Altered Cellular Protein Quality Control System Modulates Cardiomyocyte Function in Volume Overload-Induced Hypertrophy.

Volume-induced hypertrophy is one of the risk factors for cardiac morbidity and mortality. In addition, mechanical and metabolic dysfunction, aging, and cellular redox balance are also contributing factors to the disease progression. In this study, we used volume overload (VO), which was induced by an aortocaval fistula in 2-month-old male Wistar rats, and sham-operated animals served as control. Functional parameters were measured by transthoracic echocardiography at termination 4- or 8-months after VO. The animals showed hypertrophic remodeling that was accompanied by mechanical dysfunction and increased cardiomyocyte stiffness. These alterations were reversible upon treatment with glutathione. Cardiomyocyte dysfunction was associated with elevated oxidative stress markers with unchanged inflammatory signaling pathways. In addition, we observed altered phosphorylation status of small heat shock proteins 27 and 70 and diminished protease expression caspases 3 compared to the matched control group, indicating an impaired protein quality control system. Such alterations might be attributed to the increased oxidative stress as anticipated from the enhanced titin oxidation, ubiquitination, and the elevation in oxidative stress markers. Our study showed an early pathological response to VO, which manifests in cardiomyocyte mechanical dysfunction and dysregulated signaling pathways associated with enhanced oxidative stress and an impaired protein quality control system.

Ca2+/calmodulin-dependent protein kinase II and protein kinase G oxidation contributes to impaired sarcomeric proteins in hypertrophy model.

AIMS: Volume overload (VO) induced hypertrophy is one of the hallmarks to the development of heart diseases. Understanding the compensatory mechanisms involved in this process might help preventing the disease progression. METHODS AND RESULTS: Therefore, the present study used 2 months old Wistar rats, which underwent an aortocaval fistula to develop VO-induced hypertrophy. The animals were subdivided into four different groups, two sham operated animals served as age-matched controls and two groups with aortocaval fistula. Echocardiography was performed prior termination after 4- and 8-month. Functional and molecular changes of several sarcomeric proteins and their signalling pathways involved in the regulation and modulation of cardiomyocyte function were investigated. RESULTS: The model was characterized with preserved ejection fraction in all groups and with elevated heart/body weight ratio, left/right ventricular and atrial weight at 4- and 8-month, which indicates VO-induced hypertrophy. In addition, 8-months groups showed increased left ventricular internal diameter during diastole, RV internal diameter, stroke volume and velocity-time index compared with their age-matched controls. These changes were accompanied by increased Ca2+ sensitivity and titin-based cardiomyocyte stiffness in 8-month VO rats compared with other groups. The altered cardiomyocyte mechanics was associated with phosphorylation deficit of sarcomeric proteins cardiac troponin I, myosin binding protein C and titin, also accompanied with impaired signalling pathways involved in phosphorylation of these sarcomeric proteins in 8-month VO rats compared with age-matched control group. Impaired protein phosphorylation status and dysregulated signalling pathways were associated with significant alterations in the oxidative status of both kinases CaMKII and PKG explaining by this the elevated Ca2+ sensitivity and titin-based cardiomyocyte stiffness and perhaps the development of hypertrophy. CONCLUSIONS: Our findings showed VO-induced cardiomyocyte dysfunction via deranged phosphorylation of myofilament proteins and signalling pathways due to increased oxidative state of CaMKII and PKG and this might contribute to the development of hypertrophy.

Long-Term Endurance Exercise Training Alters Repolarization in a New Rabbit Athlete's Heart Model.

In the present study, the effect of long-term exercise training was investigated on myocardial morphological and functional remodeling and on proarrhythmic sensitivity in a rabbit athlete's heart model. New-Zealand white rabbits were trained during a 12-week long treadmill running protocol and compared with their sedentary controls. At the end of the training protocol, echocardiography, in vivo and in vitro ECG recordings, proarrhythmic sensitivity with dofetilide (nM) were performed in isolated hearts, and action potential duration (APD) measurements at different potassium concentrations (4.5 and 2 mM) were made in the isolated papillary muscles. Expression levels of the slow component of delayed rectifier potassium current and fibrosis synthesis and degradation biomarkers were quantified. Echocardiography showed a significantly dilated left ventricle in the running rabbits. ECG PQ and RR intervals were significantly longer in the exercised group (79 ± 2 vs. 69 ± 2 ms and 325 ± 11 vs. 265 ± 6 ms, p < 0.05, respectively). The in vivo heart rate variability (HRV) (SD of root mean square: 5.2 ± 1.4 ms vs. 1.4 ± 0.2 ms, p < 0.05) and Tpeak-Tend variability were higher in the running rabbits. Bradycardia disappeared in the exercised group in vitro. Dofetilide tended to increase the QTc interval in a greater extent, and significantly increased the number of arrhythmic beats in the trained animals in vitro. APD was longer in the exercised group at a low potassium level. Real-time quantitative PCR (RT-qPCR) showed significantly greater messenger RNA expression of fibrotic biomarkers in the exercised group. Increased repolarization variability and higher arrhythmia incidences, lengthened APD at a low potassium level, increased fibrotic biomarker gene expressions may indicate higher sensitivity of the rabbit "athlete's heart" to life-threatening arrhythmias.

Long-term endurance training-induced cardiac adaptation in new rabbit and dog animal models of the human athlete's heart.

Sudden cardiac death in athletes is rare and most often unexpectable. For a better understanding of cardiac remodeling, this study presents the effects of chronic vigorous exercise on cardiac structure and electrophysiology in new rabbit and dog athlete's heart models. Rabbits and dogs were randomized into sedentary ('Sed'), exercised (subjected to 16 weeks chronic treadmill exercise ('Ex') groups, and a testosterone-treated ('Dop') group in dogs. Echocardiography and electrocardiogram were performed. Proarrhythmic sensitivity and autonomic responses were tested in conscious dogs. 'Ex' animals exhibited left ventricular enlargement with bradycardia (mean RR in 'Ex' vs. 'Sed' rabbits: 335 ± 15 vs. 288 ±19 ms, p ≤ 0.05, and in 'Dop' vs. 'Ex' vs. 'Sed' dogs: 718 ± 6 vs. 638 ± 38 vs. 599 ± 49 ms) accompanied by an increase of heart rate variability in both species (e.g. SD RR in 'Ex' vs. 'Sed' rabbits: 3.4 ± 0.9 vs. 1.4 ± 0.1 ms, p ≤ 0.05, and in 'Dop' vs. 'Ex' vs. 'Sed' dogs: 156 ± 59 vs. 163 ± 44 vs. 111 ± 49 ms) indicating an increased vagal tone. A lower response to parasympatholytic agent atropine and more pronounced QTc interval lengthening after dofetilide challenge were found in 'Ex' and 'Dop' dogs compared to the 'Sed' group. No morphological and functional changes were found after chronic steroid treatment in dogs. The structural-functional findings share more similarities with human athlete's heart. Slight repolarization sensitivity in the exercised dogs may indicate an increased risk of arrhythmias in athletes under different circumstances. These animal models might be useful for the further investigations of the cardiovascular effects of competitive training.

The Effect of a Novel Highly Selective Inhibitor of the Sodium/Calcium Exchanger (NCX) on Cardiac Arrhythmias in In Vitro and In Vivo Experiments.

BACKGROUND: In this study the effects of a new, highly selective sodium-calcium exchanger (NCX) inhibitor, ORM-10962 were investigated on cardiac NCX current, Ca2+ transients, cell shortening and in experimental arrhythmias. The level of selectivity of the novel inhibitor on several major transmembrane ion currents (L-type Ca2+ current, major repolarizing K+ currents, late Na+ current, Na+/K+ pump current) was also determined. METHODS: Ion currents in single dog ventricular cells (cardiac myocytes; CM), and action potentials in dog cardiac multicellular preparations were recorded utilizing the whole-cell patch clamp and standard microelectrode techniques, respectively. Ca2+ transients and cell shortening were measured in fluorescent dye loaded isolated dog myocytes. Antiarrhythmic effects of ORM-10962 were studied in anesthetized ouabain (10 µg/kg/min i.v.) pretreated guinea pigs and in ischemia-reperfusion models (I/R) of anesthetized coronary artery occluded rats and Langendorff perfused guinea pigs hearts. RESULTS: ORM-10962 significantly reduced the inward/outward NCX currents with estimated EC50 values of 55/67 nM, respectively. The compound, even at a high concentration of 1 µM, did not modify significantly the magnitude of ICaL in CMs, neither had any apparent influence on the inward rectifier, transient outward, the rapid and slow components of the delayed rectifier potassium currents, the late and peak sodium and Na+/K+ pump currents. NCX inhibition exerted moderate positive inotropic effect under normal condition, negative inotropy when reverse, and further positive inotropic effect when forward mode was facilitated. In dog Purkinje fibres 1 µM ORM-10962 decreased the amplitude of digoxin induced delayed afterdepolarizations (DADs). Pre-treatment with 0.3 mg/kg ORM-10962 (i.v.) 10 min before starting ouabain infusion significantly delayed the development and recurrence of ventricular extrasystoles (by about 50%) or ventricular tachycardia (by about 30%) in anesthetized guinea pigs. On the contrary, ORM-10962 pre-treatment had no apparent influence on the time of onset or the severity of I/R induced arrhythmias in anesthetized rats and in Langendorff perfused guinea-pig hearts. CONCLUSIONS: The present study provides strong evidence for a high efficacy and selectivity of the NCX-inhibitory effect of ORM-10962. Selective NCX inhibition can exert positive as well as negative inotropic effect depending on the actual operation mode of NCX. Selective NCX blockade may contribute to the prevention of DAD based arrhythmogenesis, in vivo, however, its effect on I/R induced arrhythmias is still uncertain.

High-dose Radiation Induced Heart Damage in a Rat Model.

BACKGROUND/AIM: Radiation-induced heart disease (RIHD) is a concern during radiotherapy. For its comprehensive study, an in vivo selective heart irradiation model was developed. MATERIALS AND METHODS: Sprague-Dawley rats were irradiated with 50 Gy and functional imaging, biochemical (circulating growth differentiation factor-15 (GDF-15), transforming growth factor-beta (TGF-beta) and morphological (picrosirius red staining of the heart) objectives were tested. RESULTS: Signs and symptoms of RIHD occurred >12 weeks after irradiation with tachypnea, systolic and diastolic dysfunction, cardiac hypertrophy and body development retardation. Plasma GDF-15 was increased 3, 12 and 26, while plasma TGF-beta was increased 12 weeks after irradiation. At autopsy, extensive pleural fluid was found in the irradiated animals. Interstitial fibrosis could be reliably detected and quantified in irradiated hearts after a follow-up time of 19 weeks. CONCLUSION: The studied parameters could be used in future experiments for testing protective agents for prevention of radiation heart injury.

Long-term pretreatment with desethylamiodarone (DEA) or amiodarone (AMIO) protects against coronary artery occlusion induced ventricular arrhythmias in conscious rats.

The aim of this investigation was to compare the effectiveness of long-term pretreatment with amiodarone (AMIO) and its active metabolite desethylamiodarone (DEA) on arrhythmias induced by acute myocardial infarction in rats. Acute myocardial infarction was induced in conscious, male, Sprague-Dawley rats by pulling a previously inserted loose silk loop around the left main coronary artery. Long-term oral pretreatment with AMIO (30 or 100 mg·(kg body mass)(-1)·day(-1), loading dose 100 or 300 mg·kg(-1) for 3 days) or DEA (15 or 50 mg·kg(-1)·day(-1), loading dose 100 or 300 mg·kg(-1) for 3 days), was applied for 1 month before the coronary artery occlusion. Chronic oral treatment with DEA (50 mg·kg(-1)·day(-1)) resulted in a similar myocardial DEA concentration as chronic AMIO treatment (100 mg·kg(-1)·day(-1)) in rats (7.4 ± 0.7 µg·g(-1) and 8.9 ± 2.2 µg·g(-1)). Both pretreatments in the larger doses significantly improved the survival rate during the acute phase of experimental myocardial infarction (82% and 64% by AMIO and DEA, respectively, vs. 31% in controls). Our results demonstrate that chronic oral treatment with DEA resulted in similar cardiac tissue levels to that of chronic AMIO treatment, and offered an equivalent degree of antiarrhythmic effect against acute coronary artery ligation induced ventricular arrhythmias in conscious rats.

Future perspectives in the pharmacological treatment of atrial fibrillation and ventricular arrhythmias in heart failure.

Heart failure (HF) is a clinical syndrome characterized by significant impairment of cardiac ventricular function. Atrial fibrillation (AF) is the most commonly observed sustained arrhythmia in clinical practice. Both HF and AF are associated with increased morbidity and mortality and their prevalence increases with age. Approximately 50% of patients with moderate HF die due to ventricular fibrillation that leads to sudden cardiac death. Patients with AF exhibit increased mortality due to HF and stroke. HF and AF often co-exist, and the development of the other condition further deteriorates prognosis. Both chronic HF and AF lead to structural and electrophysiological changes in the heart called remodeling, modifying therapeutic targets including those for antiarrhythmic intervention. Current pharmacological treatment of arrhythmias has major limitations due to low efficacy and serious adverse effects. In this review, the main aspects of electrical remodeling in HF and AF are discussed along with possible novel targets identified for future pharmacological antiarrhythmic therapy.

Biomarkers and endogenous determinants of dofetilide-induced torsades de pointes in α(1) -adrenoceptor-stimulated, anaesthetized rabbits.

BACKGROUND AND PURPOSE: Torsades de pointes (TdP) liability is a stochastic event, which indicates that unidentified factors have an important role in facilitating the initiation of TdP by increasing the probability of TdP occurrence. We sought to identify factors that facilitate drug-induced TdP. EXPERIMENTAL APPROACH: We studied dofetilide-induced TdP in pentobarbital-anaesthetized, phenylephrine-sensitized rabbits, seeking biomarkers that discriminated between the animals that experienced TdP ('TdP+' animals) and those that did not ('TdP-' animals). As novel variables, the beat-to-beat variability and instability of ECG intervals were measured at preset times, irrespective of whether or not hearts were in stable sinus rhythm ('absolute' variability and instability). Autonomic activity was also determined. KEY RESULTS: Dofetilide delayed repolarization and induced arrhythmias prior to TdP. The variability of the coupling interval and shape of arrhythmic beats before TdP were significantly greater in the 'TdP+' group than in the 'TdP-' group. Accordingly, the 'absolute' variability and instability of the ECG intervals were significantly elevated in the 'TdP+' group. Phenylephrine increased significantly the up-baroreflex sensitivity in the 'TdP+' group before dofetilide administration. CONCLUSIONS AND IMPLICATIONS: 'Preceding' arrhythmias have characteristics that permit prediction of TdP occurrence: the more chaotic the ventricular rhythm, the greater the probability of TdP initiation. This suggests that complexity of the arrhythmic beats may play an important mechanistic role in TdP genesis. The electrical instability quantified by the novel 'absolute' variability and instability parameters correlates with the probability of TdP occurrence. Baroreflex may contribute to TdP genesis in vivo.

Effects of 3-aminopyridine-induced seizures on platelet eicosanoid synthesis.

We investigated the influence of recurrent epileptic seizures on the arachidonic acid (AA) cascade in platelets and brain microvessels, using [(14)C]AA as a tracer substrate and chromatographic determination. The recurrent epileptic seizures of male Wistar rats were induced every second day with 3-aminopyridine (3-AP, 25 mg/kg ip) for two weeks. In the chronic 3-AP model, the earlier epileptic insults resulted in a decreased incidence of limbic seizures and higher survival rate at later administration of 3-AP. After 3-AP treatment, the formation of lipoxygenase products was unchanged, but the total amount of cyclooxygenase (COX) metabolites was decreased both in platelets and brain microvessels. The reduction in COX-mediated eicosanoid synthesis after recurrent seizures was due to the decreased synthesis of vasodilator and vasoconstrictor COX metabolites. In platelets, the 3-AP-treatment reduced the synthesis of vasodilator prostacyclin (PGI(2)), prostaglandin E(2) (PGE(2)) and 12-L-hydroxy-5,8,10-heptadecatrienoic acid (12-HHT), while the synthesis of prostaglandin D(2) (PGD(2)) remained unchanged. In isolated brain capillaries, the PGD(2), PGE(2) and 12-HHT synthesis was decreased after recurrent seizures. As for the vasoconstrictor COX metabolites, both platelets and brain microvessels synthesized significantly lesser amount of prostaglandin F(2alpha) (PGF(2alpha)) and thromboxane A(2) (TxA(2)) upon 3-AP administration. Our results indicate that platelets and isolated brain capillaries synthesize significantly lesser amount of COX metabolites after chronic 3-AP treatment. The decreased conversion of AA into different COX products may play a role in the neuroprotective/preconditional adaptation of the brain against subsequent seizures.

Selective cardiac plasma-membrane K(ATP) channel inhibition is defibrillatory and improves survival during acute myocardial ischemia and reperfusion.

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.

Lack of endothelium-derived hyperpolarizing factor (EDHF) up-regulation in endothelial dysfunction in aorta in diabetic rats.

It is not known whether the impairment of nitric oxide (NO)-dependent vasodilation of the aorta of diabetic rats is associated with any changes in the endothelial production of vasoactive prostanoids and endothelium-derived hyperpolarizing factor (EDHF). Therefore, we analyzed the contribution of NO, vasoactive prostanoids and EDHF to the decreased endothelium-dependent vasorelaxation in Sprague-Dawley rats at 4 and 8 weeks after diabetes mellitus induced by streptozotocin (STZ). The acetylcholine-induced (Ach) endothelium-dependent relaxation was significantly decreased in the thoracic aorta 8 weeks after the STZ-injection (Ach 10(-6) M: 73.1 +/- 7.4% and 56.7 +/- 7.9% for control and diabetic rats, respectively). The sodium nitroprusside-induced (NaNP) endothelium-independent vasodilation was also impaired in the diabetic rats (8 weeks after STZ) (NaNP 10(-8) M: 74.2 +/- 11.4% and 35.9 +/- 9.4% for control and diabetic rats, respectively). In contrast, the basal NO production, as assessed by the N omega-nitro-L-arginine methyl ester (L-NAME)-induced vasoconstriction was not modified in diabetes. Moreover, the amount of 6-keto-PGF(1 alpha) (stable metabolite of prostacyclin / prostaglandin I2 / PGI2 ), 12-L-hydroxy-5,8,10-heptadecatrienoic acid (12-HHT) and thromboxane B2 (TxB2 ) (stable metabolite of thromboxane A2 - TxA2) were significantly increased in the 8 weeks diabetic rat aorta. The EDHF-pathway did not change in the aortic endothelium during the development of STZ-induced diabetes. Our results indicate that STZ-induced diabetes mellitus did not modify the basal NO production, but induced the impairment of acetylcholine- and sodium nitroprusside-induced vasodilation in the thoracic aorta. In parallel with the impairment of NO-dependent vasodilation, the basal PGI2, 12-HHT and TxA2 synthesis were increased. The EDHF-pathway did not contribute to the endothelium-dependent relaxation either in control or diabetic aorta. The above alterations in the endothelial function may play an important role in the development of endothelial dysfunction and vascular complications of diabetes.

Preconditioning effects of levosimendan in a rabbit cardiac ischemia-reperfusion model.

The preconditioning effects of levosimendan were investigated on ischemia-reperfusion induced morphological and functional cardiac damage. Langendorff-perfused rabbit hearts were reserved as controls or subjected either to global myocardial ischemic preconditioning or to perfusion with levosimendan (0.1 micromol/l) for two 5-minute cycles. After a washout period, all hearts were then subjected to 30 minutes of global ischemia and 120 minutes of drug-free reperfusion. Intraventricular pressure and coronary flow were measured, and infarct size determined after nitroblue-tetrazolium staining on completion of the experiments. Levosimendan pretreatment resulted in a significantly smaller elevation from the preischemic level in left ventricular end-diastolic pressure during reperfusion (37 +/- 17 mm Hg) compared with controls (56 +/- 14 mm Hg) and ischemia-preconditioned hearts (53 +/- 34 mm Hg). The left ventricular developed pressure-representing the functional recovery of the heart after ischemia-that was significantly improved by levosimendan pretreatment (38 +/- 6% vs 16 +/- 5% in controls, P < 0.05). In addition, contractility and relaxability parameters (+dP/dt and -dP/dt, respectively) were better preserved in the levosimendan hearts. The volume of infarcted myocardium after global ischemia-reperfusion was significantly (P < 0.05) decreased by both ischemic preconditioning (38 +/- 2%) or levosimendan pretreatment (45 +/- 2%) versus controls (52 +/- 2%). The results of this study suggest that levosimendan pretreatment is capable of decreasing infarct size in an ischemia-reperfusion model and improving recovery of cardiac function following ex vivo global ischemia.

Distinct modulation of angiotensin II-induced early left ventricular hypertrophic gene programming by dietary fat type.

Long-term dietary fatty acid intake alters the development of left ventricular hypertrophy, but the linking signaling pathways are unclear. We studied the role and underlying signaling mechanisms of dietary fat intake in the early phase of the hypertrophic process. Rats assigned for 4 weeks of high-oil, high-fat, or standard diet were subjected to angiotensin II (Ang II; 33 microg/kg/h, subcutaneous) or vehicle infusion for 24 h. The Ang II-induced increase in left ventricular mRNA levels of hypertrophy-associated genes was higher in rats fed the high-oil diet compared with the standard diet. Western blotting revealed that, in parallel with changes in gene expression, the high-oil diet increased c-Jun N-terminal kinase phosphorylation (P < 0.001). Ang II increased p38 mitogen-activated protein kinase (MAPK) phosphorylation in rats fed the high-fat diet (3-fold; P < 0.01). The increase in transcription factor activator protein-1 (AP-1) DNA binding activity in response to Ang II was higher in rats fed the high-oil diet compared with those fed the standard diet (P < 0.001). Ang II downregulated inducible nitric oxide synthase mRNA levels in fatty acid-supplemented groups compared with the standard diet group. These results show that dietary fat type modulates the early activation of hypertrophic genes in pressure-overloaded myocardium involving the distinct activation of AP-1 and MAPK signal transduction pathways.

Effect of long-term oral pretreatment with levosimendan on cardiac arrhythmias during coronary artery occlusion in conscious rats.

Heart failure is frequently associated with cardiac arrhythmias. The aim of the present study was to investigate the effect of levosimendan, a new cardiotonic drug for the treatment of congestive heart failure, on experimental ischaemic arrhythmias. Acute coronary artery occlusion was produced in conscious rats 7-10 days after placement of ligature around the left main coronary artery. Acute pretreatment with levosimendan (0.2 or 0.6 mg/kg orally 1 h before coronary artery occlusion) did not influence the incidence, onset and duration of arrhythmias. Long-term pretreatment with levosimendan (0.2 or 0.6 mg/kg orally twice a day for 2 weeks) increased the survival rate (50% and 81% vs. 44% in controls) and the number of animals without any arrhythmia (37% and 31% vs. 5% in controls). The present results demonstrate that chronic oral treatment with levosimendan could be beneficial in congestive heart failure and arrhythmias resulting from regional myocardial ischaemia.

Proarrhythmic effects of intravenous quinidine, amiodarone, D-sotalol, and almokalant in the anesthetized rabbit model of torsade de pointes.

The proarrhythmic effects of four antiarrhythmic agents were examined during alpha1-adrenoceptor stimulation in chloralose-anesthetized rabbits. Each dose of almokalant (26, 88, and 260 microg/kg), D-sotalol, quinidine, or amiodarone (each 3, 10, and 30 mg/kg) was infused i.v. over 5 min and there was a 20-min interval between each infusion. D-sotalol and almokalant evoked torsade de pointes (TdP) and other arrhythmics, frequently. The incidences of TdP were 0, 50, and 40% after administering the first, second, and third doses of the nonselective I(Kr) inhibitor D-sotalol, respectively. Similarly, these values were 20, 40, and 33% after administering the first, second, and third doses, respectively, of the selective I(Kr) inhibitor almokalant. Quinidine elicited only a few arrhythmics, but not TdP. Quinidine, D-sotalol, and almokalant evoked conduction blocks in a dose-related manner (p < 0.05) and prolonged QT and QT(c) intervals (p < 0.05). Amiodarone neither prolonged QT and QT(c) nor evoked ventricular tachyarrhythmias, blocks, or other proarrhythmias. In conclusion, these results show no direct correlation between the occurrence of TdP and the infusion rate or dose of anti-arrhythmics. Furthermore, the lack of TdP with quinidine warns of false-negative results in the applied model.