Search

Even though rodents are accessible model animals, their electrophysiological properties are deeply different from those of humans, making the translation of rat studies to humans rather difficult. We compared the mechanisms of ventricular repolarization in various animal models to those of humans by measuring cardiac ventricular action potentials from ventricular papillary muscle preparations using conventional microelectrodes and applying selective inhibitors of various potassium transmembrane ion currents. Inhibition of the I K1 current (10 µmol/L barium chloride) significantly prolonged rat ventricular repolarization, but only slightly prolonged it in dogs, and did not affect it in humans. On the contrary, I Kr inhibition (50 nmol/L dofetilide) significantly prolonged repolarization in humans, rabbits, and dogs, but not in rats. Inhibition of the I Kur current (1 µmol/L XEN-D0101) only prolonged rat ventricular repolarization and had no effect in humans or dogs. Inhibition of the I Ks (500 nmol/L HMR-1556) and I to currents (100 µmol/L chromanol-293B) elicited similar effects in all investigated species. We conclude that dog ventricular preparations have the strongest translational value and rat ventricular preparations have the weakest translational value in cardiac electrophysiological experiments. more...

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of morbidity and mortality. Traditional antiarrhythmic agents used for restoration of sinus rhythm have limited efficacy in long-term AF and they may possess ventricular proarrhythmic adverse effects, especially in patients with structural heart disease. The acetylcholine receptor-activated potassium channel (I K,ACh ) represents an atrial selective target for future AF management. We investigated the effects of the I K,ACh blocker tertiapin-Q (TQ), a derivative of the honeybee toxin tertiapin, on chronic atrial tachypacing-induced AF in conscious dogs, without the influence of anesthetics that modulate a number of cardiac ion channels. Action potentials (APs) were recorded from right atrial trabeculae isolated from dogs with AF. TQ significantly and dose-dependently reduced AF incidence and AF episode duration, prolonged atrial effective refractory period, and prolonged AP duration. The reference drugs propafenone and dofetilide, both used in the clinical management of AF, exerted similar effects against AF in vivo. Dofetilide prolonged atrial AP duration, whereas propafenone increased atrial conduction time. TQ and propafenone did not affect the QT interval, whereas dofetilide prolonged the QT interval. Our results show that inhibition of I K ,ACh may represent a novel, atrial-specific target for the management of AF in chronic AF. more...

A reliable assessment of the pro-arrhythmic potential for drugs in the development phase remains elusive. Rabbits and dogs are commonly used to create models of pro-arrhythmia, but the differences between them with respect to repolarizing potassium currents are poorly understood. We investigated the incidence of drug-induced torsades de pointes (TdP) and measured conventional ECG parameters and the short-term variability of the QT interval (STVQT) following combined pharmacological inhibition of IK1+IKs and IK1+IKr in conscious dogs and anesthetized rabbits. A high incidence of TdP was observed following the combined inhibition of IK1+IKs in dogs (67% vs. 14% in rabbits). Rabbits exhibited higher TdP incidence after inhibition of IK1+IKr (72% vs. 14% in dogs). Increased TdP incidence was associated with significantly larger STVQT in both models. The relatively different roles of IK1 and IKs in dog and rabbit repolarization reserve should be taken into account when extrapolating the results from animal models of pro-arrhythmia to humans. A stronger repolarization reserve in dogs (likely due to stronger IK1 and IKs), and the more human-like susceptibility to arrhythmia of rabbits argues for the preferred use of rabbits in the evaluation of adverse pro-arrhythmic effects. more...

Sudden death among athletes is very rare (1:50,000-1:100,000 annually) but it is still 2-4 times more frequent than in the age-matched control population and attracts significant media attention. We propose a mechanism underlying sudden cardiac death in athletes that does not relate to myocardial ischemia but is based on repolarization abnormalities due to potassium channel downregulation and can also be best explained by the concurrent presence of several factors such as cardiac hypertrophy (athlete's heart), and/or hypertrophic cardiomyopathy, increased sympathetic tone, genetic defects, drugs, doping agents, food, or dietary ingredients. These factors together can increase the repolarization inhomogeneity of the heart ("substrate") and an otherwise harmless extrasystole ("trigger") occurring with a very unfortunate timing may sometimes induce life-threatening arrhythmias. The effective and possible prevention of sudden cardiac death requires the development of novel cost effective cardiac electrophysiological screening methods. Athletes identified by these tests as individuals at higher proarrhythmic risk should then be subjected to more costly genetic tests in order to uncover possible underlying genetic causes for alterations in ionic channel structure and/or function. more...

Our recent data demonstrate that activation of pmKATP channels polarizes the membrane of cardiomyocytes and reduces Na+/Ca2+ exchange-mediated Ca2+ overload. However, it is important that these findings be extended into contractile models of hypoxia/reoxygenation injury to further test the notion that pmKATP channel activation affords protection against contractile dysfunction and calcium overload. Single rat heart right ventricular myocytes were enzymatically isolated, and cell contractility and Ca2+ transients in field-stimulated myocytes were measured in a cellular model of metabolic inhibition and reoxygenation. Activation of pmKATP with P-1075 (5 microM) or inhibition of the Na+/Ca2+ exchanger with KB-R7943 (5 microM)reduced reoxygenation-induced diastolic Ca2+ overload and improved the rate and magnitude of posthypoxic contractile recovery during the first few minutes of reoxygenation. Moreover,diastolic Ca2+ overload and posthypoxic contractile dysfunction were aggravated in ventricular myocytes either subjected to specific blockade of pmKATP with HMR1098 (20 microM) or expressing the dominant-negative pmKATP construct Kir6.2(AAA) in the presence of P-1075. Our results suggest that a common mechanism, involving resting membrane potential-modulated increases in diastolic [Ca2+]i, is responsible for the development of contractile dysfunction during reoxygenation following metabolic inhibition. This novel and highly plausible cellular mechanism for pmKATP-mediated cardioprotection may have direct clinical relevance as evidenced by the following findings: a hypokalemic polarizing cardioplegia solution supplemented with the pmKATP opener P-1075 improved Ca2+ homeostasis and recovery of function compared with hyperkalemic depolarizing St. Thomas' cardioplegia following contractile arrest in single ventricular myocytes and working rat hearts. We therefore propose that activation of pmKATP channels improves posthypoxic cardiac function via reductions in abnormal diastolic Ca2+ homeostasis mediated by reverse-mode Na+/Ca2+ exchange. more...

We investigated the effect of ATP-sensitive K+ channel (KATP) openers (pinacidil and cromakalim), and a KATP blocker (glibenclamide) on reperfusion-induced arrhythmias in pentobarbitone-anaesthetized rats. Arrhythmias were induced by reperfusion following a 6 min ligation of the left main coronary artery. Rats were pretreated with pinacidil (0.1 or 0.3 mg/kg), or cromakalim (28 or 56 micrograms/kg), or glibenclamide (5 mg/kg), or vehicle. Pinacidil and cromakalim produced dose-related reductions in blood pressure. Pinacidil (0.1 mg/kg) and cromakalim (56 micrograms/kg) significantly decreased the incidence of reperfusion-induced ventricular fibrillation and increased survival. Glibenclamide did not decrease ventricular fibrillation incidence, yet improved survival by increasing the possibility of recovery from ventricular fibrillation. The present study suggests that both opening and blocking KATP channels may increase survival during coronary occlusion and reperfusion in anaesthetized rats. more...