clamikalant and Ventricular-Fibrillation

Sudden cardiac death resulting from ventricular tachyarrhythmias remains the leading cause of death in industrially developed countries, accounting for between 300,000 and 500,000 deaths each year in the United States. Yet, despite the enormity of this problem, the development of safe and effective anti-arrhythmic agents remains elusive. The identification of effective anti-arrhythmic agents is critically dependent upon the use of appropriate animal models of human disease. During the last 25 years, a canine model of sudden cardiac death has proven to be useful in both the identification of factors contributing to ventricular fibrillation (VF) and the evaluation of potential anti-arrhythmic therapies. The present review provides a detailed retrospective analysis of the data obtained with this model. Briefly, VF was reliably and reproducibly induced by the combination of acute myocardial ischemia at site distant from a previous myocardial infarction during submaximal exercise (to activate the autonomic nervous system). This exercise plus ischemia test identified 2 stable populations of dogs: those that development malignant arrhythmias (susceptible, n=303) and those that rarely developed even single premature ventricular activation (resistant, n=209). The susceptible animals exhibited an elevated sympathetic activation (due to an enhanced beta2-adrenoceptor responsiveness) and a subnormal parasympathetic regulation. Several interventions have proven to be particularly effective in preventing VF in the susceptible dogs; including calcium channel antagonists, left stellate ganglion disruption, ATP-sensitive potassium channel antagonists, beta-adrenoceptor antagonists, and non-pharmacological interventions (endurance exercise training and dietary omega-3 fatty acids).

Topics: Animals; Anti-Arrhythmia Agents; Autonomic Nervous System; Blood Pressure; Calcium; Death, Sudden, Cardiac; Disease Models, Animal; Dogs; Electrocardiography; Exercise; Fish Oils; Heart; Heart Rate; Humans; Sulfonamides; Thiourea; Ventricular Fibrillation

Patients with sustained ventricular tachyarrhythmias are at high risk for sudden cardiac death. The mechanisms leading to multiple temporally related episodes of ventricular fibrillation (VF) are not yet fully elucidated, and treatment options are limited. We investigated whether K(ATP)-channels could be involved in triggering VF.. We determined postarrhythmic changes of monophasic action potentials (MAP) after repetitive induction of VF in 32 Langendorff-perfused rabbit hearts.. Postarrhythmic action potential duration (APD) was significantly shorter compared with baseline (100 +/- 12 ms vs. 140 +/- 8 ms, P < 0.05). With increasing numbers of VF and shortening of recovery intervals between VF episodes (2 min) inducibility of VF increased, and abbreviation of APD became more prominent (90 +/- 5 ms vs. 130 +/- 4 ms, P < 0.05). Pre-treatment with the selective K(ATP) blocking agent HMR 1883 led to a significant increase of postarrhythmic APDs compared with control hearts (100 +/- 12 ms vs. 118 +/- 3 ms, P = 0.0013). Moreover, HMR 1883 significantly reduced inducibility of VF and increased the rate of successful defibrillation.. Repetitive episodes of VF result in postarrhythmic abbreviation of APDs, a phenomenon thought to be of potential relevance for incessant tachyarrhythmias in patients. Prevention of postarrhythmic MAP-shortening by HMR 1883 might be useful in suppressing VF.

Topics: Action Potentials; Animals; Cardiac Pacing, Artificial; Disease Models, Animal; Female; In Vitro Techniques; Male; Potassium Channel Blockers; Potassium Channels; Rabbits; Recurrence; Sulfonamides; Thiourea; Ventricular Fibrillation

ATP-dependent potassium channels (K(ATP)) have been implicated in cardioprotection both during myocardial ischemia and reperfusion. We compared the effect of a non-selective K(ATP) inhibitor glibenclamide, a selective mitochondrial K(ATP) inhibitor 5-hydroxy-decanoate (5-HD) and a selective sarcolemmal K(ATP) blocker HMR 1883, on survival and incidence of arrhythmias during myocardial ischemia in conscious, and during ischemia-reperfusion in pentobarbitone anesthetized rats. Glibenclamide (5 mg/kg i.p.) or HMR 1883 (3 mg/kg i.v.) reduced ischemia-induced irreversible ventricular fibrillation and improved survival during myocardial ischemia (64% and 61% vs. 23% in controls, respectively). 5-HD (5 mg/kg i.v.) did not influence survival and the incidence of ventricular arrhythmias. The incidence of reperfusion-induced arrhythmias was reduced by both glibenclamide and HMR 1883 (3 or 10 mg/kg) resulting in improved survival during reperfusion (81%, 82% and 96% vs. 24% in controls, respectively) in anesthetized rats. 5-HD did not reduce the incidence of lethal reperfusion arrhythmias. Glibenclamide and HMR 1883 prolonged (89+/-4.6 and 89+/-4.9 ms vs. 60+/-2.4 ms in controls), while 5-HD did not change the QT interval. In conclusion, inhibition of sarcolemmal K(ATP) reduces the incidence of lethal ventricular arrhythmias and improves survival both during acute myocardial ischemia and reperfusion in rats. This beneficial effect correlates with the prolongation of repolarization. Inhibition of mitochondrial K(ATP) does not improve survival or reduce the occurrence of ischemia and/or reperfusion-induced arrhythmias and does not prolong the QT interval. The present results also suggest that the antiarrhythmic effect of K(ATP) inhibitors is not influenced by pentobarbitone anesthesia.

Topics: Acute Disease; Anesthesia; Animals; Anti-Arrhythmia Agents; Autonomic Nervous System; Blood Pressure; Cell Membrane; Decanoic Acids; Electrocardiography; Glyburide; Heart; Hydroxy Acids; KATP Channels; Male; Organ Specificity; Potassium Channel Blockers; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sarcolemma; Sulfonamides; Survival; Thiourea; Ventricular Fibrillation

HMR 1883 (the free acid form of HMR 1098) selectively inactivates myocardial ATP sensitive potassium channels, which may be a potential important therapeutic approach to prevent life-threatening arrhythmias. This study was designed to assess the effects of HMR 1883 combined with adrenaline on haemodynamic variables, blood gases, and cardiac arrhythmias in a porcine cardiac arrest model.. After 8 min of untreated cardiac arrest, followed by 1 min of cardiopulmonary resuscitation (CPR), 12 pigs weighing 30-40 kg were assigned randomly to receive either 45 microg/kg adrenaline alone (n=6), or 45 microg/kg adrenaline combined with 3 mg/kg HMR 1883 (n=6), followed by up to three defibrillation attempts 2 min later. Five minutes after return of spontaneous circulation, cardiac arrest was induced for 1 min, with the CPR protocol following as described above. All animals subsequently underwent four cardiac arrest intervals of 1, 2, 3, and 4 min duration which were separated by four episodes of 5 min of return of spontaneous circulation.. Haemodynamic variables, cardiac arrhythmias in the acute resuscitation phase between termination of chest compressions and return of spontaneous circulation, and after return of spontaneous circulation in both groups were comparable throughout the experiment. Survival rates throughout the experiment were comparable between groups. Arterial blood gases, electrolyte, glucose, and lactate levels in both groups during the experiment indicated comparable severe metabolic acidosis, with increasing levels after each episode of simulated refibrillation, and subsequent return of spontaneous circulation.. Combining HMR 1883 with adrenaline during CPR resulted in comparable haemodynamic variables, return of spontaneous circulation rates, cardiac arrhythmias, lactate and glucose levels compared with adrenaline alone. This indicates that injection of HMR 1883 was safe under these conditions.

Topics: Animals; Blood Gas Analysis; Cardiopulmonary Resuscitation; Drug Therapy, Combination; Epinephrine; Heart Arrest; Hemodynamics; Models, Animal; Potassium Channel Blockers; Sulfonamides; Swine; Thiourea; Ventricular Fibrillation

Clinical evidence indicates an antiarrhythmic effect of sulfonylureas, which might be blunted by their vascular action. We wanted to investigate the effect of glibenclamide and the new sulfonylthiourea compound 1-[[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]-sulfonyl]-3 -me thylthiourea (HMR1883) on cardiac electrophysiology in the course of regional ischemia and reperfusion. Isolated rabbit hearts (Langendorff-technique) were pretreated with either vehicle (n=14), 3 micromol/l glibenclamide (n=7) or 3 micromol/l HMR1883 (n=7) before regional ischemia was induced by left coronary artery branch occlusion (45 min) followed by 45 min reperfusion. Unipolar epicardial electrocardiograms were recorded from 256 epicardial AgCl electrodes. Coronary ligation resulted in a decrease in coronary flow (CF) by 35% and in left ventricular pressure (LVP) by 40% in all series. The occluded zone was 23+/-3% in all series. Ischemia led to shortening of the epicardial activation-recovery interval (ARI) in the ischemic area, which was inhibited by both drugs especially in the early phase. In the non-ischemic area, ARIs remained stable and there was no effect of the drugs. Ischemia led to an increase in the regional difference in ARI between ischemic center and border zone. This increase was significantly inhibited by both substances during late ischemia and early reperfusion (until 15 min reperfusion). In addition, the dispersion of ARIs was reduced by both drugs during late ischemia and reperfusion. Ventricular fibrillation was observed in 7/14 (control), 0/7 (glibenclamide), and 0/7 (HMR1883). All ventricular fibrillation occurred during reperfusion. In glibenclamide but not in HMR1883-treated hearts recovery of CF upon reperfusion was significantly depressed (control: 25.5+/-4; HMR1883: 23+/-2.5; glibenclamide: 16+/-1 ml/min, values at 2 min reperfusion), while the elevation of ST-segments of the electrograms in early ischemia was fully prevented by both treatments. We conclude that both glibenclamide and HMR1883 exert an antiarrhythmic effect in this model, and reduce the shortening of the ARIs in the ischemic area, thus attenuating regional differences in ARIs between ischemic and non-ischemic area. Furthermore, unlike glibenclamide HMR1883 does not interfere with postischemic hyperemia.

Topics: Animals; Arrhythmias, Cardiac; Electrocardiography; Electrophysiology; Glyburide; Heart; In Vitro Techniques; Male; Myocardial Ischemia; Myocardial Reperfusion; Potassium Channel Blockers; Potassium Channels, Inwardly Rectifying; Rabbits; Sulfonamides; Thiourea; Ventricular Fibrillation

Ventricular fibrillation (VF) is a major cause of sudden cardiac death in which myocardial ischemia plays a leading role. During ischaemia activation of ATP-sensitive potassium channels (K(ATP)) occurs, leading to potassium efflux from cardiomyocytes and shortening of the action potential favoring the genesis of ventricular fibrillation. In confirmation of this concept the sulfonylurea glibenclamide, which stimulates insulin release by inhibition of pancreatic K(ATP) channels, has been shown to inhibit VF in different models of ischaemia by inhibition of myocardial K(ATP) channels. HMR 1883 (1-[15-12-(5-chloro-o-anisamido)ethyl]-methoxyphenyl]sulfonyl]-3-m ethylthiourea) was designed as a cardioselective K(ATP) channel blocker. The aim of this study was to show that with this compound it is possible to separate the antifibrillatory from the insulin-releasing effect for the treatment of patients at risk of ischaemia-induced arrhythmias and sudden death. In the present study HMR 1883 reduced VF in Sprague-Dawley rats during prolonged ischaemia and also diminished mortality and the duration of VF in a separate reperfusion experiment at 3 mg/kg and 10 mg/kg with no effect on blood glucose or insulin. Glibenclamide, which was antifibrillatory at 0.3 mg/kg and 1 mg/kg, increased plasma insulin and lowered blood glucose already at a dose as low as 0.01 mg/kg. In conclusion, based on its antifibrillatory action and the absence of significant pancreatic effects at therapeutic doses, HMR 1883 is of potential clinical utility for the prevention of severe arrhythmias in patients with ischaemic heart disease.

Topics: Adenosine Triphosphate; Administration, Oral; Animals; Arrhythmias, Cardiac; Arterial Occlusive Diseases; Blood Glucose; Blood Pressure; Dose-Response Relationship, Drug; Glyburide; Heart Rate; Injections, Intravenous; Insulin; Male; Myocardial Ischemia; Myocardial Reperfusion; Potassium Channel Blockers; Rats; Rats, Sprague-Dawley; Sulfonamides; Thiourea; Time Factors; Ventricular Fibrillation

The activation of the ATP-sensitive potassium channel (KATP) during myocardial ischemia leads to potassium efflux, reductions in action potential duration and the formation of ventricular fibrillation (VF). Drugs that inactivate KATP should prevent these changes and thereby prevent VF. However, most KATP antagonists also alter pancreatic channels, which promote insulin release and hypoglycemia. Recently, a cardioselective KATP antagonist, HMR 1883, has been developed that may offer cardioprotection without the untoward side effects of existing compounds. Therefore, VF was induced in 13 mongrel dogs with healed myocardial infarctions by a 2-min coronary artery occlusion during the last minute of a submaximal exercise test. On subsequent days, the exercise-plus-ischemia test was repeated after pretreatment with HMR 1883 (3.0 mg/kg i.v., n = 13) or glibenclamide (1.0 mg/kg i.v., n = 7). HMR 1883 (P < .001) and glibenclamide (P < .01) prevented VF in 11 of 13 and 6 of 7 animals, respectively. Glibenclamide, but not HMR 1883, elicited increases in plasma insulin and reductions in blood glucose. Glibenclamide also reduced (P < .01) both mean coronary blood flow and left ventricular dP/dt maximum as well as the reactive hyperemia induced by 15-sec coronary occlusions (-30.3 +/- 11%), whereas HMR 1883 did not alter this increase in coronary flow (-3.0 +/- 4.7%). Finally, myocardial ischemia (n = 10) significantly (P < .01) reduced refractory period (control, 121 +/- 2 msec; occlusion, 115 +/- 2 msec), which was prevented by either glibenclamide or HMR 1883. Thus, the cardioselective KATP antagonist HMR 1883 can prevent ischemically induced reductions in refractory period and VF without major hemodynamic effects or alterations in blood glucose levels. These data further suggest that the activation of KATPs may play a particularly important role in both the reductions in refractory period and lethal arrhythmia formation associated with myocardial ischemia.

Topics: Adenosine Triphosphate; Animals; Dogs; Glyburide; Heart; Hemodynamics; Myocardial Ischemia; Potassium Channel Blockers; Refractory Period, Electrophysiological; Sulfonamides; Thiourea; Ventricular Fibrillation