Epinephrine-induced Arrhythmias Research Articles

Novel Antiarrhythmic and Cardioprotective Effects of Brilliant Blue G

In this study, we investigated the effects of the purinergic P2X7 receptor antagonist brilliant blue G (BBG) on cardiac arrhythmia and myocardial injury induced by intravenously (i.v.) administered epinephrine in anesthetized rats. We also examined the possible involvement of beta-adrenergic receptors or cholinergic mechanisms in the effects of BBG. Sprague-Dawley rats were treated with epinephrine (10 μg/kg, i.v.). Brilliant blue G (100 mg/kg) was intraperitoneally (i.p.) administered thirty minutes prior to i.v. epinephrine. The effects of pretreatment with propranolol (2 mg/kg, i.p.) or atropine (2 mg/kg, i.v.) given prior to BBG and epinephrine were examined. The control group received saline. Moreover, the effects of only BBG on electrocardiogram (ECG) parameters were investigated. Results showed that compared with the saline control, BBG caused significant bradycardia (from 405.8 ± 1.18 to 239.4 ± 6.69 beats/min), increased RR interval (from 0.149 ± 0.002 to 0.254± 0.007 sec) and PR interval (from 0.051 ± 0.0008 to 0.059 ± 0.0004 sec), increased R wave amplitude (from 0.238 ± 0.019 to 0.548 ± 0.009 mv), and shortened QTc interval (from 0.169 ± 0.006 to 0.141 ± 0.003 sec) over 15 minutes after of BBG administration. BBG did not cause cardiac arrhythmia. Meanwhile, epinephrine produced significant bradycardia (209.8 ± 28.78 vs. 405.8 ± 1.18 beats/min), increased PR interval, prolonged the QRS complex, shortened QTc interval, decreased R wave amplitude and induced ventricular tachycardia. Brilliant blue G given prior to epinephrine increased heart rate and completely suppressed the epinephrine-induced ventricular arrhythmia. The inhibitory effect of BBG on the arrhythmia caused by epinephrine was prevented by atropine. In contrast the epinephrine induced arrhythmia was completely suppressed with propranolol and BBG. The histopathological study showed that epinephrine caused necrosis and apoptosis of cardiac muscle cells, degeneration of cardiac muscle fibers, and interstitial haemorrhages. These changes were markedly prevented by BBG alone, propranolol/BBG and to a less extent by atropine/BBG pretreatment. The study provided the first evidence for a cardioprotective and anti-arrhythmogenic actions for BBG against epinephrine-induced arrhythmia and myocardial damage, and suggested that cholinergic mechanisms are involved in its anti-arrhythmogenic action.

The Effects of Nitric Oxide Synthase Inhibition on Epinephrine-Induced Arrhythmia and Myocardial Damage

We have recently reported that methylene blue (MethyB) was able to inhibit epinephrine-induced arrhythmias and cardiac muscle injury. In this study, we investigated the effect of nitric oxide synthase inhibition by NG-nitro-L-arginine methyl ester (L-NAME) on cardiac arrhythmias, and myocardial damage induced by epinephrine in rats. Whether nitric oxide inhibition would affect the antiarrhythmic and cardiac protective actions of MethyB was also examined. L-NAME (40 mg/kg), L-arginine (200 mg/kg) + L-NAME, or MethyB (100 mg/kg) + L-NAME were given intraperitoneally (i.p.). Cardiac arrhythmia was then induced with intravenous (i.v.) injection of 10 μg/kg epinephrine. Results showed that epinephrine injection caused marked bradycardia (221.0 ± 1.37 vs. 409.4 ± 3.18 beats/min), shortened QTc interval (0.096 ± 0.0093 vs. 0.177 ± 0.0008 s), increased QRS duration (0.040 ± 0.0035 vs. 0.0185 ± 0.0002 s), decreased R wave amplitude (0.176 ± 0.0051 vs. 0.21 ± 0.0009 mv), ST segment height (-0.026 ± 0.007 vs. -0.002 ± 0.0005 mv), and induced ventricular extrasystoles. L-NAME given to untreated control rats resulted in a decrease in heart rate (288.2 ± 0.88 vs. 409.4 ± 3.18 beats/min), and increased R wave amplitude (0.436 ± 0.004 vs. 0.21 ± 0.0009 mv) compared to controls. L-NAME did not cause extrasystoles in untreated control rats but significantly increased the number of extrasystoles and duration of arrhythmia in the epinephrine-treated group. The administration of L-arginine (200 mg/kg, i.p.) to epinephrine plus L-NAME-treated rats resulted in increased heart rate and markedly decreased the number of extrasystoles and duration of arrhythmia. Methylene blue given at 100 mg/kg to rats treated with epinephrine and L-NAME caused a marked increase in heart rate. It also normalized QRS duration, prevented ST segment depression, markedly suppressed ventricular extrasystoles, and decreased the duration of arrhythmia compared with either epinephrine or L-NAME plus epinephrine-treated groups. Epinephrine injection caused disorganization, and necrosis of cardiac cells, interstitial hemorrhage, and cellular infiltrations. These changes were markedly improved by treatment with either L-NAME or L-NAME/MethyB. These results suggest that (i) inhibiting nitric oxide synthase by L-NAME increases epinephrine-induced arrhythmia which is inhibited by L-arginine or MethyB; (ii) either L-NAME alone or in combination with MethyB prevented cardiac muscle injury induced by epinephrine; (iii) L-NAME did not prevent the cardiac protective and antiarrhythmic actions of MethyB.

Cardioprotection by methylene Blue Against Epinephrine-Induced Cardiac Arrhythmias and Myocardial Injury

Methylene blue is used in the treatment of vasoplegic syndrome after cardiac surgery, anaphylaxis, and septic shock refractory to epinephrine and fluid resuscitation. In this study, we investigated the potential protective effect of methylene blue on the development of cardiac arrhythmias after injection of epinephrine in rats. Methylene blue was given intraperitoneally at doses of 50 or 100 mg/kg. Cardiac arrhythmia was then induced with 10 μg/kg of epinephrine intravenously. In untreated, control rats, epinephrine caused bradycardia (96.48 ± 1.06 vs. 365.03 ± 0.68 beats/min), increased PR interval (0.54 ± 0.04 vs. 0.039 ± 0.004), RR interval (0.64 ± 0.003 vs. 0.16 ± 0.004 sec), shortened QTc interval (0.067 ± 0.05 vs. 0.1 ± 0.004 sec), increased QRS duration (0.048 ± 0.005 vs. 0.028 ± 0.002 sec), decreased R wave amplitude (0.3 ± 0.03 vs. 0.49 ± 0.04 mv), decreased the height of the ST segment (-0.0696 ± 0.004 vs. -0.0054 ± 0.003 mv), and caused ventricular extrasystoles (7.92 ± 0.56 vs. 0.5 ± 0.5). Methylene blue given at 50 or 100 mg/kg increased the heart rate, decreased RR interval, QRS duration and the drop in the ST height, increased duration of QTc interval and R wave amplitude and decreased the number of extrasystoles. The histological study showed that methylene blue protected against myocardial structural disorganization, cellular damage, necrosis, and haemorrhage between muscle fibres induced by epinephrine injection. We conclude that methylene blue dose-dependently prevented epinephrine-induced arrhythmias and cardiac muscle injury.

Characterization of Magnesium Sulfate as an Antiarrhythmic Agent.

BACKGROUND: Recently, intravenous magnesium therapy has been used for the treatment of ventricular arrhythmias, but data to establish a causal link between the electrophysiological properties and the antiarrhythmic actions are lacking. METHODS AND RESULTS: The acute antiarrhythmic effect of magnesium sulfate was assessed using epinephrine-, digitalis-, and coronary ligation-induced canine ventricular arrhythmia models. The intravenous administration of magnesium sulfate (100 mg/kg) reduced the incidence of the ventricular arrhythmias of all models. The antiarrhythmic effect on the epinephrine-induced arrhythmia was potent and long-lasting, while those on the other arrhythmia models were weak and transient. The direct cardiovascular effects were assessed using the canine isolated, blood-perfused sinus node, papillary muscle, and atrioventricular node preparations. The intracoronary administration of magnesium sulfate (0.1-30 mg) suppressed sinoatrial automaticity and ventricular contraction, while it increased atrio-His and His-ventricular conduction time, coronary blood flow, and the duration of monophasic action potential in a dose-dependent manner. The effects on His-ventricular conduction and monophasic action potential duration were less potent compared with the other cardiovascular effects. CONCLUSIONS: These results suggest that magnesium sulfate possesses multiple electrophysiological properties and that the effects related to the calcium channel inhibition may be the most relevant for the antiarrhythmic actions.

Effects of phosphodiestrase type 5 inhibitors in epinephrine-induced arrhythmia in rats: Involvement of lactate dehydrogenase and creatine kinase downregulation and adiponectin expression.

Cardiac arrhythmia is a common cause of mortality, and its progression may be due to abnormal sympathetic nerve activity and catecholamine release. Besides, lactate dehydrogenase (LDH) and creatine kinase (CK) downregulation and adiponectin expression play important roles in promoting coronary artery disease. The study aimed to examine the possible cardioprotective effect of members of phosphodiesterase type 5 (PDE-5) inhibitors in epinephrine-induced arrhythmia in rats. Arrhythmia was induced by cumulative boluses of epinephrine (4, 8, 16, 32, 64, and 128 mg/kg) given at 10-min intervals. Rats were randomly allocated into five groups. Group I: Normal control group received only saline. Group II: Rats injected with epinephrine and served as arrhythmia group. Groups III, IV, and V: Rats received daily oral sildenafil (0.5 mg/kg), vardenafil (3 mg/kg), and tadalafil (10 mg/kg), respectively, for 30 days prior to epinephrine injections. Injection of epinephrine to rats decreased heart rate and QTc interval but increased RR interval and duration of arrhythmia. Epinephrine group had lower serum reduced glutathione (GSH) and adiponectin levels and higher serum malondialdehyde (MDA), nitric oxide (NO), heart LDH, and CK contents. Histopathological investigations of epinephrine group provoked necrotic changes with strong positive immunoreactivity for caspases-3. While pretreatment of rats with PDE-5 inhibitors improved GSH and adiponectin contents, ameliorated serum MDA and NO levels and heart LDH and CK contents and corrected epinephrine-induced histopathological changes. PDE-5 inhibitors may delay epinephrine-induced arrhythmia through expression of adiponectin and downregulation of heart LDH and CK.

Antiarrhythmic and α-Adrenoceptor Antagonistic Properties of Novel Arylpiperazine Derivatives of Pyrrolidin-2-one.

In an effort to develop α-adrenoceptor antagonists with antiarrhythmic activity, we designed a series of pyrrolidin-2-one derivatives. The α1- and α2-adrenorecepor affinities of the new pyrrolidin-2-one derivatives were determined using a radioligand binding assay. The most active compound was then tested in vitro for intrinsic activity toward α(1A)- and α(1B)-adrenoceptors and in vitro for antiarrhythmic activity in epinephrine-induced arrhythmia in rats. The highest affinity for the α1-adrenoceptor (pK(i) = 7.01) was displayed by 1-{4-[4-(2-methoxy-5-chlorophenyl)-piperazin-1-yl]-methyl}-pyrrolidin-2-one (9). 1-[4-(2-Fluorophenyl)-piperazin-1-yl]-methyl-pyrrolidin-2-one (7) showed the highest affinity toward the α2-adrenoceptor (pK(i) = 6.52). Intrinsic activity studies of compound 9 showed that this compound is an antagonist of both α(1A)- (EC50 = 0.5 nM) and α(1B)- (EC50 = 51.0 nM) adrenoceptors. Compound 9 displayed antiarrhythmic activity in rats (ED50 = 5.0 mg/kg (3.13-7.99)). New derivatives of pyrrolidin-2-one with α1 -adrenoceptor affinity were identified. We propose that the antiarrhythmic activity of compound 9 is related to its antagonism of α(1A)- and α(1B)-adrenoceptors.

Prophylactic antiarrhythmic effect of anesthetics at subanesthetic concentration on epinephrine-induced arrhythmias in rats after brain death.

The present study using brain death model of rats was designed to examine whether prophylactic administration of volatile anesthetics and propofol prevent the epinephrine-induced arrhythmias. A Fogarty catheter was placed intracranially for induction of brain death. After brain death, the rats were randomly assigned to five groups: the control group (no anesthetics), the sevoflurane group (0.8%), the isoflurane group (0.5%), the halothane group (0.3%), and the propofol group (195 μg·kg−1 ·min−1). These anesthetics were about 30% of ED50 of each anesthetic. The arrhythmogenic dose of epinephrine was determined in each anesthetic group. In addition, we examined left ventricular levels of connexin 43 phosphorylation 30 min after administration of each anesthetic with Western blot analysis. The arrhythmogenic dose of epinephrine in the sevoflurane group was significantly higher than that in the control group, while the arrhythmogenic dose of epinephrine in any other anesthetic group was not different. On the other hand, the ratio of phosphorylated-connexin 43/total connexin 43 was also similar among the study groups. Thus, prophylactic administration of subanesthetic dose of sevoflurane is effective in preventing epinephrine-induced arrhythmias after brain death, but phosphorylation of connexin is not involved in the antiarrhythmic property of sevoflurane.

Alpha blockade potentiates CPVT therapy in calsequestrin-mutant mice.

Spontaneous calcium release evoking delayed afterdepolarization is believed to cause catecholaminergic polymorphic ventricular tachycardia (CPVT), a lethal human arrhythmia provoked by exercise or emotional stress. β-Adrenergic blockers are the drug of choice, but fail to achieve complete arrhythmia control in some patients. These individuals often require flecainide, device implantation, and/or sympathetic denervation. To optimize the arrhythmia therapy by pharmacological inhibition of the sympathetic nervous system in the homozygous calsequestrin knockout (CASQ2(Δ/Δ)) mouse model of CPVT2. A heart telemetry device was implanted for continuous electrocardiographic recording at rest and during provocation testing. Calcium transients and abnormal calcium release were studied in cardiomyocytes isolated from adult mice. Adrenergic receptor expression was determined by using Western blotting and confocal microscopy. Adult CASQ2(Δ/Δ) mice suffer from complex ventricular arrhythmia at rest and ventricular tachycardia during treadmill exercise and after epinephrine injection. β-Adrenergic blockers, propranolol and metoprolol, attenuated arrhythmia at rest but not after stress. Reserpine had no efficacy in controlling arrhythmia. Agents with α-blocking activity, phentolamine or labetalol, abolished both exercise- and epinephrine-induced arrhythmia. In contrast, injection of α-adrenergic agonist phenylephrine reproducibly provoked ventricular tachycardia. Isolated cardiomyocytes from CASQ2(Δ/Δ) mice had delayed calcium release waves upon exposure to sympathetic agonists, which were abolished by phentolamine. Hearts of calsequestrin-mutant mice expressed more α1-adrenergic receptor than did wild type control mice (P < .05). We identified a contribution of the α-adrenergic pathway to the pathogenesis of catecholamine-induced arrhythmia. α-Blockade emerges as an effective therapy in the murine model of CPVT2 and should be tried in humans resistant to β-blockers.

Deterioration in brain and heart functions following a single sub-lethal (0.8 LCt 50) inhalation exposure of rats to sarin vapor: : A putative mechanism of the long term toxicity

The main injuries among victims of the terrorist act in the Tokyo subway resulted from sub-lethal inhalation and whole body exposure to sarin vapor. In order to study the long term effects of such exposure and to simulate these conditions, freely moving rats were exposed to sarin vapor (27.2 ± 1.7 μg/l) for 10 min. About 50% of the rats showed no overt symptoms and the rest had mild to moderate clinical symptoms that subsided within 4 h following exposure. A reduction of weight was noted during the first 3 days with full recovery on the 4th day. Rat's heart was challenged with epinephrine 1 and 6 months post exposure. A significant reduction in the threshold for epinephrine-induced arrhythmia (EPIA) was noted in rats exposed to sarin. A time dependent increase in the kD and Bmax values of muscarinic auto receptors (M2) was recorded in the rat's cortex and striatum. No changes were recorded in the rats' brain trans locator protein (TSPO) levels, concomitant with no observed changes in the animals' performance in A Morris water maze test. A significant increase in open field activity was noted 6 months following exposure to sarin vapor as well as a significant decrease in prostaglandin E 2 (PGE 2) production in the brain. It is speculated that down regulation of the M2 auto receptor function, caused hyper reactivity of the cholinergic system which leads to the changes described above. The continuous reduction in M2 auto-receptor system through an unknown mechanism may be the cause for long lasting decline in sarin-exposed casualties' health.

Structure-cardiovascular activity relationships in a group of new 8-alkylamino-1,3-dimethyl-7-(2-hydroxy-3-aminopropyl)-3,7-dihydro-1H-purine-2,6-diones

On the basis of our earlier studies in a group of 7,8-disubstituted derivatives of 1,3-dimetyl-3,7-dihydropurine-2,6-dione, a series of new 8-alkylamino-1,3-dimethyl-7-(2-hydroxy-3-aminopropyl)-3,7-dihydropurine-2,6-diones (8-15) were synthesized and tested for their electrocardiographic, antiarrhythmic and hypotensive activity and for α1- and α2-adrenoreceptor affinities. Among the new derivatives, compounds with the 7-[2-hydroxy-3-(4-phenylpiperazine)-propyl] substituent (9-11) displayed prophylactic antiarrhythmic activity in epinephrine-induced arrhythmia. Analogue 10 with the 8-(2-morpholin-4-yl)-ethylamino group was the most active (ED50=3.9mg/kg and TI=59.8), which may indicate that this substituent is preferably important for the antiarrhythmic effect. Only compound 11 with the 8-(2-diethylamino)-ethylamino group significantly decreased the systolic (20.4–28.1%) and diastolic (23.4–33.2%) pressure, but this effect lasted for only 1–5min. The pharmacologically active compounds 9–11 with the phenyl-piperazine moiety showed affinity for α1-receptors (Ki=0.143–0.383µM), but the other compounds were almost (12–15) or completely (8) inactive at this site. Compounds 9–11 and 13–15 displayed moderate to low affinity for α2-receptors (Ki=0.36–2.7µM).

Synthesis and pharmacological evaluation of pyrrolidin-2-one derivatives as antiarrhythmic, antihypertensive and α-adrenolytic agents

A series of novel arylpiperazines bearing a pyrrolidin-2-one fragment were synthesized and evaluated for their binding affinity for α1– and α2 -adrenoceptors (ARs) as well as their antiarrhythmic and antihypertensive activities. The highest affinity for the α1-AR was displayed by 1-{3-[4-(2-chloro-phenyl)-piperazin-1-yl]-propyl}-pyrrolidin-2-one 7, which binds with a pKi=7.13. The highest affinity for the α2-AR was shown by 1-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-propyl}-pyrrolidin-2-one 18, which binds with a pKi=7.29. Among the compounds tested, 1-{3-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-propyl}-pyrrolidin-2-one 13 had the highest prophylactic antiarrhythmic activity in epinephrine-induced arrhythmia in anesthetized rats. Its ED50 value was 1.0mg/kg intravenously (iv). The compounds with a hydroxy group in the 4-position of the phenyl ring or two substituents such as fluorine atoms in the 2 and 4 positions of the phenyl ring significantly decreased systolic and diastolic pressure in normotensive anesthetized rats at a dose of 2.5mg/ kg iv, and their hypotensive effects lasted for longer than an hour.

Modification of Epinephrine-induced Arrhythmias by N-Acetyl-L-Cysteine and Vitamin E

Sprague-Dawley rats were pretreated for 21 days with N-acetyl-L-cysteine (NAC) or vitamin E to investigate their influence on arrhythmias induced by a bolus injection or by cumulative doses of epinephrine. Electrocardiographic analysis revealed that both NAC and vitamin E decreased the duration and increased the time of onset of epinephrine-induced arrhythmias in a dose-dependent manner. The antiarrhythmic effects of NAC were comparable with those seen in the vitamin E-pretreated animals. The lipid peroxidation due to cumulative doses of epinephrine was reduced in both pretreated groups; however, NAC, unlike vitamin E, failed to decrease the basal level of malondialdehyde. Although the plasma concentrations of both norepinephrine and epinephrine were markedly increased, the level of aminochromes on epinephrine administration was decreased by both NAC and vitamin E pretreatments. The results support the view that antioxidants may prevent the catecholamine-induced heart rhythm disorders by reducing the formation of oxidized catecholamines.

Adaptation of the cardiovascular system to postinfarction cardiosclerosis in rats with congenital adrenoreactivity of the myocardium

Three months after myocardial infarction the severity of heart failure and size of postinfarction scars in August rats with inherently reduced adrenoreactivity of the myocardium were similar to those in Wistar rats. The mortality rate in August rats was 2.5-fold lower than in Wistar rats. During the postinfarction period, myocardial adrenoreactivity in August rats remained lower, while the efficiency of cardiac function was 62% higher than in Wistar rats. The incidence of epinephrine-induced arrhythmias in August rats was much lower than in Wistar rats.

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The main injuries among victims of the terrorist act in the Tokyo subway resulted from sub-lethal inhalation and whole body exposure to sarin vapor. In order to study the long term effects of such exposure and to simulate these conditions, freely moving rats were exposed to sarin vapor (27.2 ± 1.7 μg/l) for 10 min. About 50% of the rats showed no overt symptoms and the rest had mild to moderate clinical symptoms that subsided within 4 h following exposure. A reduction of weight was noted during the first 3 days with full recovery on the 4th day. Rat's heart was challenged with epinephrine 1 and 6 months post exposure. A significant reduction in the threshold for epinephrine-induced arrhythmia (EPIA) was noted in rats exposed to sarin. A time dependent increase in the kD and Bmax values of muscarinic auto receptors (M2) was recorded in the rat's cortex and striatum. No changes were recorded in the rats' brain trans locator protein (TSPO) levels, concomitant with no observed changes in the animals' performance in A Morris water maze test. A significant increase in open field activity was noted 6 months following exposure to sarin vapor as well as a significant decrease in prostaglandin E2 (PGE2) production in the brain. It is speculated that down regulation of the M2 auto receptor function, caused hyper reactivity of the cholinergic system which leads to the changes described above. The continuous reduction in M2 auto-receptor system through an unknown mechanism may be the cause for long lasting decline in sarin-exposed casualties' health.

Reduced susceptibility to epinephrine-induced arrhythmias in cirrhotic rats: The roles of nitric oxide and endogenous opioid peptides

The clinical relevance of QT prolongation, the most widely recognized cardiac electrophysiological abnormality of cirrhosis, is still undefined. The aim of this study is to examine the susceptibility of chronic (4-week) bile duct-ligated rats to epinephrine-induced arrhythmias. The roles of nitric oxide and endogenous opioids were also evaluated. Sham-operated and cirrhotic rats were treated with daily subcutaneous administrations of normal saline (1 ml/kg/day), L-NAME (a non-selective nitric oxide synthase inhibitor, 3mg/kg/day), and naltrexone (20mg/kg/day) during the fourth week after operation. In order to evaluate the effects of acute nitric oxide synthesis inhibition, additional groups of animals were treated by acute intraperitoneal L-NAME injections (3mg/kg). Arrhythmias were induced by intravenous injections of 10 microg/kg epinephrine. Despite QT prolongation (P<0.001), epinephrine induced fewer arrhythmias in cirrhotic rats compared to sham-operated animals (P<0.05). Chronic, but not acute, L-NAME administration corrected the QT prolongation in cirrhotic rats (P<0.001), and restored the susceptibility of cirrhotic rats to arrhythmias (P<0.05). Naltrexone injection without a significant effect on epinephrine-induced arrhythmias corrected QT interval in cirrhotic rats (P<0.001). This study shows that despite QT prolongation, cirrhotic animals are resistant against epinephrine-induced arrhythmias. This resistance is mediated by chronic nitric oxide overproduction.

181 QT prolongation is associated with resistance against epinephrine-induced arrhythmia in cirrhotic rats: The role of nitric oxide and endogenous opioid peptides

181 QT prolongation is associated with resistance against epinephrine-induced arrhythmia in cirrhotic rats: The role of nitric oxide and endogenous opioid peptides

Identification of the Central Imidazoline Receptor Subtype Involved in Modulation of Halothane-Epinephrine Arrhythmias in Rats

We previously reported that imidazoline receptors in the central nervous system are involved in modulation of halothane-epinephrine arrhythmias. These receptors have been subclassified as I1 and I2 subtypes, but it is not known which receptor subtype is involved in halothane-epinephrine-induced arrhythmias. We designed the present study to clarify the involvement of central imidazoline receptor subtype in the modulation of halothane-epinephrine-induced arrhythmias. Rats were anesthetized with halothane and monitored continuously for systemic arterial blood pressure and premature ventricular contractions. The arrhythmogenic dose of epinephrine was defined as the smallest dose that produces three or more premature ventricular contractions within a 15-s period. Intracisternal moxonidine dose-dependently inhibited the epinephrine-induced arrhythmias during halothane anesthesia. Intracisternal efaroxan, a selective I1 antagonist with little affinity for I2 subtype, but not rauwolscine, an alpha2 antagonist without affinity for imidazoline receptors, blocked the antiarrhythmic effect of moxonidine. Intracisternal BU 224 and 2-BFI, selective I2 ligands, also inhibited the epinephrine-induced arrhythmias dose-dependently; however, these effects were abolished by efaroxan. We conclude that central I1, but not I2, receptors play an important role in inhibition of halothane-epinephrine arrhythmia.

Sex Differences in Susceptibility to Epinephrine-Induced Arrhythmias

Gender differences in incidence of cardiac arrhythmias have been documented. It is generally believed that cardiac pathology provides an arrhythmogenic substrate but that a trigger such as sympathetic nervous system activation is required to initiate arrhythmias. This study was done to determine whether there is a sex difference in susceptibility to epinephrine-induced arrhythmias in healthy rats without preexisting pathology and to determine whether gonadal hormones play a role in development of arrhythmias. Untreated, sham-operated, and gonadectomized male and female rats were anesthetized and given IV boluses of epinephrine. ECG, heart rate, and blood pressure were measured continuously for 1 minute and intermittently over a period of 30 minutes. Male rat hearts have a higher occurrence and frequency of epinephrine-induced premature ventricular contractions, missed beats, and blocks than female rat hearts. Ovariectomy increases arrhythmias, thereby abolishing the female advantage. Castration has no effect on occurrence and frequency of premature ventricular contractions but attenuates missed beats and blocks. Sex differences and effect of gonadectomy on epinephrine-induced alterations in heart rate and blood pressure implicate baroreceptor reflex in the dimorphic arrhythmogenic response. Male rat hearts are more susceptible than female hearts to epinephrine-induced arrhythmias, and gonadal hormones play a role in this disparity.

Acute and Long-Lasting Cardiac Changes Following a Single Whole-Body Exposure to Sarin Vapor in Rats

Epinephrine-induced arrhythmias (EPIA) are known to be associated with local cardiac cholinergic activation. The present study examined the development of QT prolongation and the effect on EPIA of whole-body exposure of animals to a potent acetylcholine esterase inhibitor. Freely moving rats were exposed to sarin vapor (34.2 +/- 0.8 microg/liter) for 10 min. The electrocardiograms (ECG) of exposed and control animals were monitored every 2 weeks for 6 months. One and six months post exposure, rats were challenged with epinephrine under anesthesia, and the threshold for arrhythmias was determined. Approximately 35% of the intoxicated rats died within 24 h of sarin exposure. Additional occasional deaths were recorded for up to 6 months (final mortality rate of 48%). Surviving rats showed, agitation, aggression, and weight loss compared to non-exposed rats, and about 20% of them experienced sporadic convulsions. Sarin-challenged rats with severe symptoms demonstrated QT segment prolongation during the first 2-3 weeks after exposure. The EPIA that appeared at a significantly lower blood pressure in the treated group in the first month after intoxication lasted for up to 6 months. This decrease in EPIA threshold was blocked by atropine and methyl-atropine. Three months post exposure no significant changes were detected in either k(D) or B(max) values of (3)H-N-methyl scopolamine binding to heart homogenates, or in the affinity of carbamylcholine to cardiac muscarinic receptors. The increase in the vulnerability to develop arrhythmias long after accidental or terror-related organophosphate (OP) intoxication, especially under challenging conditions such as stress or intensive physical exercise, may explain the delayed mortality observed following OP exposure.

Prevention of Epinephrine-induced Arrhythmias with Lidocaine during Thiopental and Methoxyflurane Anesthesia in Sheep

Edjtehadi, M. and Mehrabani, D. 2005. Prevention of epinephrine-induced arrhythmias with lidocaine during thiopental and methoxy flurane anesthesia in sheep. J Appl. Anim. Res., 27: 55–59. The present experiment was designed to evaluate efficacy of lidocaine for prevention of epinephrine induced arrhythmias in sheep. The results indicated that lidocaine alone could prevent these arrhythmias in non-anesthetized and thiopental and methoxyflurane anesthetized animals. The results from electrocardiogram parameters indicated hat lidocaine could not prevent the decrease in P wave, PR, QT, ST intervals and, an increase in T amplitude induced with epinephrine in such animals. Nevertheless, T amplitude in all groups increased significantly more than control value. In conclusion, we suggest that lidocaine could be safely used clinically to prevent the lethal arrhythmias, due to catecholamine-anesthetic interaction, in non-anesthetized and thiopental and methoxyflurane anesthetized animals.