Sustainabiliti the Technological Development of the Hungarian Agriculture

The final outcome of agricultural production basically depends on applied technologies. In a simplified definition technology is the method of production, the chain of logically and rationally connected operations. The technological development itself has no cease being a self propelling process. The logical development strategy for Hungarian agriculture „here and now” depends on several aspects. The countries in the world can be divided into two major groups; industrialised and developing ones. Hungary would be placed somewhere between the two. The previous „socialist” system has exhausted already, however the new, market-oriented system is not yet established. The paper is dealing with the Hungarian problems and possibilities of agricultural technological development concerning sustainable production

Proaritmiás gyógyszermellékhatások vizsgálata transzgenikus hosszú QT-szindrómás nyúlmodellek segítségével

A gyógyszer okozta ritmuszavar a különböző vegyületek súlyos és potenciálisan halálos mellékhatása. A proaritmiás mellékhatást gyakran az adott gyógyszernek a szívizom-repolarizáló ionáramait gátló hatásaival hozzák összefüggésbe, ami az EKG-n a QT-intervallum meghosszabbodásához vezet. A gyógyszerfejlesztésben alkalmazott kifinomult szűrési módszerek ellenére a proaritmia megbízható előrejelzése továbbra is jelentős kihívást jelent. Bár a gyógyszerek által kiváltott QT-idő megnyúlással összefüggő proaritmiás hatás iránt fokozottan érzékenyítenek a betegek repolarizációs tartalékát csökkentő kórfolyamatok, a legtöbb gyógyszerbiztonsági szűrésre használt modellrendszer normális, egészséges sejteket, szöveteket és állatokat használ fel. A közelmúltban több, csökkent repolarizációs tartalékkal rendelkező transzgenikus hosszú QT-szindrómás (LQTS) nyúlmodellt hoztak létre. Összefoglaló közleményünkben e modellek lehetséges felhasználását tárgyaljuk a gyógyszerindukált aritmiák előrejelzésére, összefüggésben a különböző modellekben tapasztalt repolarizáló szívizom ionáram-károsodással. Emellett áttekintjük a rendelkezésre álló transzgenikus LQTS-nyúlmodellek elektrofiziológiai jellemzőit, a modelleken végzett farmakológiai elvi bizonyító vizsgálatokat, kiemelve a transzgenikus nyúl LQTS-modellek előnyeit és hátrányait a gyógyszerindukálta ritmuszavar kutatásában

Different effects of amiodarone and dofetilide on the dispersion of repolarization between well-coupled ventricular and purkinje fibers

Increased transmural dispersion of repolarization is an established contributing factor to ventricular tachyar-rhythmias. In this study, we evaluated the effect of chronic amiodarone treatment and acute administration of dofetilide in canine cardiac preparations containing electrotonically coupled Purkinje fibers (PFs) and ventricular muscle (VM) and compared the effects to those in uncoupled PF and VM preparations using the conventional microelectrode technique. Dispersion between PFs and VM was inferred from the difference in the respective action potential durations (APDs). In coupled preparations, amiodarone decreased the difference in APDs between PFs and VM, thus decreasing dispersion. In the same preparations, dofetilide increased the dispersion by causing a more pronounced prolongation in PFs. This prolongation was even more emphasized in uncoupled PF preparations, while the effect in VM was the same. In uncoupled preparations, amiodarone elicited no change on the difference in APDs. In conclusion, amiodarone decreased the dispersion between PFs and VM, while dofetilide increased it. The measured difference in APD between cardiac regions may be the affected by electrotonic coupling; thus, studying PFs and VM separately may lead to an over-or underestimation of dispersion. © 2021, Canadian Science Publishing. All rights reserved

Mechanisms of ventricular rate adaptation as a predictor of arrhythmic risk.

Background: Protracted QT interval (QTI) adaptation to abrupt heart rate (HR) changes has been identified as a clinical arrhythmic risk marker. This study investigates the ionic mechanisms of QTI rate adaptation and its relationship to arrhythmic risk. Methods and Results: Computer simulations and experimental recordings in human and canine ventricular tissue were used to investigate the ionic basis of QTI and action potential (AP) duration (APD) to abrupt changes in HR with a protocol commonly used in clinical studies. Time for 90% QTI adaptation is 3.5 min in simulations, in agreement with experimental and clinical data in human. APD adaptation follows similar dynamics, being faster in midmyocardial cells (2.5 min) than in endocardial/epicardial cells (3.5 min). Both QTI and APD adapt in two phases following an abrupt HR change: a fast initial phase with time constant 2 min driven by [Na(+)]i dynamics. Alterations in [Na(+)]i dynamics due to Na(+)/K(+) pump (INaK) inhibition result in protracted rate adaptation, and is associated with increased proarrhythmic risk, as indicated by AP triangulation and faster ICaL recovery from inactivation, leading to formation of early afterdepolarizations (EADs). Conclusions: This study suggests that protracted QTI adaptation could be an indicator of altered [Na(+)]i dynamics following INaK inhibition as it occurs in patients with ischemia or heart failure. Increased risk of cardiac arrhythmias in patients with protracted rate adaptation may be due to increased risk of EAD formation. Key words: action potentials, ventricles, ion channels, arrhythmia

Hidden Cardiotoxicity of Rofecoxib Can be Revealed in Experimental Models of Ischemia/Reperfusion

Cardiac adverse effects are among the leading causes of the discontinuation of clinical trials and the withdrawal of drugs from the market. The novel concept of 'hidden cardiotoxicity' is defined as cardiotoxicity of a drug that manifests in the diseased (e.g. ischemic/reperfused), but not in the healthy heart or as a drug-induced deterioration of cardiac stress adaptation (e.g. ischemic conditioning). Here, we aimed to test if the cardiotoxicity of a selective COX-2 inhibitor rofecoxib that was revealed during its clinical use, i.e., increased occurrence of proarrhythmic and thrombotic events, could have been revealed in early phases of drug development by using preclinical models of ischemia/reperfusion (I/R) injury. Rats that were treated with rofecoxib or vehicle for four weeks were subjected to 30 min. coronary artery occlusion and 120 min. reperfusion with or without cardioprotection that is induced by ischemic preconditioning (IPC). Rofecoxib increased overall the arrhythmias including ventricular fibrillation (VF) during I/R. The proarrhythmic effect of rofecoxib during I/R was not observed in the IPC group. Rofecoxib prolonged the action potential duration (APD) in isolated papillary muscles, which was not seen in the simulated IPC group. Interestingly, while showing hidden cardiotoxicity manifested as a proarrhythmic effect during I/R, rofecoxib decreased the infarct size and increased the survival of adult rat cardiac myocytes that were subjected to simulated I/R injury. This is the first demonstration that rofecoxib increased acute mortality due to its proarrhythmic effect via increased APD during I/R. Rofecoxib did not interfere with the cardiprotective effect of IPC; moreover, IPC was able to protect against rofecoxib-induced hidden cardiotoxicity. These results show that cardiac safety testing with simple preclinical models of I/R injury uncovers hidden cardiotoxicity of rofecoxib and might reveal the hidden cardiotoxicity of other drugs

Diclofenac Prolongs Repolarization in Ventricular Muscle with Impaired Repolarization Reserve

Background: The aim of the present work was to characterize the electrophysiological effects of the non-steroidal anti- inflammatory drug diclofenac and to study the possible proarrhythmic potency of the drug in ventricular muscle. Methods: Ion currents were recorded using voltage clamp technique in canine single ventricular cells and action potentials were obtained from canine ventricular preparations using microelectrodes. The proarrhythmic potency of the drug was investigated in an anaesthetized rabbit proarrhythmia model. Results: Action potentials were slightly lengthened in ventricular muscle but were shortened in Purkinje fibers by diclofenac (20 mM). The maximum upstroke velocity was decreased in both preparations. Larger repolarization prolongation was observed when repolarization reserve was impaired by previous BaCl 2 application. Diclofenac (3 mg/kg) did not prolong while dofetilide (25 mg/kg) significantly lengthened the QT c interval in anaesthetized rabbits. The addition of diclofenac following reduction of repolarization reserve by dofetilide further prolonged QT c . Diclofenac alone did not induce Torsades de Pointes ventricular tachycardia (TdP) while TdP incidence following dofetilide was 20%. However, the combination of diclofenac and dofetilide significantly increased TdP incidence (62%). In single ventricular cells diclofenac (30 mM) decreased the amplitude of rapid (I Kr ) and slow (I Ks ) delayed rectifier currents thereby attenuating repolarization reserve. L-type calcium current (I Ca ) was slightly diminished, but the transient outward (I to ) and inward rectifier (I K1 ) potassium currents were not influenced. Conclusions: Diclofenac at therapeutic concentrations and even at high dose does not prolong repolarization markedly and does not increase the risk of arrhythmia in normal heart. However, high dose diclofenac treatment may lengthen repolarization and enhance proarrhythmic risk in hearts with reduced repolarization reserve

Investigations on different aspects of cardiac ventricular repolarization: repolarization reserve and adaptation to heart rate

Investigations on different aspects of cardiac ventricular repolarization: repolarization reserve and adaptation to heart rate Introduction 1. The proper assessment of the pro-arrhythmic potential of candidate compounds is a major concern for drug development, since drug-induced arrhythmias, including Torsades de Pointes (TdP), can lead to sudden cardiac death. The prediction of TdP in clinical setting is very difficult since the incidence of drug-induced TdP is very low (1:100 000), however, drug associated sudden cardiac deaths have led to the withdrawal of a number, otherwise successful, compounds in the past. Importantly, current cardiac electrophysiological safety methods concentrate mostly on testing the hERG blocking and/or ventricular repolarization prolonging effects of candidate compounds and they use mostly healthy tissues and animals. It is, therefore, not entirely surprising that these cardiac safety tests are not sensitive enough. A large and still growing number of animal experimental and clinical studies suggest that the degree of repolarization prolongation does not show a close correlation with subsequent ventricular arrhythmia development. In these cases, without marked prolongation of the QT interval, repolarization reserve may be reduced with a consequent increase in arrhythmia susceptibility. According to the concept of repolarization reserve, normal cardiac repolarization is controlled by different potassium currents in a redundant way, and congenital or acquired (e.g. mild potassium current inhibition by a non-cardiovascular drug) decrease in the function of a single repolarizing current does not always lead to marked repolarization prolongation, since other currents can compensate for the lost function. In the case of reduced repolarization reserve, additional inhibition of another repolarizing current can result in excessive prolongation of repolarization and can provoke serious ventricular arrhythmias. Evidence points to a critically important role for the slow component of the delayed rectifier potassium current (IKs) in ventricular repolarization reserve, however, other potassium currents may also significantly contribute to repolarization reserve. There is considerable variation in the expression of key repolarizing potassium channels in different mammalian species, including dog and rabbit that are frequently used species in pro-arrhythmia models. Therefore, it is reasonable to assume that species specific ion channel expression profiles may result in species dependent alterations in responses to potassium channel blockers. Such differences may significantly influence the value of data obtained in these models for human extrapolation, however, it is unclear how species specific potassium channel expressions translate into differences in arrhythmia development in dogs and rabbits. 2. Disturbances in another important aspect of cardiac ventricular repolarization adaptation can also play a significant role in the development of serious cardiac arrhythmias and sudden cardiac death. Clinical, animal experimental and theoretical studies have shown that abrupt changes in heart rate result in a progressive adaptation of the QT interval measured on the ECG due to short-term cardiac memory effects. Patients exhibiting protracted QT interval heart rate adaptation dynamics have been identified to be at greater risk of developing cardiac arrhythmias and sudden cardiac death. Furthermore, clinical data also suggest that the extent of amiodarone-induced acceleration of QT interval heart rate adaptation could be used as a therapeutic marker of antiarrhythmic drug efficacy. However, despite strong evidence suggesting an important role of short-term cardiac memory in arrhythmogenesis, the underlying ionic mechanisms are still controversial. Aims 1. It is not clear, how species specific potassium channel expressions translate into differences in arrhythmia development in dogs and rabbits, two species frequently used in pro-arrhythmia models. It has been shown previously that repolarization reserve impairment by inhibition of IKs increased arrhythmia susceptibility during subsequent IKr inhibition in dogs and rabbits in a similar degree. A possibly important role for IK1 has been suggested in repolarization reserve. In the first series of experiments we studied the effects of combined pharmacological inhibition of IK1 and IKs, as well as IK1 and IKr on ECG parameters and the incidence of TdP in conscious dogs and anesthetized rabbits. We also investigated whether TdP development was paralleled by increased short-term variability of the QT interval, a novel ECG parameter suggested for more reliable prediction of drug-induced ventricular arrhythmias. 2. The aim of the second series of experiments was to investigate another important aspect of cardiac venricular repolarization adaptation: we performed studies on the ionic mechanisms of QT interval heart rate adaptation in ventricula