bleeding risk respectively, suggesting potential OAT3-mediated DDI between amiodarone and rivaroxaban. Future work involving physiologically-based pharmacokinetic modelling is crucial in holistically predicting the complex DDIs between the benzofuran antiarrhythmic agents and rivaroxaban.     

Novel hypotensive agents from Verbesina caracasana: structure,synthesis and pharmacology

The number and the pharmacological activities of drugs featuring a guanidine group is actually amazing. Many synthetic guanidine derivatives have attracted pharmacologists in search of new antihypertensive drugs for their ability to block adrenergic nerve activity through central and/or peripheral mechanisms. As a result, compounds such as guanethidine, guanabenz, guanfacine, and pinacidil have been introduced in antihypertensive drug therapy. A crude methanol extract of the Venezuelan plant Verbesina caracasana Fries (Compositae), intravenously administered to mice, was found to induce biological effects such as erection of hair, initial stimulation and subsequent blockade of breathing. Biologically controlled purification yielded a series of active guanidine derivatives, namely G1-G7, which were extensively studied with the focus on the following items: (1) The structure determination of the active compounds by spectral data and a set of reactions; (2) The confirmation of the structures by a biogenetically oriented synthesis; (3) The study of the pharmacological profiles of the isolated drugs; (4) The synthesis of analogous and homologous products in the effort to shed some light on the structure-activity relationship. The metabolites of V. caracasana were characterized, in anesthetized rats, as hypotensive drugs of high (G2), mild (G1, G7) and low (G3,G5,G6) potency, devoid of consistent actions in heart rate, and provided with moderate stimulatory effects on cardiac inotropism and breathing (at selected non-toxic intravenous doses). Autonomic neurogenic components and/or peripheral adrenergic and cholinergic receptor-related pathways were involved in the cardiovascular effects. Synthetic analogs and homologs of G1 and G5 were all shown to be hypotensive drugs of low-mild potency, not affecting appreciably cardiac inotropism and/or breathing. The pharmacodynamic differences among the studied compounds were likely to depend on their ability to cross the blood-brain barrier, lipophilicity and pharmacokinetics. Since most of the compounds did not induce reflex tachycardia and depression of myocardial contractility as the majority of the antihypertensive drugs, they might be useful in the treatment of arterial hypertension of various genesis.     

Clinical pharmacokinetics of the newer antiarrhythmic agents

This article reviews clinical pharmacokinetic data on 8 new antiarrhythmic agents. Some of these drugs have been studied extensively while others are relatively new, with incomplete data due to limited evaluation. Amiodarone is a class III antiarrhythmic drug which is effective in treating many atrial and ventricular arrhythmias that are refractory to other drugs. Amiodarone accumulates extensively in tissues and its disposition characteristics are best described by models with 3 and 4 compartments. Its apparent volume of distribution is very large (1300 to 11,000L) and its elimination half-life very long (53 days). A delay of up to 28 days from of treatment to onset of antiarrhythmic effect may be observed, and the antiarrhythmic effect may persist for weeks to months following cessation of therapy. Clinically significant drug interactions have been observed with amiodarone and warfarin, digoxin, quinidine and procainamide. Encainide is a class Ic antiarrhythmic drug. Although it has a short elimination half-life (1 to 3h), 2 major metabolites with antiarrhythmic effects accumulate in the plasma of patients during long term therapy. Plasma concentrations of O-demethyl encainide appear to correlate with the antiarrhythmic effect. Flecainide, another class Ic antiarrhythmic agent, has an elimination half-life of 14 hours which makes it suitable for twice daily dosing. Flecainide elimination is prolonged in patients with low output heart failure. Significant drug interactions with digoxin and cimetidine have been reported. Lorcainide is also a class Ic antiarrhythmic drug, the bioavailability of which is nonlinear. Clearance of the drug is reduced during long term therapy. A major active metabolite, norlorcainide, accumulates in the plasma of patients during long term therapy and its concentration exceeds that of lorcainide by a factor of 2. The elimination half-lives of lorcainide (9h) and norlorcainide (28h) allow for once or twice daily dosing. Mexiletine, a class Ib antiarrhythmic drug, is structurally similar to lignocaine (lidocaine). A sustained release formulation provides effective plasma concentrations when administered twice daily. The apparent volume of distribution of mexiletine is 5.0 to 6.6 L/kg, and the elimination half-life varies from 6 to 12 hours in normal subjects and from 11 to 17 hours in cardiac patients. Mexilitine is extensively metabolised but the metabolites are not pharmacologically active. Renal elimination of mexiletine is pH dependent. Drugs which induce hepatic metabolism significantly alter the pharmacokinetics of mexiletine.(ABSTRACT TRUNCATED AT 400 WORDS)     

新型抗心律失常药物多非利特

多非利特是一个新型的第 3类抗心律失常药物。它通过延长动作电位时间和有效不应期来终止折返激动。主要用于心房颤动、心房扑动转律和转律后维持窦性节律。具有疗效显著、不良反应相对较小等优点     

Dofetilide, a new class III antiarrhythmic agent

Dofetilide is a new antiarrhythmic agent recently approved for conversion and maintenance of sinus rhythm in patients with atrial fibrillation (AF) and atrial flutter (AFl). It is a class III antiarrhythmic that works by selectively blocking the rapid component of the delayed rectifier outward potassium current. Dofetilide prolongs the effective refractory period in accessory pathways, both anterograde and retrograde. This can be seen on the electrocardiogram through a dose-dependent prolongation of the QT and QTc intervals, with parallel increases in ventricular refractoriness. Approximately 80% of drug is excreted in urine, so dosing must be based on creatinine clearance. The elimination half-life is approximately 10 hours. In clinical trials dofetilide was superior to flecainide in converting patients with AFl to normal sinus rhythm (NSR; 70% vs 9%, p<0.01). It also was more effective than sotalol in converting patients with both AF and AFl to NSR (29% vs 6%, p<0.05) and maintaining them in NSR for up to 1 year. Most patients converted within 24-36 hours. Dofetilide has a favorable risk:benefit profile. Torsades de pointes is the most serious side effect; it occurs in 0.3-10.5% of patients and is dose related. To minimize the risk of induced arrhythmia, patients who start or restart the drug should be hospitalized a minimum of 3 days for creatinine clearance measurements, continuous electrocardiographic monitoring, and cardiac resuscitation, if necessary.