Early detection of anthracycline cardiotoxicity in a rabbit model: left ventricle filling pattern versus troponin T determination

Anthracycline cardiotoxicity represents a serious risk of anticancer chemotherapy. The aim of the present pilot study was to compare the potential of both the left ventricular (LV) filling pattern evaluation and cardiac troponin T (cTnT) plasma levels determination for the early detection of daunorubicin-induced cardiotoxicity in rabbits. The echocardiographic measurements of transmitral LV inflow as well as cTnT determinations were performed weekly for 10 weeks in daunorubicin (3 mg/kg weekly) and control groups (n=5, each). Surprisingly, no significant changes in LV-filling pattern were observed through the study, most likely due to the xylazine-containing anesthesia, necessary for appropriate resolving of the E and A waves. In contrast to the echographic measurement, the dP/dt(min) index obtained invasively at the end of the study revealed a significant impairment in LV relaxation, which was further supported by observed disturbances in myocardial collagen content and calcium homeostasis. However, at the same time cTnT plasma levels were progressively rising in the daunorubicin-treated animals from the fifth week (0.024+/-0.008 microg/l) until the end of the experiment (0.186+/-0.055 microg/l). Therefore, in contrast to complicated non-invasive evaluation of diastolic function, cTnT is shown to be an early and sensitive marker of anthracycline-induced cardiotoxicity in the rabbit model.     

Cardiac troponin T following repeated administration of pyridoxal isonicotinoyl hydrazone in rabbits

Pyridoxal isonicotinoyl hydrazone (PIH) is a new tridentate Fe-chelating agent that should be very promising in many pathological states resulting from both an iron-overload and formation of free radicals. The aim of our study was to investigate the effect of PIH on the cardiovascular system focusing to the regulatory protein -- cardiac troponin T (cTnT). The study was carried out in two groups of Chinchilla male rabbits: 1) PIH (50 mg/kg dissolved in 10 % Cremophor i.p., once a week, 10 administrations, n=8) and 2) Cremophor (2 ml/kg i.p. in the same schedule, n=7). Plasma concentrations of cTnT (as a marker of myocardial damage) were measured using a commercial kit (Roche). cTnT was within the physiological range (i.e. < 0.1 microg/l) during the whole experiment in the Cremophor group. In the PIH group, the cTnT levels were not significantly increased when compared with the control group or with the initial values (except with those before the 5th administration). Furthermore, we analyzed the cytosolic and myofibrillar fraction of cTnT in the left ventricular myocardium. Using SDS-PAGE and Western blot we resolved three isoforms. The profiling of TnT did not differ significantly between the PIH-treated group and the Cremophor-treated group. Our data concerning cTnT support the opinion that the possible cardiotoxicity of PIH is very low.     

Exercise improves impaired ventricular function and alterations of cardiac myofibrillar proteins in diabetic dyslipidemic pigs.

Chronic diabetes is often associated with cardiomyopathy, which may result, in part, from defects in cardiac muscle proteins. We investigated whether a 20-wk porcine model of diabetic dyslipidemia (DD) would impair in vivo myocardial function and yield alterations in cardiac myofibrillar proteins and whether endurance exercise training would improve these changes. Myocardial function was depressed in anesthetized DD pigs (n = 12) compared with sedentary controls (C; n = 13) as evidenced by an approximately 30% decrease in left ventricular fractional shortening and an approximately 35% decrease in +dP/dt measured by noninvasive echocardiography and direct cardiac catheterization, respectively. This depression in myocardial function was improved with chronic exercise as treadmill-trained DD pigs (DDX) (n = 13) had significantly greater fractional shortening and +dP/dt than DD animals. Interestingly, the isoform expression pattern of the myofibrillar regulatory protein, cardiac troponin T (cTnT), was significantly shifted from cTnT1 toward cTnT2 and cTnT3 in DD pigs. Furthermore, this change in cTnT isoform expression pattern was prevented in DDX pigs. Finally, there was a decrease in baseline levels of cAMP-dependent protein kinase-induced phosphorylation of the myofibrillar proteins troponin I and myosin-binding protein-C in DD animals. Overall, these results indicate that 20 wk of DD lead to myocardial dysfunction coincident with significant alterations in myofibrillar proteins, both of which are prevented with endurance exercise training, implying that changes in myofibrillar proteins may contribute, at least in part, to cardiac dysfunction associated with diabetic cardiomyopathy.     

Field immobilization and euthanasia of American opossum

Seventeen recently trapped opossum, Didelphis virginiana, (median weight 2.45 kg; range = 1.6-5.0 kg; quartiles = 1.8-3.3 kg) were immobilized with either telazol (15 or 30 mg/kg) or a mixture of medetomidine (100 micrograms/kg), butorphanol (0.2 mg/kg), and ketamine HCl (10 mg/kg) based on estimated weights. Anesthetized animals were subjected to cardiac puncture for blood withdrawal and toe pinch. Euthanasia was accomplished by intracardiac administration of 1 ml of concentrated pentobarbital sodium/phenytoin solution. Weights were underestimated for 14 of 17 animals, but were within 0.5 kg of the actual weight. Both drug combinations provided rapid and calm immobilization. Median time to recumbency for the medetomidine-butorphanol-ketamine group (n = 5) was 6 min (range = 4-10 min; quartiles = 6 and 8 min). The median time to recumbency was not statistically different for the low (n = 6) and high dose (n = 6) telazol groups, 3 and 3.5 min respectively (quartiles 3; 3.5 and 4; 5.5 min). The stronger heart beat with telazol immobilization facilitated cardiac puncture. All five animals administered the medetomidine-butorphanol-ketamine mixture and three of six animals given the low telazol dose reacted to cardiac puncture. Only one of six animals given the estimated 30 mg/kg dose of telazol reacted slightly to cardiac puncture. We conclude that 30 mg/kg telazol provides sufficient immobilization and analgesia to allow accurate cardiac puncture of the opossum if the procedure is performed within 5 to 10 min of recumbency. Intracardiac administration of concentrated pentobarbital sodium/phenytoin solution followed by bilateral thoracotomy provides appropriate euthanasia suitable for field situations.     

The influence of NMDA receptor agonist and antagonist on morphine state-dependent memory of passive avoidance in mice

The measurement of step-down latency in passive avoidance has been used to study memory in laboratory animals. The pre-training injection of 5 mg/kg morphine impaired memory, which was restored when 24 h later the same dose of the drug was administered. To explore the possible involvement of NMDA modulators on morphine-induced memory impairment, we have investigated the effects of intracerebroventricular (i.c.v.) administration of NMDA and the competitive NMDA antagonist, DL-AP5, on morphine-induced memory impairment or recall, on the test day. Morphine (5 mg/kg, s.c.) was administered 30 min before training to induce impairment of memory and 24 h later, 30 min before test to improve it. Pre-test administration of NMDA (0.00001, 0.0001 and 0.001 microg/mouse, i.c.v.) did not alter the retention latency compared to the saline-treated animals. But restored the memory impairment induced by pre-training morphine (5 mg/kg, s.c.). Pre-test administration of DL-AP5 (1, 3.2 and 10 microg/mouse, i.c.v.) by itself decreased the retention latencies. The same doses of DL-AP5 increased pre-training morphine-induced memory impairment. Co-administration of NMDA (0.0001 and 0.001 microg/mouse, i.c.v.) and morphine (5 mg/kg, s.c.) on the test day increased morphine memory improvement. Conversely, DL-AP5 (1, 3.2 and 10 microg/mouse, i.c.v.) inhibited morphine-induced memory recall. It is concluded that NMDA receptors may be involved, at least in part, in morphine state-dependent learning in mice.     

Anthracycline cardiotoxicity in transgenic mice overexpressing SR Ca2+-ATPase

Chronic anthracycline administration results in a time- and dose-dependent cardiomyopathy. The Ca-ATPase of the sarcoplasmic reticulum, SERCA2, has been implicated as a principal target for anthracycline-induced cardiotoxicity. This hypothesis predicts that improved SERCA2 function would provide protection from cardiotoxic effects of anthracycline administration. Doxorubicin was administered (1.7 mg/kg three times weekly; cumulative dose of 20 mg/kg) to 10 transgenic mice that overexpressed SERCA2 and to 10 isogenic littermates. Survival was monitored for 60 days and histologic comparisons were made of cardiac tissue. Survival in the transgenic mice was worse (1/10 60-day survivors) compared to isogenic control mice (7/10 60-day survivors). There was a greater degree of histologic damage exhibited in hearts from transgenic mice compared to isogenic controls when all available hearts were examined. These data do not support a role of SERCA2 in ameliorating anthracycline cardiotoxicity.     

The lack of involvement of central nervous system in the antiarrhythmic effects of prostaglandins E2, F2 alpha, and I2 in cat

The role of the central nervous system (CNS) in the antiarrhythmic effects of prostaglandins (PGs) E2, F2 alpha, and I2 was studied by administering each agent into the left lateral cerebral ventricle (i.c.v. administration) of chloralose-anaesthetized cats. The cardiac arrhythmias were produced by intravenous (i.v.) infusion of ouabain (1 microgram/kg/min). The PGs E2, F2 alpha and I2 on i.c.v. administration in the dose range of 1 ng to 10 micrograms failed to inhibit ouabain-induced cardiac arrhythmias. However, when infused i.v., PGE2 (1 microgram/kg/min), PGF2 alpha (5 micrograms/kg/min), and PGI2 (2 micrograms/kg/min) effectively suppressed these arrhythmias. The standard antiarrhythmic drug propranolol (0.5-8.0 mg) on i.c.v. administration also significantly reduced the ouabain-induced cardiac arrhythmias. It is suggested that the CNS is not the site of action of PGs E2, F2 alpha, and I2 in antagonising the ouabain-induced cardiotoxicity in cats.     

The protective effect of a purified extract of <Emphasis Type="Italic">Withania somnifera</Emphasis> against doxorubicin-induced cardiac toxicity in rats

The therapeutic value of doxorubicin as an effective antineoplastic agent is limited by its cardiotoxic side-effects. The administration of doxorubicin (10 mg/kg) to male Wistar rats induced necrosis and apoptosis in heart tissues. It also caused oxidative stress damage as evidenced by the elevation of malondialdehyde and protein carbonyl levels and catalase activity, accompanied by the concurrent depletion of total antioxidant capacity and of superoxide dismutase level in cardiac tissues. The doxorubicin-induced cardiotoxicity and oxidative stress damage were also accompanied by increases of myeloperoxidase activity, total calcium content, and the expression of Bcl-2 protein in heart tissues. Most of these doxorubicin-induced biochemical and histological alterations were effectively attenuated by prior administration of purified standardized extract (1.5% withanolides; manufactured by Idea Sphere Inc., American Fork, UT, USA) of Withania somnifera (300 mg/kg). Thus, Withania may play a role in the protection against cardiotoxicity and thus might be a useful adjuvant therapy where doxorubicin is the cancer-treating drug.     

Vitamin E and telmisartan attenuates doxorubicin induced cardiac injury in rat through down regulation of inflammatory response

ABSTRACT: BACKGROUND: The importance of doxorubicin (Dox), as a potent antitumor antibiotic, is limited by the development of life-threatening cardiomyopathy. It has been shown that free radicals are involved in acute doxorubicin-induced toxicity. The aim of this study was to determine the protective effect of vitamin E and telmisartan in acute doxorubicin induced cardiotoxicity. METHODS: Thirty two male Sprague - Dawly rats were involved in this study and were randomly separated into 4 groups, eight rats in each group, one group received normal saline I.P as control and second group received doxorubicin 20 mg/kg I.P, the other two groups also received doxorubicin 20 mg/kg I.P as single dose after seven cumulative doses (for seven days) of vitamin E (100 mg/kg) and telmisartan (1 mg/kg) respectively. Immunofluorescent staining for monocytes infiltration and analyses of plasma by (ELISAs) for MCP-1and troponin I. Western immunoblotting assay for ICAM-1, while left ventricular function was analyzed by microcatheter, also estimated the level of oxidative stress parameters (MDA and Catalase) and cardiac enzymes activities (CK-MB and LDH) before starting drugs treatment and after treatment period by 48 hours. RESULTS: The immunofluorescent staining showed that administration of vitamin E and telmisartan are attenuated of mononuclear cell infiltration; (p < 0.05 vs. Dox group), also reduced the level of chemokines MCP-1 and ICAM-1 expression compared with Dox group only, and there is marked reduction of myocardial troponin-I levels with improved LV function in vitamin E and telmisartan treated group. Doxorubicin treatment increased MDA, LDH, CK-MB levels significantly (P < 0.01), and were counteracted by administration of vitamin E and telmisartan, but did not significantly affect serum catalase activity. CONCLUSIONS: Antioxidant effect (Vitamin E and telmisartan) have been shown to decrease doxorubicininduced cardiotoxicity.     

Intravenous rutin in rat exacerbates isoprenaline-induced cardiotoxicity likely due to intracellular oxidative stress

Objectives: Rutin, quercetin-3-O-rutinoside, a natural flavonol glycoside, has shown various in vitro benefits with potential use treating human diseases, especially cardiovascular system disorders. Antioxidant properties are assumed to underlie the majority of these benefits. Yet rutin pro-oxidant properties have been reported as well. Our research group has recently shown aggravating effects on isoprenaline (ISO)-induced cardiotoxicity in Wistar:Han rats after 24?hours.

Methods: This study was designed to examine in more detail the reasons for the negative effects of rutin (11.5 and 46?mg/kg, i.v.) after administration of ISO (100?mg/kg, s.c.) in rats within 2?hours of continuous experiment and in the H9c2 cardiomyoblast-derived cell line.

Results: Like our previous findings, rutin did not (11.5 or 46?mg/kg, i.v.) reduce the ISO-induced mortality within 2?hours although the lower dose significantly reduced cardiac troponin T (cTnT) and partly improved the histological findings. In contrast, the higher dose increased the mortality in comparison with solvent (1.26% w/v sodium bicarbonate). This was not caused by any specific haemodynamic disturbances. It appears to be associated with oxidative stress as rutin enhanced intracellular reactive oxygen species formation in vitro and had the tendency to increase it in vivo.

Conclusions: Rutin, likely due to its pro-oxidative effects, can exacerbate catecholamine cardiotoxicity depending on the dose used.     

Epigallocatechin gallate potentially attenuates Fluoride induced oxidative stress mediated cardiotoxicity and dyslipidemia in rats

The present study was undertaken to evaluate the cardioprotective role of (−)-epigallocatechin-gallate (EGCG) against Fluoride (F) induced oxidative stress mediated cardiotoxicity in rats. The animals exposed to F as sodium Fluoride (NaF) (25 mg/kg BW) for 4 weeks exhibited a significant increase in the levels of cardiac troponins T and I (cTnT & I), cardiac serum markers, lipid peroxidative markers and plasma total cholesterol (TC), triglycerides (TG), phospholipids (PL), free fatty acids (FFA), low density lipoprotein cholesterol, very low density lipoprotein cholesterol as well as cardiac lipids profile (TC, TG and FFA) with the significant decrease of high density lipoprotein cholesterol and cardiac phospholipids. F intoxication also decreased the levels of mitochondrial enzymes such as ICDH, SDH, MDH, α-KGDH and NADH in the cardiac tissue of rats. The mitochondrial Ca²⁺ ion level was also significantly reduced along with the significant decrease in the levels of enzymatic and non enzymatic antioxidants. Furthermore, F treatment significantly increased the DNA fragmentation, up regulate cardiac pro-apoptotic markers, inflammatory markers and down-regulate the anti-apoptotic markers in the cardiac tissue. Pre administration of EGCG (40 mg/kg/bw) in F intoxicated rats remarkably recovered all these altered parameters to near normalcy through its antioxidant nature. Thus, results of the present study clearly demonstrated that treatment with EGCG prior to F intoxication has a significant role in protecting F-induced cardiotoxicity and dyslipidemia in rats.     

S100A1 as a Potential Diagnostic Biomarker for Assessing Cardiotoxicity and Implications for the Chemotherapy of Certain Cancers

This study examined the value of blood marker S100A1 in detecting cardiotoxicity induced by chemotherapy agents; trastuzumab and lapatinib, in normal rat heart. The rats were divided into three groups: control (n = 8, no treatment), T (n = 8, one time ip treatment with 10 mg/kg trastuzumab) and L (n = 8, oral treatment with 100 mg/kg/day lapatinib for 7 days). The activities of oxidative stress parameters Malondialdehyde (MDA), Superoxide dismutase (SOD), Catalase (CAT) and Glutathione (GSH) were measured from the extracted cardiac tissues. The levels of troponinI and S100A1 expressions were measured from blood samples. All biomarkers responded to the treatments as they exhibited alterations from their normative values, validating the chemically induced cardiotoxicity. S100A1 expression attenuated significantly (75%), which made the sensitive detection of cardiotoxicity feasible. Assessment of cardiotoxicity with S100A1 may be a valuable alternative in clinical oncology of cancers in some organs such as breast and prostate, as they do not overexpress it to compete against.     

Creatine Kinase-Overexpression Improves Myocardial Energetics,Contractile Dysfunction and Survival in Murine Doxorubicin Cardiotoxicity

Doxorubicin (DOX) is a commonly used life-saving antineoplastic agent that also causes dose-dependent cardiotoxicity. Because ATP is absolutely required to sustain normal cardiac contractile function and because impaired ATP synthesis through creatine kinase (CK), the primary myocardial energy reserve reaction, may contribute to contractile dysfunction in heart failure, we hypothesized that impaired CK energy metabolism contributes to DOX-induced cardiotoxicity. We therefore overexpressed the myofibrillar isoform of CK (CK-M) in the heart and determined the energetic, contractile and survival effects of CK-M following weekly DOX (5mg/kg) administration using in vivo ³¹P MRS and ¹H MRI. In control animals, in vivo cardiac energetics were reduced at 7 weeks of DOX protocol and this was followed by a mild but significant reduction in left ventricular ejection fraction (EF) at 8 weeks of DOX, as compared to baseline. At baseline, CK-M overexpression (CK-M-OE) increased rates of ATP synthesis through cardiac CK (CK flux) but did not affect contractile function. Following DOX however, CK-M-OE hearts had better preservation of creatine phosphate and higher CK flux and higher EF as compared to control DOX hearts. Survival after DOX administration was significantly better in CK-M-OE than in control animals (p<0.02). Thus CK-M-OE attenuates the early decline in myocardial high-energy phosphates and contractile function caused by chronic DOX administration and increases survival. These findings suggest that CK impairment plays an energetic and functional role in this DOX-cardiotoxicity model and suggests that metabolic strategies, particularly those targeting CK, offer an appealing new strategy for limiting DOX-associated cardiotoxicity.     

Protective effect of DL-alpha-lipoic acid on cyclophosphamide induced oxidative cardiac injury

Cyclophosphamide (CP), one of the most widely prescribed antineoplastic drugs could cause a lethal cardiotoxicity. The present study is aimed at evaluating the role of DL-alpha-lipoic acid (LA) in oxidative cardiac damage induced by CP. Adult male Wistar rats were divided into four treatment groups. Two groups received single intraperitoneal injection of CP (200 mg/kg BW) to induce cardiotoxicity, one of these groups received LA treatment (25 mg/kg BW for 10 days). A vehicle treated control group and a LA drug control were also included. Cardiotoxicity, evident from increased activities of serum creatine phosphokinase, lactate dehydrogenase, aspartate transaminase and alanine transaminase in CP administered rats, was reversed by LA treatment. CP administered rats showed abnormal levels of enzymic (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase) and non-enzymic antioxidants (glutathione, vitamin C and vitamin E) along with high malondialdehyde levels. However, normalized lipid peroxidation and antioxidant defenses were reported in the LA treated rats. These findings highlight the efficacy of LA as a cytoprotectant in CP induced cardiotoxicity.     

Intranasal midazolam in piglets: pharmacodynamics (0.2 vs 0.4 mg/kg) and pharmacokinetics (0.4 mg/kg) with bioavailability determination

Intranasal midazolam was studied in two series of piglets: series 1, n = 20 (18 +/- 3 kg), a randomized double blind pharmacodynamic study to compare doses of 0.2 mg/kg and 0.4 mg/kg; series 2, n = 9 (42 +/- 8 kg), a pharmacokinetic study with a 0.4 mg/kg dose administered either intravenously (i.v.) or intranasally (i.n.) in a cross-over protocol with a one-week wash-out period between each. In series 1, midazolam caused significant anxiolysis and sedation within 3 to 4 min, without a significant difference between 0.2 and 0.4 mg/kg doses for any of the studied parameters. In series 2, after intranasal midazolam administration of 0.4 mg/kg, plasma concentrations attained a maximum (Cmax) of 0.13 +/- 0.04 mg/l at 5 min (median Tmax) and remained higher than 0.04 mg/l until 60 min. The bioavailability factor (F) in this study was F = 0.64 +/- 0.17 by the intranasal route. The terminal half-life (T1/2 lambda z) = 145 +/- 138 min was comparable with the i.v. administration half-life (158 +/- 127 min). In conclusion, optimal intranasal midazolam dose in piglets was 0.2 mg/kg, which procures rapid and reliable sedation, adapted to laboratory piglets.     

The inhibitory effect of ouabain on the response of slowly adapting pulmonary stretch receptors to hyperinflation in the rabbit

The combined effects of ouabain (Na(+)-K(+) ATPase inhibitor) and hyperinflation (inflation volume=three tidal volumes) on slowly adapting pulmonary stretch receptors (SARs) were studied before and after administration of nifedipine (an L-type Ca(2+) channel blocker) and KB-R7943 (a reverse-mode Na(+)-Ca(2+) exchanger blocker) in anesthetized, artificially ventilated rabbits after bilateral vagotomy. Before ouabain administration, hyperinflation stimulated SAR activity. After 20 min of ouabain administration (30 microg/kg) the SARs increased discharge rates in normal inflation. Under these conditions, hyperinflation initially stimulated SAR activity but subsequently inhibited the activity at peak inflation. Additional administration of 60 microg/kg ouabain (total dose=90 microg/kg) caused a further stimulation of SAR activity, but 20 min later both normal inflation and hyperinflation resulted in a greater inhibition of the receptor activity. The hyperinflation-induced SAR inhibition in the presence of ouabain (30 microg/kg) was not significantly altered by administration of either nifedipine (2 and 4 mg/kg) or KB-R7943 (1 and 3 mg/kg). In another series of experiments, we further examined the combined effects of ouabain and hyperinflation in veratridine (a Na(+) channel opener, 40 microg/kg)-treated animals. After recovery from the veratridine effect on SAR activity, which vigorously stimulated the receptor activity, ouabain treatment (30 microg/kg) that silenced the receptor activity at peak inflation greatly inhibited hyperinflation-induced SAR stimulation. These results suggest that hyperinflation-induced SAR inhibition in the presence of ouabain may be related to a Na(+) overload, but not to a Ca(2+) influx via activation of L-type Ca(2+) channels, in the SAR endings.     

Pharmacological analysis of the mechanisms involved in the tachycardic and vasopressor responses to the antimigraine agent, isometheptene, in pithed rats

The present study set out to investigate the pharmacological profile of the cardiovascular responses induced by the antimigraine agent, isometheptene, in pithed rats. For this purpose, intravenous (i.v.) administration of blocking doses of the antagonists prazosin (alpha1; 100 microg/kg), rauwolscine (alpha2; 300 microg/kg), the combination of prazosin (100 microg/kg) plus rauwolscine (300 microg/kg), propranolol (beta; 1000 microg/kg), ritanserin (5-HT2; 100 microg/kg) or equivalent volumes of saline (1 ml/kg) were used. Isometheptene (0.03, 0.1, 0.3, 1 and 3 mg/kg, i.v.) produced dose-dependent increases in heart rate and diastolic blood pressure which were highly reproducible as they remained unaltered after saline. These tachycardic responses to isometheptene remained unaffected after prazosin, rauwolscine, ritanserin or the combination prazosin plus rauwolscine, but were abolished after propranolol. In contrast, the isometheptene-induced vasopressor responses were not significantly modified after the above doses of rauwolscine, ritanserin or propranolol, but were markedly blocked after prazosin or the combination of prazosin plus rauwolscine; the latter blockade did not significantly differ from that produced by prazosin alone. Interestingly, in rats pretreated intraperitoneally (i.p.) with reserpine (5 mg/kg; -24 h), isometheptene-induced tachycardic responses were abolished whereas the corresponding vasopressor responses were markedly attenuated and subsequently blocked by prazosin. It is concluded that isometheptene-induced tachycardic responses seem to involve only an indirect (tyramine-like action) mechanism mediated by beta-adrenoceptors, whilst the corresponding vasopressor responses are mediated by a predominantly indirect (tyramine-like action), as well as a minor direct (alpha1-adrenoceptors), sympathomimetic mechanism.     

Acute but not chronic tempol treatment increases ischemic and reperfusion ventricular arrhythmias in open-chest rats

The effect of the chronic and acute antioxidant tempol (superoxide dismutase mimetic) treatment on cardiac ischemic tolerance was investigated in adult male Wistar rats. The first experimental group was given tempol (1 mM) in drinking water for three weeks, the second group received tempol (100 mg/kg, i.v.) 10 min before test ischemia, and control rats received the same volume of solvent. Anesthetized open-chest animals (pentobarbitone 60 mg/kg, i.p.) were subjected to 20-min coronary artery occlusion and 3-h reperfusion for infarct size determination. Ventricular arrhythmias were monitored during ischemia and at the beginning (5 min) of reperfusion. Acute tempol administration shifted the time profile of ischemic arrhythmias to the later phase and significantly increased the number of ischemic and reperfusion premature ventricular complexes, respectively (504+/-127 and 84+/-21) as compared with the chronically treated group (218+/-36 and 47+/-7) or controls (197+/-26 and 31+/-7). Acute tempol-treated rats exhibited a tendency to decrease infarct size (P = 0.087). The mechanism of proarrhythmic tempol action during ischemia and reperfusion remains to be elucidated.     

Low-intensity exercise training during doxorubicin treatment protects against cardiotoxicity.

Doxorubicin (Dox) is a highly effective antineoplastic antibiotic associated with a dose-limiting cardiotoxicity that may result in irreversible cardiomyopathy and heart failure. The purpose of this study was to examine the effects of low-intensity exercise training (LIET) during the course of Dox treatment on cardiac function, myosin heavy chain expression, oxidative stress, and apoptosis activation following treatment. Male Sprague-Dawley rats either remained sedentary or were exercise trained on a motorized treadmill at 15 m/min, 20 min/day, 5 days/wk (Monday through Friday) for 2 wk. During the same 2-wk period, Dox (2.5 mg/kg) or saline was administered intraperitoneally to sedentary and exercised rats 3 days/wk (Monday, Wednesday, Friday) 1-2 h following the exercise training sessions (cumulative Dox dose: 15 mg/kg). Five days following the final injections, hearts were isolated for determination of left ventricular (LV) function, lipid peroxidation, antioxidant enzyme protein expression, 72-kDa heat shock protein expression, caspase-3 activity, and myosin heavy chain isoform expression. Dox treatment significantly impaired LV function and increased caspase-3 activity in sedentary animals (P < 0.05). LIET attenuated the LV dysfunction and apoptotic signal activation induced by Dox treatment and increased glutathione peroxidase expression, but it had no significant effect on lipid peroxidation, protein expression of myosin heavy chain isoforms, 72-kDa heat shock protein, or superoxide dismutase isoforms. In conclusion, our data suggest that LIET applied during chronic Dox treatment protects against cardiac dysfunction following treatment, possibly by enhancing antioxidant defenses and inhibiting apoptosis.     

Effect of digitalis on the diaphragm in anesthetized dogs

We examined the effect of digitalis on diaphragmatic contractility and fatigability in 19 anesthetized mechanically ventilated dogs. The diaphragmatic force was assessed from transdiaphragmatic pressure (Pdi) developed at functional residual capacity against an occluded airway during cervical phrenic nerve stimulation. In a first group of five dogs, Pdi-stimulus frequency relationships were compared before and after administration of ouabain in doses of 0.01, 0.02, and 0.04 mg/kg. In a second group, diaphragmatic fatigue was produced by bilateral phrenic nerve stimulation at 30 Hz. Ten seconds of stimulation and 15 s of mechanical ventilation were repeated for 30 min. The rates of decrease in Pdi were compared between two groups, one of 0.05 mg/kg deslanoside-treated dogs (n = 7) and one of nontreated dogs (n = 7). After ouabain administration Pdi was significantly greater at each frequency in a dose-dependent manner. On the other hand, the rate of decrease in Pdi in the deslanoside group was significantly smaller than that in the nontreated group, whereas deslanoside did not greatly change the Pdi-frequency curves in fresh diaphragm. We conclude that ouabain improves contractility of the fresh diaphragm and that deslanoside has a protective effect against fatigability.