摘要:

AbstractAlthough cardiac arrhythmias remain a serious clinical problem in many patients with heart disease, the exact role of antiarrhythmic drug therapy is currently under intense evaluation. Within the last several years it has become clear that there are significant risks as well as potential benefits associated with existing agents. Ongoing studies in large patient populations should help determine the benefit/risk ratio of traditional therapy. Regardless of the outcome of these trials, current electrophysiological dogma will have to be re‐evaluated and newer concepts evolve for drug development to make further progress. The goal of this symposium is to exchange information among basic and clinical investigators so as to facilitate the emergence of novel electrophysiological concepts that will form the basis for future generations of antiarrhythmic drug

ISSN:0272-4391    

DOI:10.1002/ddr.430190202

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractIn heart as in other excitable tissues, potassium channel currents play an important role in maintaining the normal cell resting potential and controlling the action potential duration. In this study both theoretical and experimental procedures were used to examine the properties of the cardiac delayed rectifier potassium current (IDR) and the inward rectifier potassium current (IIR) and to determine the role that each plays in the repolarization of the action potential. IIR, a relatively time‐independent current, conducts potassium ions more readily in the inward than outward direction with outward current observed solely over the voltage range of ‐70 through ‐30 mV. Because of this behavior, IIRcontributes only to the final stages of action potential repolarization. In contrast, IDR, a time‐dependent current with slow kinetics, conducts potassium ions outward over a broad positive voltage range and thus plays a dominant role in initiating and sustaining repolarization. A number of approaches, including single channel analysis and pharmacological interventions, have been begun to further characterize these two important ion c

ISSN:0272-4391    

DOI:10.1002/ddr.430190203

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractRecent cellular electrophysiologic studies have begun to clarify the basis of antiarrhythmic drug action. The Class I agents have been shown to block cardiac sodium channels in a use‐dependent manner, and the kinetics and potency of sodium channel block correlated with molecular weight and lipid solubility of drug. The Class IA agents, like quinidine, which increase cardiac action potential duration and refractory period in addition to their effects on conduction, also appear to have potent blocking actions on the potassium channels responsible for repolarization in myocardial cells, whereas the Class IB agents, like lidocaine, shorten action potential duration and are relatively specific in their block of sodium channels. In contrast, Class III agents, which prolong the action potential without slowing conduction, appear to exert their primary blocking action on the potassium channel only. Conversion from Class I to Class III electrophysiologic profiles can be achieved by the substitution of electron‐withdrawing groups (e.g., NO2) in place of electron‐donating groups (e.g., NH2) on the aromatic portion of the basic local anesthetic pharmacophore. Class III agents appear to be most effective against ventricular fibrillation and ventricular tachycardia due to re‐entry, but are generally without activity in the 24 hr Harris dog arrhythmia model. Further evaluation of the mechanism of antiarrhythmic drug action will require use of well‐defined arrhythmia models in a combination with a detailed understanding of drug‐channel i

ISSN:0272-4391    

DOI:10.1002/ddr.430190204

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractSpecimens of diseased human ventricle and of infarcted cardiac tissue obtained from animal models contain admixtures of both well‐polarized and partially depolarized cells which may contribute to the development of cardiac arrhythmias. Recently, it has been suggested that the partially depolarized potentials result from low potassium permeability (PK) since some of the partially depolarized cells can be hyperpolarized by measures which increase Pkincluding increased external potassium (K+o) and rapid pacing (McCullough et al.:Circulation66:II–198, 1982;Circulation70:II–889, 1984). In the present study, we examined the electrophysiological actions of BRL 34915 (Cromakalim), a vasorelaxant agent reported to increase Pkof vascular smooth muscle cells, on the resting potential (RP) and the background K current (IK1) of isolated guinea pig ventricular myocytes by using whole‐cell voltage‐clamping techniques. BRL 34915 (5 μM) significantly hyperpolarized RP at all K+otested, the extent of hyperpolarization decreasing with increasing K+o. The slope of the relationship between RP and K+oincreased in the presence of BRL 34915 from −41.4 to −54.8 mV. BRL 34915 inhibited IK1by decreasing the inward current at potentials negative to RP and the outward current between RP and ∼−20 mV. Outward current positive to −20 mV was unaffected. Higher concentrations (50–100 μM) of BRL 34915 increased this current. These results suggest that the hyperpolarization induced by low concentrations of BRL 34915 resulted from an increase in selectively of the membrane for potassium. Higher concentrations may increase an outward potassium current. Potential therapeutic applications of cardiac selective potassium channel a

ISSN:0272-4391    

DOI:10.1002/ddr.430190205

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractAlthough cardiac arrhythmias are major cause of morbidity and mortality, widespread use of antiarrhythmic drugs is not appropriate at this time for two major reasons: (1) There is no evidence that antiarrhythmic drugs alter mortality in the vast majority of patients; further data will be forthcoming from large‐scale multicentered clinical trials which are currently underway. (2) Side effect are a prominent feature of therapy with antiarrhythmic drugs. The most striking of these toxicities is apparently paradoxical provocation of, rather than suppression of, cardiac arrhythmias by these agents. Two common clinical entities have been recognized. Therapy with action‐potential‐prolonging agents, including quinidine, sotalol, and the major active metabolite of procainamide, N‐acetyl procainamide, has been associated with the development of a morphologically distinctive polymorphic ventricular tachycardia, Torsades de Points, in approximately 5% of patients. Bradycardia and hypokalemia are commonly associated clinical features. In vitro studies indicate that triggered automaticity, in the from of early afterdepolarizations, are responsible for the genesis of Torsades de Pointes. The second common form of arrhythmia aggravation by antiarrhythmic drugs is the development of a marked increase in frequency of sustained ventricular tachycardia events in patients being treated for ventricular tachycardia. Therapy with sodium channel blockers of the “class Ic” subtype, including flecainide and encainide, are most commonly implicated. Since the underlying mechanism for sustained ventricular tachycardia in this patient population is thought to be microreentry, it appears likely that slow conduction due to the “class Ic” properties of the drugs may under appropriate conditions enable rather than block reentrant circuits. A variation on this clinical entity is the increasingly recognized phenomenon of drug‐induced impaired ventricular defibrillation. Although this is recognised with agents of the “class Ic” subtype, other sodium channel blockers have also been implicated, while action potential prologation actually appears associated with a decrease in defibrillation energy requirements. These adverse electrophysiologic drug action are not tightly linked to high plasma concentrations; rather, they represent an interplay among drug dose, plasma concentration, and underlying substrate. However, subsets of patients with variant drug metabolism on a genetic on a genetic basis have been identified and, under appropriate circumstances, these may be at increased risk for adverse electrophysiologic drug actions. Thus, intensive study of the clinical features of arrhythmia aggravation by antiarrhythmic drugs and their correlates in the basic laboratory have resulted not only in improved patient care but also in an increased understanding of the fundamental mechanisms responsible, and, potentially, may result in improved method for identifying new and safer ant

ISSN:0272-4391    

DOI:10.1002/ddr.430190206

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractA variety of in vivo models have been used to detect and develop novel antiarrhythmic/antifibrillatory agents. However, most of these models primarily have identified the class I agents that block sodium ion currents during the upstroke of the cardiac action potential. Since we are interested in identifying agents with a class III electrophysiologic action, i.e. delayed repolarization of the cardiac action potential, we have focused our drug discovery process on a specific, somewhat uncommon in vivo canine model. These studies have demonstrated that class I agents such as encainide, disopyramide, or U58797, a novel benzamide, are clearly identified in the ouabain‐toxic dog or the postinfarction (24–48 hr) conscious dog. In contrast, class III agents such as clofilium sotalol are identified in an acute canine model of coronary artery occlusion and reperfusion. This occlusion‐reperfusion model allows us to further identify the antiarrhythmic and antifibrillatroy actions of novel class III a

ISSN:0272-4391    

DOI:10.1002/ddr.430190207

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractMany factors have been identified in the genesis of cardiac arrhythmias. The relative importance of any given factor over another can vary from individual to individual, and may change with time. Successful antiarrhythmic drug therapy, therefore, must be effective against a multifaceted and evolving matrix. Clinically, the more successful antiarrhythmic agents have complex pharmacological profiles. For example, quinidine and amiodarone have several mechanistic actions which contribute to their antiarrhythmic efficacy. Multiple unfocused actions often result in side effects such as proarrhythmia, which has been demonstrated for both the above agents. Another approach to treating arrhythmias is to use different, selective agents in combination. Using programmed electrical stimulation techniques in dogs, we demonstrated that propranolol was ineffective in preventing reentrant tachycardia. However, subtherapeutic doses of the class III agent sematilide when combined with propranolol prevented reentry. A multivalent approach may also be useful in solving the problem of proarrhythmia. Using standard microelectrode techniques in vitro, we demonstrated that clofilium produced early after depolarizations, as well as an increase in triggered activity. In vivo, clofilium increased the number of ectopic events in infarcted dogs. The addition of a class I or a class IV antiarrhythmic agent in these animals was effective in suppressing the increased ectopic activity. These data suggest that combination therapy, by combining either single agents with selective actions or developing agents with multiple, focused actions may be an effective way to increase antiarrhythmic efficacy and decrease side effects.

ISSN:0272-4391    

DOI:10.1002/ddr.430190208

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractSudden cardiac death (SCD) or sudden coronary death, occurring in patients with unstable angina (angina at rest), myocardial ischemia with or without myocardial infarction (MI), and congestive heart failure (CHF), emerges as one of the most important challenges in cardiovascular medicine at present. Of the 1.5 million cases of myocardial infarction that occur each year in the U.S., about 540,000 patients will die and more than 300,000 of these will die before they reach a hospital, mostly due to ventricular fibrillation (VF) and/or SCD. About 4.8 million people alive in the U.S. have a history of myocardial infarction, angina pectoris, or both and are prime candidates for SCD. About 3 million people in the U.S. have congestive heart failure (CHF) and about 400,000 new cases are reported each year. One year mortality due to CHF is 33–58% and about 45% of the deaths are sudden. These patients were not those who had deleterious hemodynamic parameters whose demise could be predicted; they were those that died suddenly and unexpectedly of VF. Current pharmacological intervention in patients with a documented myocardial infarction with marketed antiarrhythmic agents has not reduced the overall mortality of SCD significantly. This suggests that an efficacious antiarrhythmic/antifibrillatory agent for the prevention of SCD does not exist at present and that there is an urgent need for such an agen

ISSN:0272-4391    

DOI:10.1002/ddr.430190209

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430190201

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY