Ischemia-reperfusion Arrhythmias Research Articles

Research progress of quercetin in cardiovascular disease.

Quercetin is one of the most common flavonoids. More and more studies have found that quercetin has great potential utilization value in cardiovascular diseases (CVD), such as antioxidant, antiplatelet aggregation, antibacterial, cholesterol lowering, endothelial cell protection, etc. However, the medicinal value of quercetin is mostly limited to animal models and preclinical studies. Due to the complexity of the human body and functional structure compared to animals, more research is needed to explore whether quercetin has the same mechanism of action and pharmacological value as animal experiments. In order to systematically understand the clinical application value of quercetin, this article reviews the research progress of quercetin in CVD, including preclinical and clinical studies. We will focus on the relationship between quercetin and common CVD, such as atherosclerosis, myocardial infarction, ischemia reperfusion injury, heart failure, hypertension and arrhythmia, etc. By elaborating on the pathophysiological mechanism and clinical application research progress of quercetin's protective effect on CVD, data support is provided for the transformation of quercetin from laboratory to clinical application.

Myocardial oxidative stress is increased in early reperfusion, but systemic antioxidative therapy does not prevent ischemia-reperfusion arrhythmias in pigs.

Arrhythmias in the early phase of reperfusion after myocardial infarction (MI) are common, and can lead to hemodynamic instability or even cardiac arrest. Reactive oxygen species (ROS) are thought to play a key role in the underlying mechanisms, but evidence from large animal models is scarce, and effects of systemic antioxidative treatment remain contentious. MI was induced in 7 male and 7 female pigs (Norwegian landrace, 35-40 kg) by clamping of the left anterior descending artery (LAD) during open thorax surgery. Ischemia was maintained for 90 min, before observation for 1 h after reperfusion. Pigs were randomized 1:1 in an operator-blinded fashion to receive either i.v. N-acetylcysteine (NAC) from 70 min of ischemia and onwards, or 0.9% NaCl as a control. Blood samples and tissue biopsies were collected at baseline, 60 min of ischemia, and 5 and 60 min of reperfusion. ECG and invasive blood pressure were monitored throughout. The protocol was completed in 11 pigs. Oxidative stress, as indicated by immunoblotting for Malondialdehyde in myocardial biopsies, was increased at 5 min of reperfusion compared to baseline, but not at 60 min of reperfusion, and not reduced with NAC. We found no significant differences in circulating biomarkers of myocardial necrosis, nor in the incidence of idioventricular rhythm (IVR), non-sustained ventricular tachycardia (NSVT), ventricular tachycardia (VT) or ventricular fibrillation (VF) between NAC-treated and control pigs during reperfusion. Myocardial oxidation was increased early after reperfusion in a porcine model of MI, but systemic antioxidative treatment did not protect against reperfusion arrhythmias.

Myocardial oxidative stress is increased in early reperfusion, but systemic antioxidative therapy does not prevent ischemia-reperfusion arrhythmias in pigs

Myocardial oxidative stress is increased in early reperfusion, but systemic antioxidative therapy does not prevent ischemia-reperfusion arrhythmias in pigs

Myocardial oxidative stress is increased in early reperfusion, but systemic antioxidative therapy does not protect against ischemia-reperfusion arrhythmias in pigs

Myocardial oxidative stress is increased in early reperfusion, but systemic antioxidative therapy does not protect against ischemia-reperfusion arrhythmias in pigs

CaMKII and reactive oxygen species contribute to early reperfusion arrhythmias, but oxidation of CaMKIIδ at methionines 281/282 is not a determining factor

BackgroundAvailable evidence suggest that Ca2+/calmodulin-dependent protein kinase type IIδ (CaMKIIδ) and reactive oxygen species (ROS) are important in early ischemia-reperfusion arrhythmias (IRA). Since ROS can activate CaMKIIδ by oxidation of two methionines at positions 281/282, oxidized-CaMKIIδ (Ox-CaMKIIδ) has been proposed to be important for IRA. However, direct evidence for this is missing. MethodsWe exposed Langendorff-perfused hearts and ventricular cardiomyocytes from C57BL/6 mice to global and simulated ischemia, respectively, and recorded arrhythmic events during early reperfusion. Hearts were collected for immunoblotting of key phosphoproteins. We evaluated the effects of beta-adrenoceptor stimulation, inhibition of CaMKII, and reduced ROS levels with isoprenaline, KN93/AIP and N-acetylcysteine (NAC), respectively. We further tested the importance of Ox-CaMKIIδ by using hearts and cardiomyocytes from mice with CaMKIIδ resistant to oxidation of methionines 281 and 282 (MMVV). ResultsHearts treated with KN93, AIP or NAC had lower incidence of early IRA, and NAC-treated cardiomyocytes had lower incidence of arrhythmogenic events. However, hearts from MMVV mice had a similar incidence of early IRA to wild type mice (WT), and MMVV and WT cardiomyocytes had a similar frequency of Ca2+ waves and Ca2+ sparks. Immunoblotting confirmed high levels of oxidation in early reperfusion, but revealed no significant differences in the phosphorylation levels of Ca2+-handling proteins in MMVV and WT hearts. ConclusionsAlthough CaMKII and ROS both contribute to early IRA, hearts from mice with CaMKII resistant to oxidation at methionines 281/282 were not protected from such arrhythmias, suggesting that oxidation at these sites is not a determining factor.

The Effects of Lipopolysaccharide Derivatives in Rodent Models of Cardiac Arrhythmia.

Several previous studies have suggested that sublethal doses of Escherichia coli lipopolysaccharide (endotoxin) and monophosphoryl lipid A Re595, a nonpyrogenic derivative of Salmonella minnesota lipopolysaccharide, exhibit antiarrhythmic effects in the rat model of ischemia-reperfusion arrhythmias. In this study, the protective effect of lipopolysaccharide derivatives was also further investigated in drug (aconitine or ouabain)-induced arrhythmia models, and conclusions were drawn with particular emphasis on the molecular characteristics of different types of lipopolysaccharide. The importance of the molecular structure for the antiarrhythmic effect of monophosphoryl lipid A and E. coli lipopolysaccharide was tested in the ischemia-reperfusion arrhythmia model. In contrast to monophosphoryl lipid A from Salmonella typhimurium SL 684 which has only monophosphoryl residue in its structure, monophosphoryl lipid A Re595, obtained from S. minnesota, and E. coli lipopolysaccharide which have both mono and diphosphoryl residue reduced the duration of ventricular tachycardia (e.g., during reperfusion: vehicle: 176 ± 22.8; monophosphoryl lipid A Re595: 132.83 ± 12.1, as second, n=8-10, P < .05) and the incidence of ventricular fibrillation. The antiarrhythmic effects of E. coli lipopolysaccharide and monophosphoryl lipid A Re595 in ischemia-reperfusion arrhythmia model were absent in either aconitine- (e.g., onset time for ventricular ectopic beats: saline 25.3 5.0, E. coli lipopolysaccharide 24.3 ± 7.1; vehicle: 24.0 ± 4.5, monophosphoryl lipid A SL684 23.8 ± 4.3, as second, n=6, P > .05) or ouabain-induced arrhythmia models in mice. Therefore, we conclude that lipopolysaccharide derivatives exhibit antiarrhythmic effect only in ischemia-reperfusion arrhythmias, and lipopolysaccharide should possess diphosphoryl groups in its subcomponent composition for this antiarrhythmic effect.

Aldehyde dehydrogenase 2 and arrhythmogenesis.

Cardiac arrhythmia is a common cardiovascular disease that leads to considerable economic burdens and significant global public health challenges. Despite the remarkable progress made in recent decades, antiarrhythmic therapy remains suboptimal. Aldehyde dehydrogenase 2 (ALDH2), a critical detoxifying enzyme, catalyzes toxic aldehydes and protects individuals from damage caused by oxidative stress. Accumulating evidence has demonstrated that ALDH2 activation has potential antiarrhythmic benefits. The correlation between ALDH2 deficiency and arrhythmogenesis has been widely recognized. In this review, we summarize recent research on the potential role of ALDH2 activation and antiarrhythmic protection, as well as the role played by the ALDH2∗2 polymorphism (rs671) in promoting arrhythmic risk. Additionally, we discuss important new findings illustrating the use of ALDH2 activators, which may prove to be promising antiarrhythmic therapy agents.

Optical Activation of the Dorsal Horn of the Thoracic Spinal Cord Prevents Ventricular Arrhythmias in Acute Myocardial Ischemia-Reperfusion Rats.

Background and ObjectivesSpinal cord stimulation can prevent myocardial ischemia and reperfusion arrhythmias, but the relevant neurons and mechanisms remain unknown. Thus, this study applied optogenetic techniques to selectively activate glutamatergic neurons at the thoracic spinal cord (T1 segment) for examining the anti-arrhythmia effects during acute myocardial ischemic-reperfusion.MethodsAdeno-associated viruses (AAVs) carrying channelrhodopsin-2 (ChR2, a blue-light sensitive ion channel) CaMKIIα-hChR2(H134R) or empty vector were injected into the dorsal horn of the T1 spinal cord. Four weeks later, optogenetic stimulation with a 473-nm blue laser was applied for 30 min. Then, the myocardial ischemia-reperfusion model was created by occlusion of the anterior descending coronary artery for ischemia (15 min) and reperfusion (30 min). Cardiac electrical activity and sympathetic nerve activity were assessed continuously.ResultsCaMKIIα-hChR2 viral transfection is primarily expressed in glutamatergic neurons in the spinal cord. Selective optical stimulation of the T1 dorsal horn in the ChR2 rat reduced the ventricular arrhythmia and arrhythmia score during myocardial ischemia-reperfusion, preventing the over-activation of cardiac sympathetic nerve activity. Additionally, optical stimulation also reduced the action potential duration at the 90% level (APD90) and APD dispersion.ConclusionSelective optical stimulation T1 glutamatergic neurons of dorsal horn prevent ischemia-reperfusion arrhythmias. The mechanism may be associated with inhibiting sympathetic nervous system overexcitation and increasing APD dispersion during myocardial ischemia-reperfusion.

Network construction of aberrantly expressed miRNAs and their target mRNAs in ventricular myocardium with ischemia\u2013reperfusion arrhythmias

BackgroundHypothermic ischemia-reperfusion arrhythmia remains the main factor affecting cardiac resuscitation under cardiopulmonary bypass. Existing research shows that certain miRNAs exhibit significantly different expressions and effects in arrhythmias, however, the effect of miRNAs on the progression of hypothermic ischemic–reperfusion arrhythmias (RA) and its potential mechanism remain to be further explored.MethodsSprague-Dawley (SD) rats were randomly divided into two groups (n = 8): a normal control group (Group C) and a hypothermic ischemia-reperfusion group (Group IR), which were used to establish a Langendorff isolated cardiac perfusion model. According to the arrhythmia scoring system, rats in group IR were divided into a high-risk group (IR-H) and a low-risk group (IR-L). miRNAs expression profiles of ventricular myocardium with global hypothermic ischemia–reperfusion and those of ventricular myocardium with hypothermic ischemia–RA were established through high-throughput sequencing. Furthermore, the aberrantly expressed miRNAs in myocardium with and without hypothermic ischemia–RA were screened and verified. The target genes of these aberrantly expressed miRNAs were predicted using RNAhybrid and MiRanda software. Based on Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, we determined the mRNA targets associated with these miRNAs and studied the miRNA–mRNA interaction during the cardiovascular disease progression. The aberrantly expressed miRNAs related to hypothermic ischemia–RA were validated by Real-time Quantitative polymerase chain reaction (RT-qPCR).ResultsEight significantly aberrantly expressed miRNAs (rno-miR-122-5p, rno-miR-429, novel_miR-1, novel_miR-16, novel_miR-17, novel_miR-19, novel_miR-30, and novel_miR-43) were identified, among which six were up-regulated and two were down-regulated. Moreover, target genes and signaling pathways associated with these aberrantly expressed miRNAs were predicted and analyzed. The miRNA–mRNA interaction network graph showed that GJA1 gene was considered as the target of novel_miR-17.ConclusionsAberrantly expressed miRNAs were possibly associated with the formation mechanism of hypothermic ischemia–RA. Specific miRNAs, such as novel_miR-17 and rno-miR-429 are probably new potential targets for further functional studies of hypothermic ischemia–RA.

Inhibition of MicroRNA-206 Ameliorates Ischemia-Reperfusion Arrhythmia in a Mouse Model by Targeting Connexin43.

Reperfusion arrhythmias (RA) are an important cause of sudden cardiac death and is closely associated with gap junction protein in the heart, connexin 43 (Cx43). This study is aimed at elucidating the molecular association between microRNA-206 (miR-206) and Cx43 in ischemia-reperfusion arrhythmia using experimental animal model. Our results showed that miR-206 inhibitor alleviated ischemia-reperfusion-induced arrhythmias, indicated by the lower extent of changes in heart rate (HR), PR interval, rate pressure product (RPP), and mean arterial pressure (MAP). miR-206 inhibitor also downregulated the serum creatine kinase isoenzyme (CKMB) and cardiac troponin I (cTnI) levels in mice under myocardial ischemia-reperfusion (IR) process. The knockdown of Cx43 inversed the protective effects of miR-206 inhibitor on cardiac arrhythmias. These results supported that inhibition of miR-206 ameliorates ischemia-reperfusion arrhythmia by targeting Cx43, and this miR-206/Cx43 axis could serve as a potential target for the management of ischemic-perfusion arrhythmia.

Therapeutic Potential and Mechanisms of Berberine in Cardiovascular Disease

Berberine is originally isolated from extracts of the Chinese herb Coptis chinensis. It was initially used to treat diarrhea. Over the past two decades, berberine has been shown to be effective for improving glycemic and lipid profiles. Interest in its protective effects against diabetes and cardiovascular risk is beginning to emerge, and research investigating the pharmacological activity of berberine is developing rapidly and being reported internationally. Some clinical evidence has demonstrated the ability of berberine to prevent endothelial dysfunction, myocardial infarction, and arrhythmia in patients with cardiovascular risks. Numerous molecular targets of berberine have been explored, including adenosine monophosphate-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), and NADPH oxidase (NOX). The aim of this review is to focus on the therapeutic potential of berberine in cardiovascular disease and to describe its underlying mechanisms in the pathogenesis of artherosclerosis, hypertension, heart failure, ischemia reperfusion heart injury, stroke, and arrhythmias.

Atorvastatin protects myocardium against ischemia–reperfusion arrhythmia by increasing Connexin 43 expression: A rat model

Atorvastatin has protective effects against myocardial ischemia–reperfusion injuries and ischemia–reperfusion arrhythmia. This study was designed to investigate whether atorvastatin is able to protect against myocardial ischemia–reperfusion injury by enhancing the expression of Connexin 43 (Cx43) via the activation of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway and mitochondrial ATP-sensitive potassium (KATP) channels. Isolated perfused rat hearts were treated with classic ischemia postconditioning (IPOST), atorvastatin, and atorvastatin combined with inhibitor of PI3K and KATP channels, respectively, after 30min of LAD ischemia and then subjected to reperfusion for 120min. The QRS duration and the ischemia–reperfusion ventricular arrhythmia were assessed. The lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CK-MB) levels were measured and the Cx43 expression was assessed by immunoblotting and immunohistochemistry. After 120min of reperfusion, atorvastatin and IPOST significantly decreased the QRS duration and inhibited ventricular arrhythmia. They also decreased the levels of LDH and CK-MB. Meanwhile, atorvastatin and IPOST also significantly enhanced the Cx43 expression and the phosphorylation of Cx43. Such protective effects were abolished in the presence of the inhibitor of PI3K or the inhibitor of mitochondrial KATP channels. This study suggests that atorvastatin protected against myocardial ischemia–reperfusion injury and enhanced the expression of Cx43 by activating the PI3K/Akt pathway and mitochondrial KATP channels.

Abstract P144: Effects of Alamandine in Post-ischemic Function

Alamandine, a biologically active peptide of the renin-angiotensin system (RAS), was recently described and characterized. Further it has been shown to present effects similar to those elicited by Ang-(1-7). It has been described that Ang-(1-7) decreases the incidence and duration of ischemia-reperfusion arrhythmias and improved the post-ischemic function in isolated perfused rat hearts. In this study we aimed to evaluate the effects of Alamandine in isolated rat hearts subjected to myocardial infarction (MI). Wistar rats weighing between 250-300g were euthanized and their hearts were placed on Langendorff apparatus to evaluate the cardiac parameters. Hearts were submitted to 30min of stabilization, 30min of partial ischemia by occlusion of the left descending coronary artery and 30min of reperfusion. Drugs (alamandine 22pM, d-pro7-ang-(1-7) 220pM) were added to the perfusion setting from the beginning of the experiment until the end. 2,3,5-trypheniltetrazolium chloride were used to evaluate the extension of infarcted area. In control hearts (CON), there was a decrease on the left ventricular systolic pressure (LVSP) on ischemic period (54,6 ± 6,9mmHg) compared to the baseline period (84,6 ± 11,6mmHg). Alamandine (ALA) attenuated that decrease in the ischemic period (66,9 ± 7,9mmHg) vs (82,3 ± 8,9mmHg). Further, ischemia led to a decrease in the left ventricular developed pressure (dLVP), dP/dt maximum and minimum when compared to baseline values. ALA, once more, kept the ischemic parameters of dLVP and dP/dt max and min (58,9 ± 8mmHg; 1629 ± 202,2mmHg/s; 1101 ± 130mmHg/s, respectively) similar to those of baseline period (68,9 ± 8,92; 1682 ± 248,8; 1179 ± 118,6 mmHg, respectively). Ischemia/reperfusion induced an arrhythmia severity index (ASI) in control hearts (4,9 ± 1,26) higher than in hearts treated with ALA (1,10 ± 0,58). ALA also reduced infarcted area (19,64 ± 2,61%) compared with CON (33,85 ± 4,55%). All those effects were blocked by D-PRO7-Ang-(1-7). In conclusion, our data shown that Alamandine exert cardioprotective effects in post-ischemic function in isolated rat hearts by preventing LVSP, dLVP , dP/dt max and min decrease. Furthermore it reduced the infarcted area and I/R arrhythmias, apparently involving MrgD receptor participation.

Heart remodeling and ischemia-reperfusion arrhythmias linked to myocardial vitamin d receptors deficiency in obstructive nephropathy are reversed by paricalcitol.

Cardiovascular disease is often associated with chronic kidney disease and vice versa; myocardial vitamin D receptors (VDRs) are among the probable links between the 2 disorders. The vitamin D receptor activator paricalcitol protects against some renal and cardiovascular complications. However, the structural and electrophysiological effects of myocardial vitamin D receptor modification and its impact on the response to ischemia-reperfusion are currently unknown. This work attempted to determine whether obstructive nephropathy induced myocardial changes (in rats) linked to vitamin D receptor deficiency and to ventricular arrhythmias in Langendorff-perfused hearts. Unilateral ureteral-obstructed and Sham-operated rats were treated with either paricalcitol (30 ng/kg/d intraperitoneal) or vehicle for 15 days. In 5 hearts from each group, we found that obstructed rats showed a reduction in VDRs and an increase in angiotensin II type 1 receptor expression (messenger RNA and protein), suffered fibrosis (determined by Masson trichrome stain) and myofibril reduction with an increase in mitochondrial size, and had dilated crests (determined by electron microscopy). These changes were reversed by paricalcitol. In 8 additional hearts per group, we found that obstructed rats showed a higher incidence of ventricular fibrillation during reperfusion (after 10 minutes of regional ischemia) than did those treated with paricalcitol. The action potential duration was prolonged throughout the experiment in paricalcitol-treated rats. We conclude that the reduction in myocardial vitamin D receptor expression in obstructed rats might be related to myocardial remodeling associated with an increase in arrhythmogenesis and that paricalcitol protects against these changes by restoring myocardial vitamin D receptor levels and prolonging action potentials.

Total flavonoids from Ganshanbian (Herba Hyperici Attenuati) effect the expression of CaL-α1C and KATP-Kir6.1 mRNA of the myocardial cell membrane in myocardial ischemia-reperfusion arrhythmia rats

ObjectiveTo observe the impact of total flavonoids from Ganshanbian (Herba Hyperici Attenuati) on the expression of vascular smooth muscle membrane L-type calcium channel alpha1 C subunit (CaL-α1C) and ATP-sensitive K+ channel (KATP)-Kir6.1 mRNA, and explore the mechanisms of the antiarrhythmic effect of Ganshanbian (Herba Hyperici Attenuati) total flavonoids. MethodsThe treatment group was fed total flavonoids from Ganshanbian (Herba Hyperici Attenuati) for 7 days by gavage with 100 mg · kg−1 · d−1. The blank control group and model control group were given the same amount of normal saline for 7 d. Arrhythmias were induced by performing a myocardial ischemia-reperfusion and electrocardiogram was observed. Reverse transcription-polymerase chain reaction was used to detect the expression of CaL-α 1Cand KATP-Kir6.1 mRNA in the myocardial cell membrane of all groups of rats. ResultsTotal flavonoids from Ganshanbian (Herba Hyperici Attenuati) can delay the appearance of myocardial ischemia reperfusion arrhythmias, shorten the duration of myocardial ischemia reperfusion arrhythmias, reduce heart rate, reduce cell membrane expression of CaL-α1C mRNA and enhance the expression of KATP-Kir6.1 mRNA in myocardial ischemia-reperfusion arrhythmic rats. ConclusionTotal flavonoids from Ganshanbian (Herba Hyperici Attenuati) can alleviate arrhythmias by affecting the expression of L-type calcium channels and ATP-sensitive K+ channels.

Dans la sclérodermie systémique, le contrôle de la maladie ulcéreuse digitale sous bosentan est associé à une amélioration du handicap de la main

The effects of acyl-coenzyme a: lysolecithin acyltransferase (LAT) inhibitor thimerosal (20, 30 and 40mgkg−1), anti-ischaemic and free radical scavenging drug trimetazidine (10mgkg−1) and endothelin ETA–ETBreceptor blocker bosentan [30mgkg−1) were investigated in an anaesthetized rat model of coronary artery ligation (7min) and release (7min) induced myocardial ischaemia-reperfusion arrhythmias. Neither of the drugs produced significant effects on blood pressure except thimerosal which induced a transient fall lasting 5–8min. The total number of ectopic beats during occlusion (controls 141.8±73.5,n=12) and reperfusion (controls 1151.1±199.1,n=10) was not modified by either trimetazidine (occlusion 452.5±128.6,n=10; reperfusion 1002.0±198.4,n=6) or bosentan (occlusion 431.2±112.8,n=10; reperfusion 1530.7±296.8,n=9) while thimerosal attenuated them (occlusion 50.2±14.9,n=10,P<0.01vscontrols; reperfusion 345.1±83.8,n=8,P<0.01vscontrols). The durations (in seconds) of ventricular tachycardia (occlusion 33.9±6.1,n=12; reperfusion 94.2±18.1,n=10) were also shortened by thimerosal (occlusion 2.6±1.0,n=10,P<0.01; reperfusion 28.5±7.8,n=8,P<0.01) while trimetazidine or bosentan did not significantly modify them. The incidences of ventricular fibrillation or mortality were not significantly modified by either of the drugs. Besides the lack of any effect of trimetazidine, we conclude that endogenous endothelin has no pathophysiological significance in this experimental model while LAT inhibition does.

Alpha lipoic acid protects the heart against myocardial post ischemia–reperfusion arrhythmias via KATP channel activation in isolated rat hearts

The cardiovascular effects of alpha lipoic acid were evaluated in isolated rat hearts exposed to ischemia–reperfusion injury in vitro. Alpha-lipoic acid raised the level of sulfane sulfur playing an important role in the release of hydrogen sulfide. H2S was shown to prevent the post-reperfusion arrhythmias and to protect the cardiomyocytes from death caused by hypoxia. The activation of potassium ATP-sensitive channels (KATP channels) is one of the most important mechanisms of action of hydrogen sulfide in the cardiovascular system. The aim of this study was to investigate whether alpha lipoic acid can prevent the occurrence of post-reperfusion arrhythmias in vitro using a Langendorff model of ischemia–reperfusion in rats affecting the KATP channels. Alpha lipoic acid significantly improved post-reperfusion cardiac function (reducing incidence of arrhythmias), especially in a dose of 10−7M. These cardiovascular effects of this compound on the measured parameters were reversed by glibenclamide, a selective KATP blocker. Alpha lipoic acid increased the level of sulfane sulfur in the hearts. This may suggest that the positive effects caused by alpha lipoic acid in the cardiovascular system are not only related to its strong antioxidant activity, and the influence on the activity of such enzymes as aldehyde dehydrogenase 2, as previously suggested, but this compound can affect KATP channels. It is possible that this indirect effect of alpha lipoic acid is connected with changes in the release of sulfane sulfur and hydrogen sulfide.

Effects of chloride ion channel and its blockers on myocardial ischemia reperfusion arrhythmias in rabbits

To explore the impact of chloride ion channel and its blockers 4, 4'-diisothiocyanostilbene-2, 2'-disulfonic acid (DIDS), cyanato-stilbene-2, 2'-disulfonic acid (SITS) and 5-nitro-2-(3-phenyl-propylamino) benzoic acid (NPPB) on arrhythmias caused by myocardial ischemia reperfusion. A total of 40 rabbits were divided into control, ischemia reperfusion, DIDS low-dose, DIDS high-dose, SITS low-dose, SITS high-dose, NPPB low-dose and NPPB high-dose groups. Myocardial ischemia reperfusion model was established by ligation of anterior descending coronary artery. And standard limb lead II of electrocardiogram (ECG) was continuously monitored during the experimental process. Then comparisons of heart rate, ECG P wave, R wave, T wave, ST segment changes and arrhythmias score were made between the above groups. During 30-minute ischemia, compared with the control group, all other groups showed significantly decreased heart rate ((199.8 ± 4.0) - (253.6 ± 2.1) vs (267.0 ± 3.4), all P < 0.01), elevated ECG P wave ((0.216 ± 0.019) - (0.356 ± 0.024) vs (0.186 ± 0.019), all P < 0.01), R wave ((0.564 ± 0.017) - (1.138 ± 0.048) vs (0.506 ± 0.018), all P < 0.01), T wave ((0.542 ± 0.013) - (0.856 ± 0.045) vs (0.278 ± 0.015), all P < 0.01) and ST segment ((0.326 ± 0.027) - (0.668 ± 0.054) vs (0.024 ± 0.023), all P < 0.01) and increased arrhythmia score ((1.4 ± 0.5) - (4.6 ± 0.5) vs (0.4 ± 0.5), all P < 0.01). Compared with the ischemia reperfusion group, the above indices significantly improved in the intervention groups (heart rate: (214.8 ± 3.4) - (246.8 ± 4.0) vs (199.8 ± 4.0), all P < 0.01; P wave: (0.216 ± 0.019) - (0.316 ± 0.011) vs (0.356 ± 0.024), all P < 0.01; R wave: (0.564 ± 0.017) - (0.980 ± 0.035) vs (1.138 ± 0.048), all P < 0.01; T wave: (0.542 ± 0.013) - (0.792 ± 0.026) vs (0.856 ± 0.045), all P < 0.01; ST segment: (0.326 ± 0.027) - (0.596 ± 0.018) vs (0.668 ± 0.054), all P < 0.01; arrhythmia score: (1.4 ± 0.5) - (3.8 ± 0.4) vs (4.6 ± 0.5), all P < 0.01). Among which, the DIDS group was the best, followed by the SITS group and then the NPPB group. And the high-dose subgroups were better than those of the low-dose subgroups. During 60-minute reperfusion, the decreased heart rate upswing significantly in each group and the elevated P wave, R wave, T wave and ST segment fell back gradually. The DIDS group showed the most obvious amplitude change, followed by the SITS group and then the NPPB group. And the high-dose subgroups were better than those of the low-dose subgroups. The arrhythmia score during reperfusion showed the same trend. Chloride ion channel is involved in the generation of myocardial ischemia reperfusion arrhythmia.Early application of chloride ion channel blockers DIDS, SITS and NPPB may improve the ECG manifestations and reduce the degree of reperfusion arrhythmia.

Effects of Ischemic and Sevoflurane-induced Preconditioning on Myocardial Infarction and Arrhythmias in Rabbits In Vivo

Objectives: The present study aimed to investigate whether ischemic or sevoflurane-induced preconditioning exerts infarct size limiting effects and depresses ischemia-reperfusion arrhythmias through opening of mitochondrial KATP channels in rabbits in vivo. Methods: Rabbits anesthetized with ketamine and xylazine given intramuscularly underwent 30 min of left anterior descending coronary artery (LAD) occlusion followed by 3 hrs of reperfusion. Before this, rabbits were randomized into one of five groups. Control rabbits received no intervention before 30 min LAD occlusion and 3 h reperfusion (Group-C). The ischemia-preconditioned (IP) rabbits underwent 5 min LAD occlusion followed by 10 min of reperfusion before prolonged ischemia-reperfusion (Group-IP). In the sevoflurane (S)–preconditioned group, 30 min of sevoflurane exposure at a 1.5% end-tidal concentration was followed by 15 min of washout before prolonged ischemia-reperfusion (Group-S). The selective mitochondrial KATP channel blocker, 5-hydroxy-decanoate (5-HD, 5 mg/kg) was given intravenously 10 min before ischemic preconditioning and sevoflurane exposure, respectively (Group-5-HD-IP, Group-5-HD-S). An electrocardiogram was recorded throughout the experiment via lead 2 of the standard electrocardiogram. At the end of the 3 hrs reperfusion period, area at risk (R) and infarct size (I) were measured. Results: RPP decreased in Group-5-HD-IP and Group-5-HD-S compared with Group-S at 30 min after ischemia. The ratio of R to left ventricular mass showed no significant difference among all groups. I/R values of each group were 51.6 ± 3.0% in Group-C, 33.3 ± 4.7% in Group-IP, 36.6 ± 4.8% in Group-S, 48.9 ± 5.2% in Group-5-HD-IP, 54.8 ± 4.2% in Group-Group-5-HD-S. There was no significant difference in duration of arrhythmias during myocardial ischemia and reperfusion among 5 groups. Conclusion: Ischemic preconditioning and sevoflurane-induced preconditioning exert infarct size limiting effects through opening of mitochondrial KATP channels. However, ischemic preconditioning and sevoflurane-induced preconditioning do not have antiarrhythmic effects. This suggests that the opening of mitochondrial KATP channels does not cause antiarrhythmic effects.

Abstract 18522: Atrial Ganglionated Plexus Stimulation Prevents Myocardial Ischemia Reperfusion Arrhythmias by Preserving Connexin43 Protein

Atrial ganglionated plexus Stimulation Prevents Myocardial Ischemia Reperfusion Arrhythmias by Preserving Connexin43 Protein Background: Vagal nerve stimulation has been shown to provide protective effect against ischemia/reperfusion (I/R) arrhythmias. Since atrial epicardial ganglionated plexuses contain a large amount of parasympathetic elements, we hypothesize atrial epicardial ganglionated plexus stimulation (GP-S) may be an alternative to vagal nerve stimulation for preventing arrhythmias induced by myocardial I/R. Methods and Results: Twenty one dogs were randomly divided into GP stimulation (GP-S) group (N=11) and control group (N=10). Myocardial I/R was induced by first 2 hours of reperfusion in dogs subjected to 45 minutes of ischemia with occlusion of the left anterior descending coronary artery (LAD). A bipolar plaque electrode was sutured overlying the fad pad containing the superior left ganglionated plexus (SLGP), which located at the junction of left pulmonary artery and left superior pulmonary vein.The GP-S was performed by applying high frequency electrical stimulation (HFS: 20Hz, 0.1msec duration) to the SLGP. The lowest voltage level of GP-S that induced approximately 10% sinus rhythm slowing was chosen as the voltage for GP-S. Compared with control group, GP-S caused significant increases in ventricular ERP and vagal indice (HF nu), as well as an evident decrease in sympathetic tone (LF/HF), the numbers of PVCs, salvos, and VT runs were significantly reduced in GP-S group. And the incidences of salvo and VT in GP-S group were significantly lower. Immunoblotting revealed that the control group showed a marked reduction in the amount of phosphorylated connexin43 (Cx43), whereas the GP-S group showed only a slight reduction. Immunohistochemistry confirmed that the myocardial I/R-induced loss of Cx43 from intercellular junctions was prevented by GP-S. Conclusions: GP-S protects against ventricular arrhythmias resulting from brief myocardial I/R by modulating connexin43. GP-S may serve as a non-pharmacological clinical approach to improve acute myocardial I/R arrhythmias such as during coronary bypass surgery.