Cardiotoxic Action Research Articles

Identificação e distribuição de lesões cardíacas em bovinos intoxicados por Amorimia exotropica

Amorimia exotropica é um arbusto escandente que pertence à família Malpighiacea, cujo princípio tóxico é o monofluoracetato de sódio e possui ação cardiotóxica em bovinos. Ela é a única representante, na região Sul do país, do grupo de plantas que causam morte súbita associada ao exercício. Este trabalho identificou e mapeou as lesões cardíacas observadas em bovinos intoxicados naturalmente por A. exotropica. Selecionaram-se nove corações bovinos, provenientes de um surto de intoxicação natural pela planta em uma propriedade de gado de corte do Rio Grande do Sul e procedeu-se o mapeamento de oito regiões topográficas distintas (ápice, ventrículos direito e esquerdo, septo interventricular, músculos papilares direito e esquerdo e átrios direito e esquerdo). À avaliação macroscópica quatro bovinos apresentaram lesão focal e bem delimitada no músculo papilar esquerdo. Estas áreas na histologia correspondiam à necrose de coagulação em diferentes estágios de evolução, similares a infartos. Todos os bovinos apresentavam necrose de cardiomiócitos, caracterizadas por retração e hipereosinofilia citoplasmática e fragmentação celular em todas as áreas amostradas. A severidade da injúria celular foi avaliada pela imuno-histoquímica anti-troponina C, a qual demonstrou acentuada perda e/ou diminuição de marcação citoplasmática em células necróticas. O músculo papilar esquerdo foi a região mais acometida nos casos de intoxicação por Amorimia exotropica.

Cardiovascular and cardiotoxic actions of sympathomimetic stimulants

Cardiovascular and cardiotoxic actions of sympathomimetic stimulants

Preclinical efficacy of Australian antivenoms against the venom of the small-eyed snake, Micropechis ikaheka, from Papua New Guinea: An antivenomics and neutralization study

There is no specific antivenom for the treatment of envenoming by the small-eyed snake, Micropechis ikaheka, a dangerous fossorial species endemic to Papua New Guinea, Irian Jaya (West Papua) and neighbouring islands. This study evaluated one marine (sea snake) and four terrestrial (tiger snake, brown snake, black snake and polyvalent) antivenoms, manufactured in Australia by bioCSL Limited, for their ability to immunoreact ('antivenomic' analysis) and neutralize enzymatic and toxic activities of M. ikaheka venom. All antivenoms neutralized lethality of the venom and attenuated, dose-dependently, myotoxic activity. The polyvalent antivenom also neutralized cardiotoxic activity. In contrast, antivenoms were ineffective in the neutralization of phospholipase A₂ (PLA₂) and anticoagulant activities. Antivenomics outcomes were in concordance with neutralization tests, for chromatographic peaks corresponding to α-neurotoxins of the three finger family, responsible for lethality, were quantitatively retained in the immunoaffinity columns, whereas peaks corresponding to PLA₂s were immunocaptured only to a partial extent. The ability of antivenoms to neutralize lethal, i.e. neurotoxic, and myotoxic activities of M. ikaheka venom, which represent the most relevant clinical manifestations of envenoming, suggests that these antivenoms may provide paraspecific protection in humans, although the poor neutralization of PLA₂ supports the need for well-designed clinical studies to not only determine which antivenoms are most appropriate for treatment of M. ikaheka envenoming, but to also fully describe the syndrome of envenoming caused by this beautiful, but lethal species. Snakebite by the small-eyed snake, Micropechis ikaheka, in Papua New Guinea can be life-threatening. The predominant clinical features in this envenoming are neurotoxicity and systemic myotoxicity. Although it accounts for only a small proportion of snakebites on the mainland, 40% of snakebites on Karkar Island are attributed to bites by the Ikaheka snake. However, no specific antivenom is available for the treatment of M. ikaheka envenoming in Papua New Guinea. This study evaluated a panel of Australian bioCSL antivenoms for their paraspecific immunoreaction and neutralization of the toxic activities of M. ikaheka venom. All antivenoms exhibited strong immunorecognition of α-neurotoxins of the 3FTx family and neutralized the lethal, i.e. neurotoxic, and myotoxic activities of M. ikaheka venom. However, these antivenoms exhibited poor neutralization of PLA₂ and anticoagulant activities. This study suggests that the Australian antivenoms may provide paraspecific protection against M. ikaheka venom in humans, a hypothesis that demands studies aimed at assessing whether these antivenoms neutralize neurotoxicity and myotoxicity in the clinical setting.

STUDY CARDIOTOXIC PROPERTIES OF NATIVE PEAT HUMIC ACIDS

The earlier pathomorphological studies of toxic properties of peat humic acids (PHAs) at intraperitoneal injection revealed that one of the causes of lethality is the direct cardiotoxic action of PHAs. For the further study of the mechanism of cardiotoxic action, electrocardiogram was recorded and ventricular fibrillation threshold was determined in male rats after intraperitoneal injection of humic acids in knowingly lethal dose – 480 mg/kg bwt. A single intraperitoneal injection of PHA to rats in knowingly lethal dose caused a significant decrease of the ventricular fibrillation threshold in comparison with intact animals. It was found that the PHA injection exerted no significant effect on the heart rate in rats and change of the PQ, QT, and QTc intervals. At the same time, the significant shortening of the QRS complex in comparison with intact animals was observed. Judging from the results obtained, the single injection of humic acids in the lethal dose induced a decrease in the electrical stability of heart, as evidenced by the drop of the ventricular fibrillation threshold. This decrease of the electrical stability of heart can be a cause of sudden cardiac death of trial rats. Disorder of the heart electrical stability is likely connected with the ionophoric action of humic acids and change of electrophysiological properties of cell membranes.

Toxicity Induced by Prasiola crispa to Fruit Fly Drosophila melanogaster and Cockroach Nauphoeta cinerea: Evidence for Bioinsecticide Action

The adverse effects of the alga Prasiola crispa extract (PcE) were investigated in a fruit fly (Drosophila melanogaster) and cockroach (Nauphoeta cinerea) model. In flies, toxicity was assessed as mortality and biochemical alterations including acetylcholinesterase (AChE) activity and oxidative stress markers. The cardiotoxic action of PcE was also examined in a model of semi-isolated cockroach heart. The administration of PcE (2 mg/ml) to flies for 24 h resulted in a marked increase in mortality rate (7.6-fold rise compared to control). AChE activity, glutathione (GSH) levels, and hydroperoxide formation remained unchanged. Fly glutathione S-transferase (GST) and catalase (CAT) activity were significantly altered after PcE treatment. Fraction III (ethyl acetate) of PcE was significantly more toxic to flies compared to fractions I (methanol) and II (ethanol). A significant decrease was noted in cockroach semi-isolated heart function. The addition of 5,5’-dithiobis-(2-nitrobenzoic acid (DTNB), an oxidizing agent, concomitant with the extract significantly blocked this effect, suggesting that reduced compounds may be involved in the cardiotoxic action produced by PcE. Our results show for the first time the adverse effects of PcE in two insect models, Drosophila melanogaster and Nauphoetacinerea. The insecticidal properties of PcE may be related to changes in important antioxidant/detoxifying systems, as well as to changes in insect cardiac function.

The utility of serum biomarkers to detect myocardial alterations induced by Imatinib in rats.

BackgroundImatinib (Imb) is a tyrosine kinase inhibitor with cardiotoxic activity (decreases in left ventricular function and congestive heart failure) in patients. Currently, clinical diagnosis of Imb cardiotoxicity relies primarily on evaluation of left ventricular function, Imb also induces cardiac lesions in rats.AimsThis study, in rats, sought to determine whether monitoring biochemical markers would be a sensitive means to detect Imb-induced changes in cardiomyocyte morphology.Materials and methodsGroups of male Sprague–Dawley rats were dosed orally with 50, 100, 200 mg kg−1 Imb or water daily for 28 days. Tissues and blood samples were collected 24 h after the last dosing. Cardiac biomarkers such as cardiac troponin I (cTnI), cardiac troponin T (cTnT), and fatty acid binding protein 3 (FABP3) were monitored by the Erenna, Elecsys, and Meso Scale immunoassay systems.ResultsImb caused microscopic myocardial lesions (myofibrillar loss, cytoplasmic vacuolization, and necrosis) at all doses as determined by unbiased histopathology analysis. The severity of the alterations was dose-related with mean lesion scores (based on a scale of 0–3) of 1.2 (50 mg kg−1), 2.1 (100 mg kg−1) and 2.9 (200 mg kg−1). However, the increases in cTnI, cTnT, and FABP3 levels were noted primarily in high-dose Imb treated animals.Discussion and conclusionThe occurrence of myocardial alterations in animals without consistent changes in cardiac troponin and FABP3 concentrations raises questions regarding the utility of these biomarkers as early indicators of Imb-induced cardiotoxicity. Due to limited numbers of animals the reasons for this discrepancy could not be determined.

The ex vivo neurotoxic, myotoxic and cardiotoxic activity of cucurbituril-based macrocyclic drug delivery vehicles.

The cucurbituril family of drug delivery vehicles have been examined for their tissue specific toxicity using ex vivo models. Cucurbit[6]uril (CB[6]), cucurbit[7]uril (CB[7]) and the linear cucurbituril-derivative Motor2 were examined for their neuro-, myo- and cardiotoxic activity and compared with β-cyclodextrin. The protective effect of drug encapsulation by CB[7] was also examined on the platinum-based anticancer drug cisplatin. The results show that none of the cucurbiturils have statistically measurable neurotoxicity as measured using mouse sciatic nerve compound action potential. Cucurbituril myotoxicity was measured by nerve-muscle force of contraction through chemical and electrical stimulation. Motor2 was found to display no myotoxicity, whereas both CB[6] and CB[7] showed myotoxic activity via a presynaptic effect. Finally, cardiotoxicity, which was measured by changes in the rate and force of right and left atria contraction, was observed for all three cucurbiturils. Free cisplatin displays neuro-, myo- and cardiotoxic activity, consistent with the side-effects seen in the clinic. Whilst CB[7] had no effect on the level of cisplatin's neurotoxic activity, drug encapsulation within the macrocycle had a marked reduction in both the drug's myo- and cardiotoxic activity. Overall the results are consistent with the relative lack of toxicity displayed by these macrocycles in whole animal acute systemic toxicity studies and indicate continued potential of cucurbiturils as drug delivery vehicles for the reduction of the side effects associated with platinum-based chemotherapy.

The Role of Echocardiography in Chemotherapy

Mailing Address: Angelo Antunes Salgado • Rua Magalhaes Couto, 237, Apt.101, 20735-180, Meier, Rio de Janeiro RJ Brazil. E-mail: angeloasalgado@gmail.com Manuscript received July, 3rd, 2013; accepted October, 14th, 2013 Introduction With the increased survival of the population, and the widespread use of early detection campaigns, there was a substantial increase in the early detection of several types of neoplasias1. The evolution of cancer treatment, both in relation to chemotherapy as radiotherapy, have not diminished the importance of cardiac monitoring of these patients, since the potentially cardiotoxic drugs usually employed as anthracyclines (doxorubicin, epirubicin, idarubicin) and alkylating agents (cyclophosphamide, ifosphamide) are well know and potentially lethal1,2 The importance of early detection of cardiotoxic action of these drugs, when the suspension can still avoid heart damage and even restore normalcy, is already very well established in echocardiography 1.3. Cardiotoxicity caused by chemotherapy days after infusion, even after several years may occur, demonstrating the importance of long-term cardiac follow-up in these patients, which may be acute, subacute or chronic and characterized mainly by electrocardiographic, myocarditis changes, pericarditis and also by cardiac insufficiency.2 Cardiotoxicity depends on the type of infused agent (anthracyclines with agents that cause more dysfunction), usually occurring more at the extremes of age ( 60 years) in female patients with previous cardiac dysfunction and a history of associated mediastinal radiation. The cumulative dose of the chemotherapeutic agent is directly related to the degree of cardiac injury, being more evident dysfunction with cumulative anthracycline dose above 400mg/m2 and infusion bolus2, 4. The incidence of cardiotoxicity caused by anthracycline ranges from 18% to 26% and may reach 36% in patients receiving cumulative doses above 600mg/m2. In some cases heart failure can occur up to 20 years after the administration of the pharmaceutical drug.5 More recent ly i t has been shown that a new immunomodulatory agent trastuzumab used for the treatment of breast cancer in patients with severe expression of the human epidermal growth factor type 2 (HER-2) receptor may also have damage to cardiomyocytes. Despite the myotoxic effect is unknown, it has the ability to reverse cardiac dysfunction after its suspension, which does not occur with anthracyclines and alkylating agents. However, the use of trastuzumab in patients who have previously made use of anthracyclines, increases the incidence of cardiac disorders 2.5.

Long-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions

Cancer is diagnosed in >12 000 children and adolescents in the United States each year.1 Progress in cancer therapeutics over the past 40 years has remarkably improved survival rates for most childhood malignancies. For all pediatric cancers, 5-year survival increased from 58% for children diagnosed between 1975 and 1977 to 82% for those diagnosed between 1999 and 2006.2 In the United States, this success translates into >325 000 survivors of childhood cancer, of whom 24% are now >30 years from diagnosis.3 During this same period, the incidence of many histological subtypes of childhood cancer has increased, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia, non-Hodgkin lymphoma, neuroblastoma, and soft-tissue and germ-cell tumors.3 Consequently, the number of childhood cancer survivors is expected to increase as a result of the rising pediatric cancer incidence and improved long-term survival rates.3 The increasing number of survivors soon revealed acute and delayed modality-specific toxicities and their impact on quality of life and early mortality. In their seminal 1974 publication, Meadows and D’Angio4 described the wide array of potential late effects of successful therapy for childhood cancer. In the past 2 decades, the Childhood Cancer Survivor Study has also improved our understanding of the long-term mortality and morbidity in this high-risk population. Among young adult survivors of childhood cancer diagnosed between 1970 and 1986, at least 1 of 6 domains of health status (general health, mental health, functional status, activity limitations, cancer-related pain, and cancer-related anxiety) declined moderately to severely in 44%.5 The cumulative incidence of a chronic health condition 30 years after cancer diagnosis is now 73%, with a cumulative incidence of 42% for severe, disabling, or life-threatening conditions or death attributable to a chronic condition.6 Also by 30 years after cancer diagnosis, the cumulative mortality rate from causes …

Regulator of G protein signaling 6 (RGS6) mediates doxorubicin‐induced myocardial cell apoptosis and cardiomyopathy

Activation of p53 and myocardial apoptosis are crucial events responsible for Dox‐induced cardiomyopathy and heart failure. Recently we discovered a novel signaling role for RGS6 in mediating activation by Dox of the ATM/p53 apoptosis pathway via reactive oxygen species (ROS), which are also strongly implicated in myocardial apoptosis. Here, we investigated whether RGS6 was involved in the pathogenic response to Dox in heart. While Dox‐treated wild type (WT) mice manifested severe left ventricular dysfunction, loss of heart and body mass, and decreased survival five days following Dox administration, RGS6−/− mice were completely protected against these pathogenic responses. The activation of ATM/p53‐apoptosis signaling by Dox in ventricles of WT mice was completely absent in their RGS6−/− counterparts. Dox‐induced ROS generation was dramatically impaired in ventricles and isolated VCM from RGS6−/− mice, and RGS6 was required for Dox‐induced apoptosis in VCM, which was also found to be ROS‐dependent. Thus, RGS6 is a previously unrecognized, but essential, mediator of the pathogenic responses to Dox in heart where RGS6 promotes activation of apoptotic signaling pathways by modulating Dox‐induced ROS generation. RGS6 inhibition might represent a viable means to circumvent the cardiotoxic actions of Dox in human cancer patients. (AHA 11SDG7580008 and NIH CA161882, HL079031, HL62494, HL70250 and HL113001)

Venomic and pharmacological activity of Acanthoscurria paulensis (Theraphosidae) spider venom

In the present study we conducted proteomic and pharmacological characterizations of the venom extracted from the Brazilian tarantula Acanthoscurria paulensis, and evaluated the cardiotoxicity of its two main fractions. The molecular masses of the venom components were identified by mass spectrometry (MALDI-TOF-MS) after chromatographic separation (HPLC). The lethal dose (LD50) was determined in mice. Nociceptive behavior was evaluated by intradermal injection in mice and the edematogenic activity by the rat hind-paw assay. Cardiotoxic activity was evaluated on in situ frog heart and on isolated frog ventricle strip. From 60 chromatographic fractions, 97 distinct components were identified, with molecular masses between 601.4 and 21,932.3 Da. A trimodal molecular mass distribution was observed: 30% of the components within 500-1999 Da, 38% within 3500–5999 Da and 21% within 6500–7999 Da. The LD50 in mice was 25.4 ± 2.4 μg/g and the effects observed were hypoactivity, anuria, constipation, dyspnea and prostration until death, which occurred at higher doses. Despite presenting a dose-dependent edematogenic activity in the rat hind-paw assay, the venom had no nociceptive activity in mice. Additionally, the venom induced a rapid blockage of electrical activity and subsequent diastolic arrest on in situ frog heart preparation, which was inhibited by pretreatment with atropine. In the electrically driven frog ventricle strip, the whole venom and its low molecular mass fraction, but not the proteic one, induced a negative inotropic effect that was also inhibited by atropine. These results suggest that despite low toxicity, A. paulensis venom can induce severe physiological disturbances in mice.

General biochemical and immunological characteristics of the venom from Peruvian scorpion Hadruroides lunatus

This communication describes the general biochemical properties and some immunological characteristics of the venom from the Peruvian scorpion Hadruroides lunatus, which is the most medically relevant species in Peru. The soluble venom of this scorpion is toxic to mice, the LD50 determined was 0.1 mg/kg and 21.55 mg/kg when the venom was injected intracranial or intraperitoneally, respectively. The soluble venom displayed proteolytic, hyaluronidasic, phospholipasic and cardiotoxic activities. High performance liquid chromatography of the soluble venom resulted in the separation of 20 fractions. Two peptides with phospholipasic activity were isolated to homogeneity and their molecular masses determined by mass spectrometry (MALDI TOF). Anti-H. lunatus venom sera were produced in rabbits. Western blotting analysis showed that most of the protein content of this venom is immunogenic. H. lunatus anti-venom displayed consistent cross-reactivity with venom antigens from the new World-scorpions Tityus serrulatus and Centruroides sculpturatus venoms; however, a weaker reactivity was observed against the venom antigens from the old World-scorpion Androctonus australis Hector.

Increasing Membrane Interactions of Local Anaesthetics as Hypothetic Mechanism for Their Cardiotoxicity Enhanced by Myocardial Ischaemia

While myocardial ischaemia enhances the cardiotoxicity of local anaesthetics, the pharmacological background remains unclear. Cardiolipin (CL) localized in mitochondrial membranes is possibly the site of cardiotoxic action of local anaesthetics and peroxynitrite is produced by cardiac ischaemia and reperfusion. We verified the hypothetic mechanism that local anaesthetics may interact with CL-containing biomembranes to change the membrane biophysical property and their membrane interactions may be increased by peroxynitrite. Biomimetic membranes were prepared with different phospholipids and cholesterol of varying compositions. The membrane preparations were reacted with peroxynitrite of pathologically relevant concentrations and local anaesthetics (bupivacaine and lidocaine) of a cardiotoxic concentration separately or in combination. Changes in membrane fluidity were determined by measuring fluorescence polarization. Peroxynitrite decreased the fluidity of biomimetic membranes at 0.1-10μM with the relative potency being CL>1-stearoyl-2-arachidonoylphosphatidylcholine>1,2-dipalmitoylphosphatidylcholine-constituting membranes, indicating the lipid peroxidation-induced membrane rigidification determined by the unsaturation degree of membrane lipids. When treated with 0.1-10μM peroxynitrite, biomimetic membranes were more rigid with elevating the CL content from 0% to 30mol%, suggesting that CL is a primary target of peroxynitrite. Bupivacaine and lidocaine fluidized at 200μM biomimetic membranes containing 10mol% CL and their effects were increased by pre-treating the membranes with 0.1 and 1μM peroxynitrite. Cardiotoxic bupivacaine and lidocaine increasingly interact with CL-containing mitochondria model membranes which are relatively rigidified by peroxynitrite. Such an increasing membrane interaction may be, at least in part, responsible for the local anaesthetic cardiotoxicity enhanced by myocardial ischaemia.

225. Proteomic Analysis and Pharmacological Activities of the Venom of the Moroccan Cobra Naja haje legionis.

Background: In Morocco, envenomation by snake bites poses a serious problem to public health. The cobra Naja haje legionis is endemic of the country and one of the most dangerous species known. In this work, we report the proteomic and pharmacological characterizations of biologically active proteins from the venom of this species. Methods: The various proteins in the crude venom were fractionated and analyzed by a combination of chromatographic separations and proteomic analysis techniques such as gel filtration, RP-HPLC, 1D electrophoresis, in-gel digestion, tandem mass spectrometry and protein database search. The pharmacological properties of Naja haje legionis venom were assessed using in vitro preparations using rodents and chicks. Results: Our venomic strategy allowed the identification of 64 proteins and peptides from known database which can classified into 17 families according to their biological activities. We were able to identify cobra venom factor, L-aminoacid oxidases, acetylcholinesterase, metalloproteinase, disintegrin, cysteine-rich secretory proteins, nerve growth factor, phospholipases A2, vespryns, kunitz-type inhibitor, short neurotoxins, long neurotoxins, weak neurotoxins, neurotoxin like proteins, muscarinic toxins, cytotoxins and cardiotoxins. Pharmacological tests showed that Naja haje legionis venom contained neurotoxic activities inducing irreversible blockage of neuromuscular transmission in both rodent and chick nerve-muscle preparations. This venom also exhibit myotoxic and cardiotoxic activities. Conclusions: These results showed the potency and the complexity of the various proteins present in the venom of Naja haje legionis,which present a very similar pattern to other cobra venoms. The contribution of the different components in venom toxicity deserves further investigations.

State-dependent inhibition of sodium channels by local anesthetics: A 40-year evolution

Knowledge about the mechanism of impulse blockade by local anesthetics has evolved over the past four decades, from the realization that Na+ channels were inhibited to affect the impulse blockade to an identification of the amino acid residues within the Na+ channel that bind the local anesthetic molecule. Within this period appreciation has grown of the state-dependent nature of channel inhibition, with rapid binding and unbinding at relatively high affinity to the open state, and weaker binding to the closed resting state. Slow binding of high affinity for the inactivated state accounts for the salutary therapeutic as well as the toxic actions of diverse class I anti-arrhythmic agents, but may have little importance for impulse blockade, which requires concentrations high enough to block the resting state. At the molecular level, residues on the S6 transmembrane segments in three of the homologous domains of the channel appear to contribute to the binding of local anesthetics, with some contribution also from parts of the selectivity filter. Binding to the inactivated state, and perhaps the open state, involves some residues that are not identical to those that bind these drugs in the resting state, suggesting spatial flexibility in the "binding site". Questions remaining include the mechanism that links local anesthetic binding with the inhibition of gating charge movements, and the molecular nature of the theoretical "hydrophobic pathway" that may be critical for determining the recovery rates from blockade of closed channels, and thus account for both therapeutic and cardiotoxic actions.

Cardiotoxic Local Anesthetics Increasingly Interact with Biomimetic Membranes under Ischemia-Like Acidic Conditions

The cardiotoxic effects of local anesthetics increase in cardiac ischemia which is characterized by the tissue pH lowering to 6.5 or less. Apart from the cardiac channel blockade, the membrane interaction has been referred to as another mode of their cardiotoxic action. By using biomimetic membranes, we verified the hypothesis that bupivacaine and lidocaine may increasingly interact with cardiac mitochondrial membranes under ischemia-like acidic conditions. Biomimetic membranes were prepared with different phospholipids and cholesterol to be unilamellar vesicles suspended in buffers of pH 7.4, 6.9, 6.4 or 5.9. Bupivacaine and lidocaine were reacted with the membrane preparations at cardiotoxically relevant concentrations and their membrane interactivities were determined by measuring fluorescence polarization. Both drugs interacted with 100 mol% 1,2-dipalmitoylphosphatidylcholine, peripheral nerve cell-mimetic and cardiomyocyte-mimetic membranes to increase membrane fluidity, although lowering the reaction pH from 7.4 to 5.9 decreased their membrane-fluidizing effects. In cardiomyocyte mitochondria-mimetic membranes containing 20 mol% cardiolipin, however, bupivacaine and lidocaine reversely increased their membrane interactivities at pH 5.9-6.4 compared with pH 7.4. Such increases were greater in anionic phospholipid membranes which consisted of substantial amounts of cardiolipin and phosphatidylserine. Positively charged bupivacaine and lidocaine would form ion-pairs with the negatively charged head-groups of anionic phospholipids under acidic conditions, thereby increasing the induced membrane fluidization. The mitochondrial membrane interactions depending on pH lowering may be, at least in part, responsible for local anesthetic cardiotoxicity enhanced in acidosis associated with cardiac ischemia.

Mechanisms of the Cardiotoxic Action of Amitriptyline

Objective: to study the mechanisms of toxic action of amitriptyline on the myocardium. Material and methods. Investigations were conducted using the hearts from 30 outbred albino rats, which had been isolated and perfused according to the procedure described by Fallen et al. There were two series of experiments: 1) amitriptyline was added in a dose of 250 ng/ml to Krebs-Henseleit solution (Group 1); 2) the agent was added at another concentration (1250 ng/ml) to the solution passing through the coronary bed (Group 2). The animals were anesthetized with thiopental sodium (25 mg/kg) peritoneally. Results. Amitriptyline depresses myocardial contractility, which is particularly obvious with high-rate pacing. This manifests itself as reduced contractile velocity and force-power parameters and elevated left ventricular diastolic pressure. Amitriptyline lowers the efficacy of glucose and increases the release of enzymes into the coronary duct. Conclusion. Hypoergosis, membrane destruction, and cardiomyocyte ion pump failure have been shown to underlie negative chronotropic and inotropic effects in amitriptyline poisoning. Key words: amitriptyline, acute poisoning, isolated heart, myocardial damage.

Central dopamine receptors and their role in digoxin-induced cardiotoxicity in the dog

The role of the dopaminergic system in digoxin-induced cardiotoxicity has been examined. Specific dopaminergic agonists and antagonists were administered into the ventriculocisternal system of pentobarbitone-anaesthetized dogs before systemic administration of digoxin. Pretreatment with apomorphine, a specific dopamine agonist, did not significantly alter the arrhythmogenic or lethal doses of digoxin. However, the digoxin-induce increase in CSF noradrenaline was decreased significantly in apomorphine-pretreated animals. Pretreatment with pimozide, a specific dopamine antagonist, significantly decreased the arrhythmogenic dose of digoxin but did not alter the lethal dose. As with apomorphine, pimozide-pretreated animals accumulated significantly less noradrenaline in CSF compared with control dogs. These results suggest that dopamine receptors are not directly related to the cardiotoxic actions of digoxin. However, dopaminergic receptors may influence the balance of central catecholaminergic systems that influence the peripheral cardiovascular system.

Snake venom neutralising factor from the root extract of Emblica officinalis Linn.

The folk use of the Indian medicinal plant Emblica officinalis Linn. root extract and its active compound (Pthalate in nature) against snake venom has been established in experimental animal models. From the root extract of Emblica officinalis, a compound was isolated through silica gel column chromatography and the structure was determined by UV, IR, 1 H-NMR, 13 C-NMR & EIMS studies. The structure was determined and the active fraction was a pthalate compound, which could neutralize viper and cobra venom induced lethal, hemorrhagic, defibrinogenating, proinflammatory, PLA2, cardiotoxic and neurotoxic activity in experimental animal models. Viper venom induced myotoxicity was antagonized by the compound as shown by the decreased levels of the myotoxicity marker enzymes CPK & LDH. The pro- inflammatory action of viper venom neutralized by the active compound, showed the involvement of the pro- inflammatory markers IL-1, IL-6, TNF-α. The present study confirmed the phytomedicinal value of an antisnake venom compound present in the root of Emblica officinalis.

Acute Cardioprotective and Cardiotoxic Effects of Bilberry Anthocyanins in Ischemia–Reperfusion Injury: Beyond Concentration-Dependent Antioxidant Activity

Despite being reported to reduce the risk of cardiovascular diseases, little is known about acute direct effects of bilberry anthocyanins on whole mammalian heart under ischemia-reperfusion (I-R) conditions. Bilberry anthocyanins were prepared from the ripe bilberries and analyzed using HPLC-DAD. Their antioxidant activity was evaluated by measuring the intrinsic free radical-scavenging capacity and by cellular antioxidant assay (CAA) on endothelial cells, where we quantified the intracellular capacity to inhibit the formation of peroxyl radicals. Experiments on the isolated rat hearts under I-R were carried out according to the Langendorff method. Perfusion with low concentrations of bilberry anthocyanins (0.01-1mg/L) significantly attenuated the extent of I-R injury as evidenced by decreasing the release rate of LDH, increasing the postischemic coronary flow, and by decreasing the incidence and duration of reperfusion arrhythmias. High concentrations (5-50mg/L) diminished cardioprotection and show cardiotoxic activity despite having their radical scavenging and intracellular antioxidant capabilities increased in a concentration-dependent manner. This study reveals the biphasic concentration-dependent bioactivity of bilberry anthocyanins under I-R, which results in strong cardioprotective activity in low concentrations and cardiotoxic activity in high concentrations.