sulcardine-sulfate and Disease-Models--Animal

In postmyocardial infarction patients, transient episodes of ischemia are associated with a greater incidence of sudden cardiac death (SCD). Ventricular tachycardia and ventricular fibrillation (VF) are responsible for the majority of SCDs, but current pharmacological interventions for prevention of lethal ventricular arrhythmias are less than satisfactory. We investigated the efficacy of HBI-3000 (HBI), a novel antiarrhythmic agent, in preventing SCD in a conscious canine model.. After 3 to 7 days of a surgically induced myocardial infarction (ie, 90-minute occlusion of the left anterior descending coronary artery followed by 30 minutes of reperfusion), conscious animals were administered vehicle (0.9% NaCl solution for injection) or HBI (15 mg/kg) intravenously. An occlusive thrombus at a site remote from the previous myocardial infarction was induced by electrolytic injury to the intimal surface of the left circumflex coronary artery.. Control animals developed premature ventricular complexes (PVCs) followed by ventricular tachycardia, which terminated in VF in 5 of the 8 dogs. HBI reduced the frequency of PVCs, and only 1 of the 9 HBI-treated animals developed VF (P < .05). In a separate group of postinfarcted animals, the electrical conversion threshold was assessed before and after the intravenous administration of HBI (5, 10, or 15 mg/kg) or flecainide (3 mg/kg), a class IC antiarrhythmic agent. The electrical conversion threshold was not altered by HBI, whereas the administration of flecainide increased the threshold (P < .01 vs baseline).. The data indicate that HBI is an effective antiarrhythmic and antifibrillatory agent for the prevention of VF or sudden cardiac death.

Topics: Animals; Anti-Arrhythmia Agents; Death, Sudden, Cardiac; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Female; Flecainide; Myocardial Infarction; Myocardial Reperfusion Injury; Sulfuric Acid Esters; Tachycardia, Ventricular; Ventricular Fibrillation; Ventricular Premature Complexes

To investigate the anti-arrhythmic effects of sulfamide analogues of changrolin and to characterize the sulfate of compound 6f (sulcardine sulfate, Sul) as a novel anti-arrhythmic agent.. The anti-arrhythmic effects of compounds were studied against aconitine-induced arrhythmias in rats and ouabain-induced arrhythmias in guinea pigs. The effects of Sul on transmembrane action potentials were investigated in isolated rabbit sinoatrial nodes and guinea-pig papillary muscles using intracellular recording. With a whole-cell recording technique, the effects of Sul on sodium current, calcium current, and potassium currents were examined in isolated single guinea-pig ventricular myocytes.. In aconitine-induced arrhythmias of rats, sulfamide analogues of changrolin (4, 5, and 6a-6p) exhibited various anti-arrhythmic activities. The sulfate of compound 6f (Sul) increased the amount of aconitine required to induce arrhythmias in each treated animal. The ED₅₀ value of Sul in rats was 196 mg/kg. In ouabain-induced arrhythmias of guinea pigs, 25, 50, and 100 mg/kg doses of Sul increased the dose of ouabain required to induce VP, VT, and VF in a dose-dependent manner. In papillary preparations, Sul produced a concentration-dependent decrease in APA and V(max), prolonged APD(90) and ERP, whereas RP was unaffected. In the spontaneously beating sinus nodes, Sul reduced APA and V(max) in a concentration-dependent manner. The whole-cell recording studies revealed that Sul produced a reversible reduction in I(Na) (IC₅₀=26.9 μmol/L) and I(Ca,L)(IC₅₀=69.2 μmol/L), whereas the inward rectifier (I(K1)) and the delayed rectifier potassium currents (I(K)) were unaffected.. As a multi-ion channel blocker, Sul may have potent efficacy in anti-atrial and ventricular arrhythmias.

Topics: Aconitine; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channels, L-Type; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Guinea Pigs; Male; Myocytes, Cardiac; Ouabain; Patch-Clamp Techniques; Potassium Channels; Rabbits; Rats; Rats, Sprague-Dawley; Sodium Channels; Sulfuric Acid Esters