thiourea and Tachycardia--Ventricular

There is increasing evidence for a fatal interaction of myocardial ischemia, ventricular arrhythmias and sudden cardiac death in some patients with coronary artery disease. Evidence comes from autopsy studies, from the evaluation of patients who survived an episode of sudden cardiac death, from follow-up data of these patients either treated or not by revascularization therapy and/or an implantable cardioverter-defibrillator and indicate that reducing the individual ischemic burden will be beneficial to reduce the incidence of sudden cardiac death. Studies in patients with stable and especially with unstable angina using Holter monitoring could demonstrate that there is a close and causal relationship between myocardial ischemia inducing or aggravating life-threatening ventricular arrhythmias and sudden cardiac death particularly in patients with unstable and postinfarction status. This review summarizes some of our clinical knowledge on this topic and indicates that preventive strategies for myocardial ischemia are the antiarrhythmic treatment of choice in patients with severe coronary artery disease and patients with evidence or at risk for ischemic proarrhythmia.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Autopsy; Blood Coagulation; Coronary Disease; Death, Sudden, Cardiac; Defibrillators, Implantable; Electrocardiography; Humans; Ligation; Male; Middle Aged; Multivariate Analysis; Myocardial Ischemia; Myocardial Revascularization; Potassium Channel Blockers; Risk; Risk Factors; Sulfonamides; Tachycardia, Ventricular; Thiourea; Time Factors

Na(+)/Ca(2+) exchanger blockade has been reported to be anti-arrhythmic in different models. The effects of KB-R7943, a Na(+)/Ca(2+) exchanger blocker, on arrhythmogenesis in hearts with chronic myocardial infarction (MI) remain unclear.. Dual voltage and intracellular Ca(2+) (Cai) optical mapping was performed in nine rabbit hearts with chronic MI and four control hearts. Electrophysiology studies including inducibility of ventricular tachyarrhythmias, ventricular fibrillation dominant frequency, action potential, Cai alternans, Cai decay, and conduction velocity were performed. The same protocol was repeated in the presence of KB-R7943 (0.5, 1, and 5μM) after the baseline studies.. KB-R7943 was effective in suppressing afterdepolarizations and spontaneous ventricular tachyarrhythmias in hearts with chronic MI. Surprisingly, KB-R7943 increased the inducibility of ventricular tachyarrhythmias in a dose-dependent manner (11%, 11%, 22%, and 56% at baseline and with 0.5, 1, and 5μM KB-R7943, respectively, p=0.02). Optical mapping analysis revealed that the underlying mechanisms of the induced ventricular tachyarrhythmias were probably spatially discordant alternans with wave breaks and rotors. Further analysis showed that KB-R7943 significantly enhanced both action potential (p=0.033) and Cai (p=0.001) alternans, prolonged Cai decay (tau value) in a dose-dependent manner (p=0.004), and caused heterogeneous conduction delay especially at peri-infarct zones during rapid burst pacing. In contrast, KB-R7943 had insignificant effects in control hearts.. In this chronic MI rabbit model, KB-R7943 has contrasting effects on arrhythmogenesis, suppressing afterdepolarizations and spontaneous ventricular tachyarrhythmias, but enhancing the inducibility of tachyarrhythmias. The mechanism is probably the enhanced spatially discordant alternans because of prolonged Cai decay and heterogeneous conduction delay.

Topics: Animals; Anti-Arrhythmia Agents; Disease Models, Animal; Electrophysiological Phenomena; Myocardial Infarction; Rabbits; Tachycardia, Ventricular; Thiourea

Present study was aimed at investigation into the role of sodium-calcium exchanger (NCX) in myocardial ischemia-reperfusion injury and ischemic preconditioning (IPC). Experiments were performed in vivo rat model of regional myocardial ischemia-reperfusion. It was shown that inhibition of reverse mode of NCX with selective blocker KB-R7943 at a dose of 10 mg/kg resulted in significant decrease in occurrence and severity of ischemic ventricular tachyarrhythmias. Furthermore, administration of KB-R7943 caused potentiation of the antiarrhythmic effect exerted by single episode of IPC. However, KB-R7943 exerted no effect on myocardial infarction size nor affected infarction size limitation by IPC. In conclusion, inhibition of reverse mode of NCX conferred significant antiarrhythmic effect against ischemic rhythm disorders but it was ineffective in terms of infarction size limitation.

Topics: Animals; Anti-Arrhythmia Agents; Ion Channel Gating; Ischemic Preconditioning, Myocardial; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Wistar; Sodium-Calcium Exchanger; Tachycardia, Ventricular; Thiourea

To test the hypothesis that the reverse mode of the Na+/Ca2+ exchange augmented by a rapid heart rate has an antiarrhythmic effect by shortening the action potential duration, we examined the effects of KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl] isothiourea methanesulfonate), a selective inhibitor of the reverse mode of the Na+/Ca2+ exchange, to attenuate this effect. We recorded the electrocardiogram, monophasic action potential (MAP), and left ventricular pressure in canine beating hearts. In comparison to the control, KB-R7943 significantly increased the QTc value and MAP duration. MAP alternans and left ventricular pressure alternans were observed after changing the cycle length to 300 milliseconds in the control studies. KB-R7943 magnified both types of alternans and produced spatially discordant alternans between right and left ventricles. Early after-depolarizations and nonsustained ventricular tachycardia occurred in the presence of KB-R7943. Our data suggest that the reverse mode of the Na+/Ca2+ exchange may contribute to suppression of arrhythmias by abbreviating action potential duration under pathophysiological conditions. This conclusion is based on further confirmation by future studies of the specificity of KB-R7943 for block of the reverse mode of the Na+/Ca2+ exchange.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Dogs; Electrocardiography; Female; Heart Rate; Heart Ventricles; Male; Myocardial Contraction; Sodium-Calcium Exchanger; Tachycardia, Ventricular; Thiourea; Ventricular Premature Complexes; Ventricular Pressure

The effects of perfusate calcium reduction, allopurinol and dimethylthiourea on reperfusion-induced arrhythmias and purine wash-out in isolated rabbit and rat hearts were compared. The overall incidence of reperfusion-induced ventricular tachycardia (VT) was 88% and 94% and that of ventricular fibrillation (VF) was 44% and 88% in the control rabbit and rat hearts, respectively. VF was reduced to 10% and 0% in rat and rabbit hearts subjected to perfusate calcium reduction (0.4 mM for 1 min before ischemia and for 1 min before and throughout reperfusion), respectively. In allopurinol, 1 mM, perfused rat hearts the overall incidence of VF was not changed and only the incidence of a sustained VF (that lasting for at least 10 min) was reduced. VT and VF were prevented in allopurinol-perfused rabbit hearts. Dimethylthiourea, 10 mM, reduced the incidence of VF in rat hearts to 16% and did not significantly affect VT and VF in rabbit hearts. In untreated rat hearts, the major purine compounds washed out upon reperfusion were inosine, hypoxanthine, xanthine and urate. Allopurinol augmented the wash-out of adenosine and abolished that of xanthine and urate. In untreated rabbit hearts, the major purine washed out were inosine, adenosine and hypoxanthine. Allopurinol did not cause further increase in adenosine wash-out in rabbit hearts. We speculate that: (1) calcium mediated arrhythmogenic mechanism is operating both in reperfused rat and rabbit heart; (2) free radical mediated mechanism is of an importance only in rat heart; (3) neither a decreased free radical production secondary to xanthine oxidase inhibition nor the augmentation of adenosine wash-out is a likely explanation for the antiarrhythmic effect of allopurinol in reperfused hearts; and (4) high level of myocardial adenosine accumulation during ischemia, probably secondary to low xanthine oxidase activity, may play a role of a natural defence mechanism in ischemic/reperfused rabbit heart.

Topics: Adenosine; Allopurinol; Animals; Arrhythmias, Cardiac; Calcium; Female; Free Radicals; Heart; Incidence; Male; Myocardium; Oxidation-Reduction; Purines; Rabbits; Rats; Rats, Wistar; Receptors, Purinergic P1; Reperfusion Injury; Tachycardia, Ventricular; Thiourea; Xanthine Oxidase