Ventricular Arrhythmias In Rats Research Articles

The risk of life-threatening ventricular arrhythmias in presence of high-intensity endurance exercise along with chronic administration of nandrolone decanoate

Anabolic steroids used to improve muscular strength and performance in athletics. Its long-term consumption may induce cardiovascular adverse effects. We assessed the risk of ventricular arrhythmias in rats which subjected to chronic nandrolone plus high-intensity endurance exercise.Animals were grouped as; control (CTL), exercise (Ex): 8weeks under exercise, vehicle group (Arach): received arachis oil, and Nan group: received nandrolone decanoate 5mg/kg twice a week for 8weeks, Arach+Ex group, and Nan+Ex. Finally, under anesthesia, arrhythmia was induced by infusion of 1.5μg/0.1mL/min of aconitine IV and ventricular arrhythmias were recorded for 15min. Then, animals’ hearts were excised and tissue samples were taken.Nandrolone plus exercise had no significant effect on blood pressure but decreased the heart rate (P<0.01) and increased the RR (P<0.01) and JT intervals (P<0.05) of electrocardiogram. Nandrolone+exercise significantly increased the ventricular fibrillation (VF) frequency and also decreased the VF latency (P<0.05 versus CTL group). Combination of exercise and nandrolone could not recover the decreasing effects of nandrolone on animals weight gain but, it enhanced the heart hypertrophy index (P<0.05). In addition, nandrolone increased the level of hydroxyproline (HYP) and malondialdehyde (MDA) but had not significant effect on glutathione peroxidase of heart. Exercise only prevented the effect of nandrolone on HYP.Nandrolone plus severe exercise increases the risk of VF that cannot be explained only by the changes in redox system. The intensification of cardiac hypertrophy and prolongation of JT interval may be a part of involved mechanisms.

Erratum to: The Effects of Nandrolone Decanoate Along with Prolonged Low-Intensity Exercise on Susceptibility to Ventricular Arrhythmias

We examined the influence of chronic administration of nandrolone decanoate with low-intensity endurance swimming exercise on susceptibility to lethal ventricular arrhythmias in rat. The animal groups included the control group, exercise group (EX), nandrolone group (Nan), vehicle group (Arach), trained vehicle group (Arach + Ex) and trained nandrolone group (Nan + Ex) that treated for 8 weeks. Then, arrhythmia induction was performed by intravenous infusion of aconitine and electrocardiogram recorded. Then, malondialdehyde (MDA), hydroxyproline (HYP) and glutathione peroxidase of heart tissue were measured. Chronic administration of nandrolone with low-intensity endurance swimming exercise had no significant effect on blood pressure, heart rate and basal ECG parameters except RR interval that showed increase (P < 0.05). Low-intensity exercise could prevent the incremental effect of nandrolone on MDA and HYP significantly. It also increased the heart hypertrophy index (P < 0.05) and reduced the abating effect of nandrolone on animal weighting. Nandrolone along with exercise significantly increased the duration of VF (P < 0.05) and reduced the VF latency (P < 0.05). The findings suggest that chronic co-administration of nandrolone with low-intensity endurance swimming exercise to some extent facilitates the occurrence of ventricular fibrillation in rat. Complementary studies are needed to elucidate the involved mechanisms of this abnormality.

The Effects of Nandrolone Decanoate Along with Prolonged Low-Intensity Exercise on Susceptibility to Ventricular Arrhythmias

We examined the influence of chronic administration of nandrolone decanoate with low-intensity endurance swimming exercise on susceptibility to lethal ventricular arrhythmias in rat. The animal groups included the control group, exercise group (EX), nandrolone group (Nan), vehicle group (Arach), trained vehicle group (Arach + Ex) and trained nandrolone group (Nan + Ex) that treated for 8 weeks. Then, arrhythmia induction was performed by intravenous infusion of aconitine and electrocardiogram recorded. Then, malondialdehyde (MDA), hydroxyproline (HYP) and glutathione peroxidase of heart tissue were measured. Chronic administration of nandrolone with low-intensity endurance swimming exercise had no significant effect on blood pressure, heart rate and basal ECG parameters except RR interval that showed increase (P < 0.05). Low-intensity exercise could prevent the incremental effect of nandrolone on MDA and HYP significantly. It also increased the heart hypertrophy index (P < 0.05) and reduced the abating effect of nandrolone on animal weighting. Nandrolone along with exercise significantly increased the duration of VF (P < 0.05) and reduced the VF latency (P < 0.05). The findings suggest that chronic co-administration of nandrolone with low-intensity endurance swimming exercise to some extent facilitates the occurrence of ventricular fibrillation in rat. Complementary studies are needed to elucidate the involved mechanisms of this abnormality.

Effects of Dantrolene Treatment on Ventricular Electrophysiology and Arrhythmogenesis in Rats With Chronic β-Adrenergic Receptor Activation.

Dantrolene, which is primarily used to treat malignant hyperthermia, has recently been suggested for the prevention of arrhythmogenesis in various animal models. In this study, the effects of dantrolene treatment on electrophysiological properties and ventricular arrhythmias (VAs) in rats with chronic β-adrenergic receptor (β-AR) activation were investigated. Rats were randomized to treatment with saline (control group), isoproterenol (ISO; ISO group), or ISO + dantrolene (ID group) for 2 weeks. An electrophysiological study was performed to assess action potential duration restitution (APDR) and induce action potential duration (APD) alternans or VA in vitro. The protein levels of Cav1.2, sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a), and ryanodine receptor 2 (RyR2) were detected by Western blot. Compared with the control group, chronic administration of ISO significantly increased APD, the maximum slope (Smax) of APDR curve, and the spatial dispersions of Smax and APD (all P < .01), and all effects were attenuated by dantrolene treatment (all P < .05). Additionally, chronic ISO administration significantly reduced the protein levels of SERCA2 and RyR2, but increased the Cav1.2 protein expression (all P < .05). However, compared with the ISO group, dantrolene treatment preserved SERCA2a and RyR2 protein levels and decreased Cav1.2 protein levels in the ID group (all P < .05). The intracellular Ca(2+) ([Ca(2+)]i) levels measured by incubating isolated cardiomyocytes with Fluo-3/alveolar macrophages were significantly increased in the ISO group compared with the control group (P < .01). Dantrolene treatment markedly reduced the rise of [Ca(2+)]i levels caused by chronic administration of ISO (P < .05). Dantrolene treatment also prevented the reductions in the APD alternans and VA thresholds induced by chronic ISO stimulation (all P < .05). These data suggest that dantrolene stabilizes ventricular electrophysiological characteristics and increases the expression of key sarcoplasmic reticulum calcium cycling proteins to reduce vulnerability to VA in rats with chronic β-AR activation.

Effects of Nardostachys chinensis on Spontaneous Ventricular Arrhythmias in Rats With Acute Myocardial Infarction

To investigate the effects and mechanisms of Nardostachys chinensis (NC) on spontaneous ventricular arrhythmias in rats with hyper-acute myocardial infarction (AMI). Seventy-two rats were randomly divided into the control group (n = 24), metoprolol group (n = 24), and the NC group (n = 24). Premature ventricular contractions (PVCs), ventricular tachycardias (VTs), ventricular fibrillations (VFs), and blood pressure were monitored for 4 hours after coronary artery ligation. The connexin 43 (Cx43) expression in ventricular myocardium was measured by immunohistochemistry, Western blot, and real-time RT-PCR. Compared with the control, metoprolol and NC decreased the VF incidence (50% vs. 4.2%, P < 0.001, and 50% vs. 12.5%, P = 0.005, respectively). There was a steady decrease in the cumulative number of PVCs and VTs within 4 hours from ligating in 3 groups. Compared with the control, metoprolol and NC reduced the cumulative number of VTs and PVCs. Compared with control, metoprolol and NC decreased the infarct size of the left ventricular tissue (55.98% ± 6.20% vs. 39.13% ± 4.53%, P < 0.001, and 55.98% ± 6.20% vs. 42.39% ± 3.44%, P < 0.001, respectively). The results from immunohistochemistry, Western blot, and real-time RT-PCR showed that the protein expression of Cx43 in the control group was significantly lower than that in the metoprolol and NC groups in the infarcted zone. NC decreased the incidence of spontaneous ventricular arrhythmias (especially VF), reduced Cx43 degradation, and improved Cx43 redistribution in myocardial infarcted zone in rats with hyper-AMI. The data of the present study indicated that NC may be a promising drug in the future to prevent patients with AMI from lethal ventricular arrhythmias in prehospital setting.

Low vagally-mediated heart rate variability and increased susceptibility to ventricular arrhythmias in rats bred for high anxiety

In humans, there is a documented association between anxiety disorders and cardiovascular disease. Putative underlying mechanisms may include an impairment of the autonomic nervous system control of cardiac function. The primary objective of the present study was to characterize cardiac autonomic modulation and susceptibility to arrhythmias in genetic lines of rats that differ largely in their anxiety level. To reach this goal, electrocardiographic recordings were performed in high-anxiety behavior (HAB, n=10) and low-anxiety behavior (LAB, n=10) rats at rest, during stressful stimuli and under autonomic pharmacological manipulations, and analyzed by means of time- and frequency-domain indexes of heart rate variability. During resting conditions, HAB rats displayed a reduced heart rate variability, mostly in terms of lower parasympathetic (vagal) modulation compared to LAB rats. In HAB rats, this relatively low cardiac vagal control was associated with smaller heart rate responsiveness to acute stressors compared to LAB counterparts. In addition, beta-adrenergic pharmacological stimulation induced a larger incidence of ventricular tachyarrhythmias in HABs compared to LABs. At sacrifice, a moderate increase in heart-body weight ratio was observed in HAB rats. We conclude that high levels of anxiety-related behavior in rats are associated with signs of i) impaired autonomic modulation of heart rate (low vagally-mediated heart rate variability), ii) poor adaptive heart rate responsiveness to stressful stimuli, iii) increased arrhythmia susceptibility, and iv) cardiac hypertrophy. These results highlight the utility of the HAB/LAB model for investigating the mechanistic basis of the comorbidity between anxiety disorders and cardiovascular disease.

Efficacy of Melissa officinalis in Suppressing Ventricular Arrhythmias following Ischemia-Reperfusion of the Heart: A Comparison with Amiodarone

Objective: We aimed to assess the influence of Melissa officinalis (lemon balm), a well-known herbal drug with numerous applications in traditional and modern medicine, on cardiac conduction and susceptibility to lethal ventricular arrhythmia. Materials and Methods: Forty-two male Wistar rats were divided into a control group (CTL), an M. officinalis group that received the aqueous extract of M. officinalis L. intraperitoneally (i.p.) at dosages of 50, 100, 200 and 400 mg/ml/kg, respectively, and an amiodarone group (Amio group) that received 30 mg/ml/kg i.p. of amiodarone. Heart ischemia/reperfusion was induced by the ligation and release of the left anterior descending branch of the left coronary artery. Results: There were no statistical differences between the groups in the basal heart rate and blood pressure. PR, corrected QT (QTc) and QRS intervals increased in the M. officinalis and Amio groups. PR and QTc were statistically significant only in the Amio group and QRS was significant only in the group receiving 400 mg of M. officinalis (M400 group) in comparison with the CTL group. During the reperfusion period, the decrease in ventricular fibrillations was statistically significant in all groups (except the M400 group) when compared with the CTL group. The score of arrhythmia severity also decreased, but was statistically significant only in the Amio group (p < 0.05 vs. CTL group). Conclusions: Our findings suggest that M. officinalis extract has a mild protective effect against reperfusion-induced lethal ventricular arrhythmias in rats.

Susceptibility to life-threatening ventricular arrhythmias in an animal model of paradoxical sleep deprivation

BackgroundAccording to some reports regarding the increase of cardiac events following sleep deprivation, our study was conducted to clarify the effects of rapid eye movement (REM) sleep deprivation on susceptibility to lethal ventricular arrhythmias in rat. MethodsThe animal groups included the control group; the sham 48 and sham 72 groups (without sleep deprivation); and the test 48 and test 72 groups, who experienced REM sleep deprivation for 48h and 72h, respectively. For induction of cardiac arrhythmia, aconitine was infused via the tail vein of the animals. ResultsAfter 72h of REM sleep deprivation, the blood pressure (BP) levels and the QTc interval of the electrocardiogram (ECG) were significantly increased (P<.05 and P<.01, respectively). However, the sleep deprivation had no significant effect on the heart rate (HR), myocardial oxygen consumption index, and plasma corticosterone level. Furthermore, sleep deprivation increased the latency times of premature ventricular contraction (PVC), ventricular tachycardia (VT), and also the PVC number; however, it did not increase the number, duration, and severity of VT and ventricular fibrillation (VF). ConclusionOur findings suggest that 72h of REM sleep deprivation is associated with increased risk for hypertension and QT interval prolongation under nonstressful conditions; however, it does not increase the susceptibility to lethal ventricular arrhythmia in rat.

Exendin-4 attenuates ischemia-induced ventricular arrhythmias in rats

Glucagon-like peptide-1 and its receptor agonist-exendin-4 (Ex-4) have been shown to provide beneficial effects for cardiovascular diseases. This study investigated the effects of Ex-4 on ischemia-induced ventricular arrhythmias in rats. Anesthetized male rats were once treated with Ex-4 (5 μg/kg, i.v.) 1 h before ischemia in the absence and/or presence of 5-hydroxydecanoic acid (5-HD, 10 mg/kg, i.v., a specific inhibitor of mitochondrial ATP-sensitive potassium [KATP] channels) which were once injected 10 min before ischemia. And then subjected to ischemia for 30 min. Ventricular arrhythmias were assessed. During the 30-min ischemia, Ex-4 significantly reduced the incidence of ventricular fibrillation (VF) (p < 0.05). The duration of ventricular tachycardia (VT) + VF, the number of VT + VF episodes and the severity of arrhythmias were all significantly reduced by Ex-4 compared to those in myocardial ischemia group (p < 0.05 for all). Administration of 5-HD abolished the protective effects of Ex-4 on VF incidence, the duration of VT + VF, the number of VT + VF episodes and the severity of arrhythmias (p < 0.05 for all). This study suggested that Ex-4 could attenuate ischemia-induced ventricular arrhythmias in rats in which mitochondrial KATP channels may be involved.

Wenxin Keli attenuates ischemia-induced ventricular arrhythmias in rats: Involvement of L-type calcium and transient outward potassium currents

Wenxin Keli is the first state‑sanctioned traditional Chinese medicine (TCM)-based antiarrhythmic drug. The present study aimed to examine whether long‑term treatment with Wenxin Keli reduces ischemia‑induced ventricular arrhythmias in rats in vivo, and if so, which mechanisms are involved. Male rats were treated with either saline (control group) or Wenxin Keli for 3 weeks and were subjected to myocardial ischemia for 30 min with assessment of the resulting ventricular arrhythmias. The L‑type calcium current (ICa,L) and transient outward potassium current (Ito) were measured by the patch clamp technique in normal rat cardiac ventricular myocytes. During the 30‑min ischemia, Wenxin Keli significantly reduced the incidence of ventricular fibrillation (VF) (P<0.05). The number of ventricular tachycardia (VT)+VF episodes and the severity of arrhythmias were significantly reduced by Wenxin Keli administration compared to the control group (P<0.05). In addition, Wenxin Keli inhibited ICa,L and Ito in a concentration‑dependent manner. These results suggest that long‑term treatment with Wenxin Keli may attenuate ischemia‑induced ventricular arrhythmias in rats and that ICa,L and Ito may be involved in this attenuation.

CARVEDILOL PREVENTS THE ETHANOL-INDUCED VENTRICULAR ARRHYTHMIAS BY MODIFYING THE GAP JUNCTION REMODELLING IN RATS

ObjectivesOur previous studies showed carvedilol blocked the abrupt termination of an ethanol regimen promoted the cardiac sympathetic predominance and the life-threatening ventricular arrhythmias in rats. However, the mechanisms by which...

Effects of ghrelin on Cx43 regulation and electrical remodeling after myocardial infarction in rats

Ghrelin is a novel growth hormone-releasing peptide, which has been shown to exert beneficial effects on ventricular remodeling. In this study, we investigated whether ghrelin could decrease vulnerability to ventricular arrhythmias in rats with myocardial infarction and the possible mechanism. Twenty-four hours after ligation of the anterior descending artery, adult male Sprague-Dawley rats were randomized to ghrelin (100μg/kg) and saline (control group) for 4 weeks. Sham animals underwent thoracotomy and pericardiotomy, but not LAD ligation. Myocardial endothelin-1 (ET-1) levels were significantly elevated in saline-treated rats at the border zone compared with sham-operated rats. Myocardial connexin43 (Cx43) expression at the border zone was significantly decreased in saline-treated infarcted rats compared with sham-operated rats. Ghrelin significantly decreased the inducibility of ventricular tachyarrhythmias compared with control group. Arrhythmias sores during programmed stimulation in saline-treated rats were significantly higher than scores in those treated with ghrelin. The electrophysiological improvement of fatal ventricular tachyarrhythmias was accompanied with increased immunofluorescence-stained Cx43, myocardial Cx43 protein and mRNA levels in ghrelin treated rats. We also shown that ghrelin significantly decreased tissue ET-1 levels at the infarcted border zone. Thus, ghrelin showed the protective effect on ventricular arrhythmias after myocardial infarction. Although the precise mechanism by which ghrelin modulates the dephosphorylation of Cx43 remains unknown, it is most likely that the ghrelin increased expression of Cx43 through the inhibition of ET-1.

Allogeneic bone marrow mesenchymal stem cells over-expressing gap junction protein connexin 43 reduce ventricular arrhythmias following myocardial infarction in rats

BackgroundMesenchymal stem cell transplantation is a promising new therapy to improve cardiac function after myocardial infarction (MI). The electrophysiological consequences of MSC implantation have not been systematically studied.ObjectiveThis study strived...

Effects of the novel amiodarone-like compound SAR114646A on cardiac ion channels and ventricular arrhythmias in rats

Amiodarone is the "gold standard" for current antiarrhythmic therapy because it combines efficacy with good hemodynamic and electrophysiological tolerance. Amiodarone is effective against both atrial and ventricular arrhythmias by intravenous (i.v.) or oral route. However, the i.v. formulation has limitations. Therefore, we identified SAR114646A, an amiodarone-like antiarrhythmic agent with good aqueous solubility suitable for i.v. application. Patch-clamp experiments were performed with isolated cardiomyocytes from guinea pigs and rats. In guinea pig ventricular cardiomyocytes, the fast Na(+) channel and the L-type Ca(2+) channels were blocked by SAR114646A with half-maximal concentrations (IC(50)) of 2.0 and 1.1μM, respectively. The tail current of the fast activating rectifying potassium channel I(Kr) was blocked with an IC(50) value of 0.6μM, whereas the IC(50) values for inhibition of the I(Ks) and I(K1) channels was >10μM. ATP-sensitive K(+) channels were evoked by application of the channel opener rilmakalim (3μM). SAR114646A blocked this current with an IC(50) value of 2.8μM. In guinea pig atrial cardiomyocytes, carbachol (1μM) was used to activate the I(KACh) and SAR114646A inhibited this current with IC(50) of 36.5 nM. The transient outward current I(to) and the sustained current I(sus) were investigated in rat ventricular myocytes. SAR114646A blocked these currents with IC(50) of 1.8 and 1.2μM, respectively. When expressed in Chinese hamster ovary cells, the currents hKv1.5 and hHCN4 were inhibited with IC(50) values of 1.1 and 0.4μM, respectively. Micropuncture experiments in isolated rabbit left atria revealed that SAR114646A prolonged the 50% repolarization significantly at 3 and 10μM. In guinea pig papillary muscle, the APD at 90% of repolarization was slightly prolonged at 3 and 10μM. SAR114646A demonstrates antiarrhythmic activity in anaesthetised rats, subjected to 5min ischemia followed by 10min reperfusion, where 1mg/kg of SAR114646A applied as i.v. bolus 5min prior to ischemia, decreased mortality to 0% compared to 80% under control conditions. In conclusion, SAR114646A is a multichannel blocker with improved water solubility, compared to amiodarone. In contrast to amiodarone, SAR114646A also blocks the K(+) channels I(to) and I(sus). A potent antiarrhythmic effect as observed in rats can also be expected in other animal models.

Minocycline attenuates ischemia-induced ventricular arrhythmias in rats

Minocycline has been shown to protect against myocardial ischemia–reperfusion injury. This study investigated the effects of minocycline on ischemia-induced ventricular arrhythmias in rats. Anesthetized male rats were once treated with minocycline (45 mg/kg, i.p.) 1 h before ischemia in the absence and/or presence of 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002, 0.3 mg/kg, i.v., a PI3K inhibitor) and 5-hydroxydecanoic acid [5-HD, 10 mg/kg, i.v., a specific inhibitor of mitochondrial ATP-sensitive potassium (K ATP) channels] which were once injected 10 min before ischemia and then subjected to ischemia for 30 min. Ventricular arrhythmias were assessed. L-type Ca 2+ current was measured by the patch-clamp technique. During the 30-minute ischemia, minocycline significantly reduced the incidence of ventricular fibrillation (VF) (P < 0.05). The duration of VT + VF, the number of VT + VF episodes and the severity of arrhythmias were all significantly reduced by minocycline compared to those in myocardial ischemia group (P < 0.05 for all). Administration of LY294002 or 5-HD abolished the protective effects of minocycline on VF incidence, the duration of VT + VF, the number of VT + VF episodes and the severity of arrhythmias (P < 0.05 for all). In addition, minocycline inhibited L-type Ca 2+ currents of normal myocardial cell membrane in a dose-dependent manner. This study suggested that minocycline could attenuate ischemia-induced ventricular arrhythmias in rats in which PI3K/Akt signaling pathway, mitochondrial K ATP channels and L-type Ca 2+ channels may be involved .

Green tea extract given before regional myocardial ischemia–reperfusion in rats improves myocardial contractility by attenuating calcium overload

There is evidence for a negative correlation between green tea consumption and cardiovascular diseases. The aim of the present study was to examine whether green tea extract (GTE) given before regional myocardial ischemia could improve depression of myocardial contractility by preventing cytosolic Ca(2+) overload. Regional ischemia-reperfusion (IR) was induced in rats by ligating the left anterior descending branch for 20min, then releasing the ligature. Ligation induced ventricular arrhythmias in rats without GTE pretreatment, but decreased arrhythmogenesis was seen in rats pretreated 30min earlier with GTE (400mg/kg). During reperfusion, arrhythmias only occurred during the initial 5min, and GTE pretreatment had no effect. After overnight recovery, serum cTnI levels were greatly increased in control post-IR rats but only slightly elevated in GTE-pretreated post-IR rats. Myocardial contractility measured by echocardiography was still depressed after 3days in control post-IR rats, but not in GTE-pretreated post-IR rats. No myocardial ischemic injury was seen in post-IR rats with or without GTE pretreatment. Using freshly isolated single heart myocytes, GTE was found to attenuate the post-IR injury-associated cytosolic Ca(2+) overload and modulate changes in the levels and distribution of myofibril, adherens junction, and gap junction proteins. In summary, GTE pretreatment protects cardiomyocytes from IR injury by preventing cytosolic Ca(2+) overload, myofibril disruption, and alterations in adherens and gap junction protein expression and distribution.

Tumor Necrosis Factor-α and Its Receptors 1 and 2

In healthy hearts, tumor necrosis factor-α (TNF-α) concentration is low, and TNF-α is mainly located in endothelium and resident mast cells.1 TNF-α receptors (TNFRs) 1 (TNFR1) and 2 (TNFR2) are expressed on most cardiac cells, including cardiomyocytes.2 During myocardial ischemia, preformed TNF-α is released within minutes from resident mast cells and macrophages.3 With persistent ischemia, TNF-α also originates from cardiomyocytes.4 In rats after myocardial infarction (MI), TNFR1 density is increased for 10 days, whereas TNFR2 density remains unchanged.5 In contrast, TNFR1 and TNFR2 are both downregulated in the failing heart, whereas soluble TNFRs are increased6 owing to proteolytic cleavage of cardiomyocyte TNFR and release from circulating exosome-like vesicles.7 Increased soluble TNFRs decrease TNF-α bioactivity while at the same time prolonging its half-life.8 Article p 1386 TNF-α contributes to both reversible (contractile dysfunction4,9) and irreversible (MI) injury.1 Preischemic treatment with TNF-α antibodies10 or soluble TNFR1,11 permanent TNF-α knockout,12 or knockout of TNFR1 but not TNFR213 all reduce infarct size. The latter finding highlights the functional difference of TNFR1 and TNFR2 activation for ischemia/reperfusion injury: Only TNFR1 signaling is detrimental (Figure). Figure. Signaling cascade activated (→) or inhibited (⊣) by TNFR1 (red) or TNFR2 (blue) activation. sTNFR1 indicates soluble TNFR1; sTNFR2, soluble TNFR2; S1-P, sphingosine-1-phosphate; NF-κB, nuclear factor-κB; SOCS3, suppressor of cytokine signaling 3; ROS, reactive oxygen species; Akt-P, phosphorylated Akt, a homologue of the transforming v-Akt; NADPH-Ox, NADPH oxidase; STAT3-P, phosphorylated signal transducer and activator of transcription; Jnk-P, phosphorylated c-jun N-terminal kinase; p38-P, phosphorylated mitogen-activated protein kinase; Erk-P, phosphorylated extracellular signal-regulated kinase; PKC, protein kinase C; CamK, calcium/calmodulin-dependent kinase; MMP-2/9, matrix metalloproteinases 2 and 9; and IL-6, interleukin 6. Red indicates proteins involved in apoptosis; purple, proteins involved in growth; green, …

Antiarrhythmic effects of growth hormone—in vivo evidence from small-animal models of acute myocardial infarction and invasive electrophysiology

Introduction A growing body of evidence suggests a possible role for growth hormone (GH) in the treatment of congestive heart failure (CHF) and myocardial infarction (MI). The aim of this study was to investigate in vivo the effects of GH treatment on incidence and severity of ventricular arrhythmias normal and MI rats. Methods Male Sprague-Dawley rats weighing approximately 350 g were randomized into 3 groups. Growth hormone–treated rats (n = 6) received 6 mg/kg of human GH. The placebo group (n = 10) received 1 mL of saline. Amiodarone-treated rats (n = 10) were injected with 25 mg/kg and served as positive controls. All animals received a single intraperitoneal injection 6 hours before induction of MI. Myocardial infarction was induced by ligation of the left coronary artery, resulting in a large (approximately 40%) anterolateral MI. A computerized electrocardiographic tracing was obtained continuously before induction of MI and up to 1 hour postinfarction. Invasive hemodynamics including intraventricular and arterial pressure were registered for 60 minutes post-MI. Qualitative as well as quantitative variables of ventricular arrhythmias were analyzed. Invasive electrophysiology with pacing in right atrium and ventricle was performed in normal rats (control, n = 13; GH, n = 6; amiodarone, n = 6) to asses inducibility of supraventricular and ventricular arrhythmias. Results Growth hormone– and amiodarone-treated rats had lower resting heart rate at baseline before induction of MI. The arrhythmia scores in the GH- (3.8 ± 1) and amiodarone-treated (3.9 ± 0.5) animals were significant lower than in the placebo group (5.9 ± 0.5, P < .05). There was no significant difference in arrhythmia score between the GH and amiodarone groups. The incident of inducible ventricular arrhythmias was lower in the GH (2/6, 33%) and amiodarone (2/6, 33%) groups compared with controls (13/16, 81%; P = .05). There was no difference in inducibility of atrial fibrillation between the GH (5/6, 83%) and control (13/14, 93%) groups, whereas the inducibility of atrial fibrillation was significantly lower in the amiodarone group (2/6, 33%; P < .05). Conclusions Pretreatment with GH reduces the burden of ventricular arrhythmias in rats with postinfarction CHF due to acute MI. Growth hormone may be useful in the treatment of CHF and acute MI.

Positive Correlation of Tumor Necrosis Factor-α Early Expression in Myocardium and Ventricular Arrhythmias in Rats with Acute Myocardial Infarction

Tumor necrosis factor-alpha (TNF-alpha) is found to play important roles in acute myocardial infarction (AMI). Ventricular arrhythmias arising from AMI are leading causes of sudden cardiac death (SCD). We sought to clarify the effect of TNF-alpha early expression on ventricular arrhythmias in rats with AMI and its mechanism. Rats with AMI were induced by left anterior descending coronary branch ligation. The mRNA and protein levels of TNF-alpha in myocardium were detected by real-time fluorescent quantitative PCR, Western blotting and histochemistry. Meanwhile, electrocardiogram was recorded. Different concentrations of TNF-alpha were added to isolated rat hearts in isolated heart perfusions. Effect of TNF-alpha on intracellular Ca(2+) concentration was detected by laser confocal technique. In AMI rats, mRNA and protein levels of TNF-alpha were higher than control (p <0.05), and the occurrence time of ventricular arrhythmias coincided with the secretion of TNF-alpha. TNF-alpha may cause ventricular arrhythmias in isolated rat heart perfusion models. Intracellular Ca(2+) intensity may quickly be increased by TNF-alpha. Our results reveal the positive correlation between TNF-alpha early expression and ventricular arrhythmias in rats with AMI. This effect may be associated with the increased intracellular Ca(2+) intensity caused by TNF-alpha.

Effects of neuropeptide Y 2 receptor blockade on ventricular arrhythmias in rats with acute myocardial infarction

Excessive sympathetic activity is believed to be the key arrhythmogenic factor both in the setting of acute myocardial infarction and during chronic heart failure. The aim of this study was to evaluate the effect of neuropeptide Y 2 blockade on malignant ventricular arrhythmias in rats with acute myocardial infarction. Vagotonic dose-finding study for neuropeptide Y2 receptor antagonist, (S)-N 2-[2-[4-[(R,S)-5,11-dihydro-6(6h)-oxodibenz[b,e]azepin-11-yl]-1-piperazinyl]-2-oxoethyl] cylopentyl] acetyl]-N-[2-[1,2-dihydro-3,5 (4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl]ethyl]-argininamid (AR-H05359) was conducted in guinea pigs ( n = 50) and rats ( n = 3). Induction of postinfarction arrhythmias was conducted in Sprague–Dawley rats that were randomized into 3 groups. Neuropeptide Y2 antagonist treated rats ( n = 7), placebo group ( n = 10) and amiodarone treated rats ( n = 8). Myocardial infarction was induced by ligation of the left coronary artery. Computerized telemetric ECG tracings were obtained continuously before induction of myocardial infarction and up to 120 min postinfarction. Occurrence of ventricular arrhythmias was analyzed according to a 10-point arrhythmia score. There was no difference in the arrhythmia scores between the neuropeptide Y 2 and the saline group. The amiodarone treated animals had lower score compared to the neuropeptide Y 2 and the placebo group ( p < 0.05). The blockade of receptors does not reduce ventricular arrhythmias in the rats with acute myocardial infarction. Further studies are needed to evaluate whether increasing vagal tonus during sympathetic activation may be valuable anti-arrhythmic strategy to prevent sudden death in patients with myocardial infarction and heart failure.